The Essential Medicinal Chemistry of Curcumin
Miniperspective
- Kathryn M. Nelson
- ,
- Jayme L. Dahlin
- ,
- Jonathan Bisson
- ,
- James Graham
- ,
- Guido F. Pauli
- , and
- Michael A. Walters
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† Department of Medicinal Chemistry, Institute for Therapeutics Discovery and Development, University of Minnesota, Minneapolis, Minnesota 55414, United States
‡ Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts 02115, United States
§ Center for Natural Product Technologies, Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, United States
∥ Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, United States
*Phone: 612-626-6864. E-mail: [email protected]
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Abstract
Curcumin is a constituent (up to ∼5%) of the traditional medicine known as turmeric. Interest in the therapeutic use of turmeric and the relative ease of isolation of curcuminoids has led to their extensive investigation. Curcumin has recently been classified as both a PAINS (pan-assay interference compounds) and an IMPS (invalid metabolic panaceas) candidate. The likely false activity of curcumin in vitro and in vivo has resulted in >120 clinical trials of curcuminoids against several diseases. No double-blinded, placebo controlled clinical trial of curcumin has been successful. This manuscript reviews the essential medicinal chemistry of curcumin and provides evidence that curcumin is an unstable, reactive, nonbioavailable compound and, therefore, a highly improbable lead. On the basis of this in-depth evaluation, potential new directions for research on curcuminoids are discussed.
Introduction
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Natural products (NPs) form the basis for many widely used drugs. This utility was recently recognized on a larger stage, as the discoverer of artemisinin shared the Nobel Prize in Physiology or Medicine in 2015 with the discoverers of the anthelmintic avermectin family of NPs. Artemisinin, a NP discovered from a traditional Chinese medicine (TCM), Artemisia annua, was developed into an effective therapy for Plasmodium falciparum malaria. Some researchers viewed this award as a validation of the general utility of TCMs. (1, 2) In marked contradistinction to this claimed vindication of the role of certain ethnic and traditional medicines (TxMs) in medical practice are recent reports labeling curcumin, a constituent of the spice turmeric and part of the mixture of compounds referred to as curcuminoids, as both a PAINS (pan assay interference compounds) (3) and an IMPS (invalid metabolic panaceas) compound. (4) Additionally, many researchers have described the potential “dark side of curcumin”: (5-9) the drawbacks noted for curcumin include its poor pharmacokinetic/pharmacodynamic (PK/PD) properties, low efficacy in several disease models, and toxic effects under certain testing conditions. (5) These cautionary reports appear to have been swept away in the torrent of papers, reviews, patents, and Web sites touting the use of curcumin (and its primary commercial source, turmeric) as an anticancer agent, (10, 11) a therapeutic for Alzheimer’s disease, (12) a treatment for hangovers, (13, 14) erectile dysfunction, (15, 16) baldness, (17, 18) hirsutism, (19) a fertility-boosting, (20) and contraceptive (21) extract, collectively establishing the properties expected of a panacea. (22, 23)
Scientific manuscripts are still published regularly that are based solely on the foundational premise of the reported activity and therapeutic utility of curcumin. In 2015, this plethora of data motivated the compilation of a Curcumin Resource Database (CRDB) that seeks to support the preclinical development of curcuminoids by putting over 1000 analogues and their alleged molecular target (24) at the fingertips of researchers via a Web interface. The CRDB coverage of over 9000 publications and 500 patents demonstrates the magnitude of both the scientific interest and vast amount of dormant information that is awaiting a more global, medicinal chemistry interpretation. It is the goal of this manuscript to primarily review curcumin (1; Figure 1) and related curcuminoids, which are the species extracted from turmeric, and largely what is sold or tested in clinical trials.
Figure 1
Figure 1. Structural comparison of curcumin and artemisinin. Curcumin has been the focus of heavy research for new drug development. Artemisinin is an FDA approved antimalarial.
A simple analogy will help us set the stage for this Miniperspective. Artemisinin (2; Figure 1) has been shown to function like an effective long-range and targeted missile that homes in on heme-loving parasites and destroys them in a spectacular burst of nonselective reactivity. (25) The peroxide-containing structure of artemisinin suggests that it would be unstable in a biological setting. However, its in vivo stability (T1/2 = 2.5 h; F = 30%) (26) provides evidence that it is sufficiently stable, from a pharmacokinetic perspective, to be an effective therapeutic. Curcumin, on the other hand, is more like a missile that has shown excellent promise in early testing (in vitro), even though this testing may have been bedeviled by design problems that led to several misfires. The structure of 1 suggests that it might be unstable in a biological setting, and in fact, it is: both its in vitro and in vivo stabilities are abysmal (T1/2 < 5 min; F < 1%) (27, 28) relative to commercial drugs.
To our knowledge, compound 1 has never been shown to be conclusively effective in a randomized, placebo-controlled clinical trial for any indication. (29) Curcumin is best typified, therefore, as a missile that continually blows up on the launch pad, never reaching the atmosphere or its intended target(s). These results have given curcumin the label of pharmacodynamically fierce (hits many targets) yet pharmacokinetically feeble (does not get to its targets). (9) While these failures would normally end further research on its use as a therapeutic, they apparently have not deterred researchers interested in its development. Accordingly, major resources have been expended on research enterprises that involve curcumin as a key study agent. From 1995 to the present, according to the NIH RePORTER database (query of the term “curcumin” in keywords, titles, and abstracts), (30) federal funds exceeding $150 million have been awarded for projects that are linked, directly or indirectly, to the biomedical exploration of curcumin. This result gives an approximate estimate of the order of magnitude of resources (not scientific significance) that are used directly or indirectly for experiments with curcumin and its analogues. Consequently, projects involving, for example, method development work where curcuminoids serve as model compounds are likely included in this estimation. However, this continued interest has resulted in the generation of manuscripts reporting biological studies of curcumin at a rate that far outpaces those published on artemisinin (Figure 2). This suggests that while artemisinin research has matured, curcumin research may have entered the steep section of the hyperbolic black hole of natural products (NPs) (4) where effort rapidly exceeds utility, a common occurrence for IMPS. Furthermore, most NPs that have been successfully developed as drugs were discovered in phenotypic assays showing activity at or near a therapeutically relevant level. This allowed for the rapid development of the parent natural product or relatively straightforward analogue development to achieve a desired therapeutic effect. (6) Such was the story for artemisinin, but careful analysis of the literature leads to a much different conclusion where curcumin is concerned.
Figure 2
Figure 2. Comparison of publication frequency for biological studies of curcumin and artemisinin. The numbers of manuscripts per year were retrieved from SciFinder by searching for the substances curcumin (CAS no. 458-37-7) or artemisinin (CAS no. 63968-64-9) and then filtering by “biological study” and “document type” = journal. (Data accessed May 3, 2016.)
In this Miniperspective, we hope to address these questions regarding curcumin: PAINS, IMPS, or promise? Solid gold or just pyrite? Valuable lead for therapeutic development or still a tough challenge for NP and medicinal chemists? These are important questions, and they cannot be fully addressed even in this platform, as there are greater than 15 000 manuscripts published related to the biological interactions of curcumin, with ∼50 more manuscripts published each week. However, it is our goal to offer guidance and orthogonal perspectives to scientists and reviewers who may not have the time or resources to trek through the forest of curcumin literature. This is especially pertinent as articles relating to curcumin bioactivity appear in such a broad range of journals as to limit the ability of one to evaluate them all, due to both time and subscription limitations. By outlining the essential medicinal chemistry of curcumin, we aspire to improve the significance of science performed in the area of turmeric (and general NP) research and ensure that ever-precious research resources are spent most effectively. First, we will present evidence that curcumin is most probably an invalid lead compound, as can be shown by a critical evaluation of its PAINS and IMPS characteristics. Second, we will critically evaluate the physicochemical and pharmacokinetic/pharmacodynamic properties of curcumin responsible for its behavior in vitro and in vivo and tie these properties to the reported activity of curcumin against a variety of biological targets. Third, we will offer a critical look at a sampling of curcumin/curcuminoids clinical trials to put its therapeutic utility in context. The final section will compile the key points from the three discussion areas and seeks to identify new aspects that could potentially guide future research on this important traditional medicine.
Overview: Allure of the “Golden Spice”
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Turmeric, the powdered rhizome of Curcuma longa, is extensively used as a spice in curries and mustards, is often responsible for their distinct color, and contributes much to their flavor due to the presence of its oleoresins and essential oil. Turmeric is a member of the ginger family (Zingiberaceae) and is prescribed abundantly for ailments in both traditional Chinese and Indian medicine. (31) For example, turmeric preparations are applied to fresh wounds and bruises and as counterirritants for insect bites. Turmeric paste is used to facilitate scabbing in chicken pox and small pox. It is used in urologic diseases, hepatobiliary diseases and as an anthelminthic. Turmeric has also been described as a cancer remedy in Indian natural medical literature.
Major phytoconstituents of turmeric are diarylheptanoids, which occur in a mixture termed curcuminoids that generally make up approximately 1–6% of turmeric by dry weight. (32) Most crude extracts prepared from turmeric, and even some refined “curcumin” materials, contain three major compounds (Figure 3): curcumin [1, (1E,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione, typically 60–70% of a crude extract], demethoxycurcumin (3, 20–27%), and bisdemethoxycurcumin (4, 10–15%), along with numerous and less abundant secondary metabolites. (33)
Although the multicomponent nature of “curcumin” is well documented, that fact and/or the unambiguous assignment of specific structures in a particular preparation is not always clear. Herein, the term “curcumin” will be used interchangeably with “curcuminoids” unless a more explicit description (e.g., of a single chemical structure) is deemed necessary. On the basis of our literature review, many in vitro studies use pure, synthetic 1, while most in vivo studies and clinical trials use a curcuminoid mixture. The dynamic nature of solubilized 1 makes it challenging to consider it a single compound in vitro or in vivo. However, regardless of the source material used in most studies, the structure of 1 is usually cited, perhaps by default, as designated active constituent that should be pursued for therapeutic benefit and is the compound used as a proposed “lead” structure for medicinal chemistry investigations. This Miniperspective will not attempt to address the potential therapeutic effects of even more complex turmeric extracts or preparations thereof but instead focuses on the reported utility of the chemical structure of the major constituent of these extracts: curcumin.
Figure 3
Figure 3. Major phytoconstituents of extracts of Curcuma longa. Compounds 1, 3, and 4, often grouped together as “curcuminoids”, generally make up approximately 1–6% of turmeric by weight. (33) Of a curcuminoid extract, 1 makes up 60–70% by weight, while 3 (20–27%) and 4 (10–15%) are more minor components. The major constituent of a curcuminoid extract, 1, and the properties important for its consideration as a lead compound for therapeutic development are the focus of this review.
From a drug discovery standpoint, 1 appears to have several attractive qualities. There is a plethora of publications reporting a wide variety of biological activities for the compound(s), which is/are “generally recognized as safe” (GRAS) by the FDA as a food additive at levels up to 20 mg per serving, (34) a designation that could conceivably help developers bypass some regulatory requirements for its approval as a therapeutic. This designation, along with the long historical and cultural use of turmeric as a medication, has contributed to its popularity as a dietary supplement marketed for many common ailments. Sales of curcumin supplements in the United States were reported to exceed $20 million in 2014, though a precise number is difficult to estimate. (35) In concert with this boom in nutraceutical applications of curcumin, DSHEA (Dietary Supplement Health and Education Act) legislation establishing the legalities of dietary supplements in the United States (1994) and advents in in vitro testing likely contributed significantly to a sharp upturn in the publication of manuscripts regarding the use of curcumin in biological studies in the late 1990s (Figure 2). Since that time, curcumin has been reported to have activity for the following indications: anti-inflammatory, anti-HIV, antibacterial, antifungal, nematocidal, antiparasitic, antimutagenic, antidiabetic, antifibrinogenic, radioprotective, wound healing, lipid lowering, antispasmodic, (36) antioxidant, (37) immunomodulating, anticarcinogenic, (38) and Alzheimer’s disease, (39) among others. In many scientific and medicinal circles, these reported effects of curcumin have marked it as a source of future breakthrough therapeutics for complex diseases that are thought to require potent but nonselective therapeutics. In this uncritical enthusiasm for curcumin’s potential utility, its “dark side” (5) is often disregarded. It is important, therefore, that any manuscript or research proposal that is based on the bioactivity (experimentally tested or computationally predicted) of curcumin or its analogues addresses additional characteristics of this natural product: its chemical instability, poor ADME properties, potential toxicological effects, and its lack of success to date in the clinic. These challenges will be addressed in further detail in subsequent sections.
Curcumin Is a PAINS, IMPS, and Poor Lead Compound
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Curcumin Is a PAINS
PAINS, or pan-assay interference compounds, are compounds that have been observed to show activity in multiple types of assays by interfering with the assay readout rather than through specific compound/target interactions. Many compound classes have been codified and identified as PAINS or potential PAINS. (40) Compound 1 exhibits all known PAINS-type behaviors: covalent labeling of proteins, (41-43) metal chelation, (44) redox reactivity, (45) aggregation, (46) membrane disruption, (47) fluorescence interference, (48) and structural decomposition. (45, 49) This suggests that any report of its activity in an assay that does not either exclude or account for these potential modes of assay interference should be treated with caution. This is a very important consideration for reviewers, for example, of U.S. federal proposals that rely on published data regarding the bioactivity of curcumin. The most recent guidelines for the review of U.S. NIH proposals require four new considerations to establish reproducibility: premise, design, variables, and authentication. Consequently, any proposal based on apparent curcumin bioactivity should ensure that the “scientific premise forming the basis of the proposed research” is sound (that is, published activity is not simply a result of assay interference) and that the “chemical resources” are “authenticated”; i.e., analytical and target engagement methods are employed to provide convincing evidence that curcumin is the causative agent of activity.
Curcumin Is an IMP
From a collective point of view, IMPS are invalid metabolic panaceas located inside the center of the black hole of natural products (4) that tend to exhaust research resources. As singular elements, IMPS are prototypes of improbable metabolic panaceas that exhibit feeble performance as drug leads. The reported bioactive properties of IMPS are highly complicated by several factors that may be in addition to PAINS characteristics but often are separate from them. (4) After evaluating bioactivity profiles of curcumin reported in the global literature, two broad observations raise red flags: (1) the high rate at which this compound, or mixture, is reported as being bioactive and especially (2) the relatively high ratio of positive activities seen in proportion to the total number of distinct bioactivities reported: just over 300 as assessed using the NAPRALERT database. (4) NAPRALERT (www.napralert.org) is a relational database on the chemistry, biological activity, and folkloric use of natural products housed since 1975 at the Program for Collaborative Research in the Pharmaceutical Sciences at the College of Pharmacy, University of Illinois at Chicago. Founded by the late Professor Norman R. Farnsworth, NAPRALERT has since compiled data from more than 190 000 literature references, with records of over 200 000 distinct chemical compounds from more than 60 000 species of organisms. As a result, NAPRALERT covers hundreds of thousands of reports of biological activity tests (including in vitro, in vivo, and clinical results) for both natural product extracts (400 000+) and chemical isolates (300 000+).
Further IMPS considerations include the PAINS characteristics of 1, chiefly chemical aggregation, (46) the presence of a reactive Michael acceptor, (50) and fluorescence activity. This last attribute is particularly important as the main categories of reported activities in NAPRALERT (see also, Supporting Information Tables 1 and 2) emerge from cellular assays, which typically involve fluorescence and quenching for end point detection. A more detailed analysis of the distribution of positive activities reported in NAPRALERT shows that 28 distinct pharmacological activities, equivalent to less than 10% of all those captured, represent approximately 50% of the total reported activities for 1. In contrast, in cases of successful NP-based drug leads such as artemisinin, ivermectin, and paclitaxel, this ratio is only between 1% and 2%. This distinctive “broad bioactivity profile” associates 1 closely with the top 100 compounds with the most promiscuous bioactivity reported. Of these top 100, the ginsenosides Rb-1 and Rg-1, genistein, quercetin, apigenin, nordihydroguaiaretic acid, resveratrol, kaempferol, and fisetin are the only compounds with even more distinct reported activities than 1. While this means that these nine compounds have a wide range of positive results in bioassays, it does not automatically mean that their pharmacological effects cover such a wide range in practice. It is equally notable that, just like 1, none of these nine compounds, or any of their derivatives, have reached maturity as a drug lead to date.
One of the most plausible explanations regarding the observed polypharmacology of curcumin, besides its apparent PAINS/IMPS character, promiscuous bioassay profile, and chemical instability (vide infra), is the variable purity status and widespread lack of characterization of “curcumin” materials. This unknown mixture represents what is termed static residual complexity (static RC; see also https://go.uic.edu/residualcomplexity): (51, 52) the assumed bioactive material and any impurities are present and constant throughout the bioassay. The high variability of curcumin preparations and sources makes static RC an important factor of variability and can lead to unpredictable or potentially irreproducible results. In contrast, dynamic residual complexity (dynamic RC) (52) is related to metabolic instability, a property that applies particularly to 1. The typical time frame for the biological experiments reported in NAPRALERT allows for significant degradation of 1 (vide infra). The degradation products will very likely have distinctly different in vitro and/or in vivo biological activities from the parent compound. In addition, biogenic metabolites are often different from the degradation products present in buffers or laboratory storage conditions, and the extended incubation times of many cellular assays make it difficult to know which degradation products are present and at what concentrations. (52) For example, a recently identified degradation product of 1 is a spiroepoxide, which is highly sensitive to acids and reacts readily with thiols. (53) This report indirectly emphasizes the relevance of dynamic RC by hypothesizing that the polypharmacology of 1 may in part, or even largely, be due to the sum of its degradation products.
Both the static and dynamic RC issues, as well as promiscuous reactivity, make the study of 1 a true challenge for both biologists and chemists, even when performed in close collaboration. Complex chemical characterization procedures need to be established and undertaken before starting biological experiments to control the initial material and characterize the remaining components at the end of the experiment (allowing the assessment of any degradation of the studied material). From the pharmacologist’s or biologist’s point of view, controlling chemical aggregation, target specificity (especially when using proteins), and photochemical conditions (absorbance, fluorescence, quenching, etc.) is paramount for achieving interpretable assay readouts and meaningful biological outcomes.
Curcumin Is a Poor Lead Compound
Compound 1 is completely out of balance as a lead compound when its PK and PD properties are weighed. While there are exceptions and some discrepancies about what makes a “good” lead, a prototypical lead compound for therapeutic discovery and development generally has less than 1 μM potency at its desired target(s), evidence of selectivity and tractable mechanism(s) of action, good bioavailability, chemical stability, and ADMET (absorption, distribution, metabolism, excretion, and toxicology) qualities that can be optimized in a reasonable number of synthetic cycles. (54) Compound 1 has none of these features. Moreover, attempts to improve its ADMET qualities (typically the most difficult properties of a compound to optimize) and increase its specificity via chemical optimization and various formulations have thus far been unsuccessful. Optimization of the PK/PD of 1 may be impossible given the multiple structural features presumably responsible for its “desirable” activity. For example, one property often marked for optimization is indiscriminate thiol reactivity (particularly with proteins), though this is most likely a chief explanation for much of its polypharmacology. Of course, covalent reactivity can be useful in the development of therapeutics. (55-62) However, this mode of action is either purposefully designed into the drug as part of the discovery process or installed after optimization of potency and ADMET properties. For example, α,β-unsaturated reactive groups are often purposefully introduced into optimized, stable compounds to increase their potency and selectivity. Optimization to improve the feeble PK of 1 will most likely lead to concomitant dulling of its PD ferocity.
The structure of 1 contains a β-diketone moiety that readily undergoes keto–enol tautomerization (Figure 4). NMR studies using a variety of solvents at pH 3–9 have confirmed that the enol tautomer (1b), rather than the diketone (1a), is the only form of the molecule present at any detectable level in solution. (63) This preference for 1b leads to a planar, intramolecularly hydrogen-bonded structure both in solution and in powder form. (64) The calculated log P of 1 has been reported between 2.3 and 3.2, and it is practically insoluble in water at room temperature and neutral pH. (9, 65) At alkaline pH, the phenols are transformed to the phenolates, enabling the dissolution of 1 in water. A range of pKa values, 8.5–10.4 for the first and 9.5–10.7 for the second, have been reported for the phenolic protons depending on the solvent and method of measurement. (48) However, at both neutral and alkaline pH, 1 degrades rapidly. Compound 1 is more structurally stable in an acidic environment, but the equilibrium shifts toward the neutral form (low/no solubility) of the molecule in parallel with decreasing pH. (27, 64) Therefore, studies in buffered solvents typically involve first dissolving 1 in a polar protic organic solvent, like methanol, then diluting it in an excess of the aqueous solution.
Figure 4
Figure 4. Tautomerization of compound 1. NMR studies show that compound 1 is not present in solution as the diketone (1a) but only as a mixture of the equally present (due to symmetry) enol structures (1b). (63)
The conjugated system of 1 absorbs in the visible range (408–500 nm), (48) and this property has been used to study its degradation in various buffers through spectroscopic and HPLC methods (see also Supporting Information Table 2). At neutral pH (7.5) and rt in aqueous buffer, the t1/2 for loss of 1 as the parent compound is approximately 20 min. (66) When the temperature is increased to 37 °C, the reported t1/2 at pH 7.2 is less than 10 min. (27) This report of rapid degradation upon heating led to a more thorough investigation of the degradation products of 1. It is known that 1 is photoreactive, as a 5% reduction in parent material is observed simply when preparing samples in clear versus amber glass. (27) Compound 1 degrades by two main pathways: solvolysis and oxidative degradation. The solvolysis (nucleophilic substitution or elimination by solvent molecules) of the heptadienedione chain in aqueous alkaline buffer results in 90% compound degradation within 30 min. The major identified products are vanillin (5), ferulic acid (6), and feruloylmethane (7, Figure 5A). While the relative abundance of these degradation products differs at different incubation pH or temperature, they are also observed upon incubation of 1 in cell culture medium (RPMI 1640, Roswell Park Memorial Institute medium) and human blood. (27) Recent spectroscopic analysis has revealed that solvolysis is only a minor pathway, and the major chemical degradation product is a bicyclopentadione (8) that is produced by autoxidation (Figure 5B). (66) The spontaneous, free-radical-driven incorporation of O2 leads to oxygenation and double cyclization of the heptadienedione chain connecting the two methoxyphenol rings. (67) Further study of the kinetics of radiolabeled compound decomposition has also identified several additional degradation products that likely appear on the pathway to compound 8 formation. (45) This oxidative reaction occurs without photochemical initiation and may account, in part, for the reported antioxidant properties observed for compound 1. These degradation pathways suggest that dynamic RC (vide supra) should be considered when interpreting the outcome of bioassays involving 1.
Figure 5
Figure 5. Major chemical degradation pathways of compound 1. (A) Solvolysis under alkaline pH in buffered aqueous solution rapidly leads to multiple fragmentation byproducts. (27) (B) Autoxidation in buffered medium creates a bicyclopentadione (8) that is the major degradation product in aqueous conditions. (66) (C) Photodegradation of 1 can occur when in crystalline form and dissolved in organic solvent. (68) (D) When dissolved in certain organic solvents (like isopropanol), photodegradation can include reaction with the solvent as a substrate. (69)
While oxidative degradation does not require photochemical initiation, photochemical degradation of 1 does occur in both the crystalline and solubilized forms. Crystalline 1 is degraded by exposure to sunlight to give primarily 5, 6, ferulic aldehyde (9), and vanillic acid (10, Figure 5C). (68) The same degradation pattern is observed for 1 in organic solvents when it is exposed to light. Several solvent-dependent products are also formed. In methanol, isopropanol, and chloroform, an internal cyclization product is formed. Isopropanol can also behave as a reactive substrate, leading to the formation of a guaiacol derivative (11, Figure 5D). (69) The mechanism of photochemical degradation is caused mostly by type I and type II reactions with molecular oxygen, which has been described in detail elsewhere. (9)
The chemical stability of 1 can be improved by encapsulation with lipids or nanoparticles. (70, 71) Other attempts at improving stability have included synthetic manipulations to remove or protect the oxidation sites (phenolic and enolic hydroxyls) (72) and derivatization of the β-diketone to reduce the activity of the enolate Michael acceptor. (73, 74) While analogues of 1 may be a more viable route to the development of a stable molecule for in vitro or in vivo evaluation, they will need to be evaluated as entirely new chemical entities and are largely outside the scope of this discussion.
The rapid degradation of 1 brings many additional requirements for its investigation in an in vitro or in vivo setting. Stability of 1 under the assay conditions should always be demonstrated. This analysis has not been reported in the vast majority of the publications reviewed here. Additionally, several publications have used computational methods to predict the activity of 1 or to explain the bioactivity observed experimentally. (75, 76) Because 1 is likely not present in situ, or at least its bioactivity is confounded by the presence of multiple reactive and/or bioactive degradation products, these models are less relevant to the targets of interest. Even when computational studies have accounted for the binding characteristics of the degradation products, other probable mechanisms of interference have not been considered. (77)
A primary requirement for most pharmaceuticals is stability under physiological conditions (a surrogate for in vivo conditions) and stability under storage conditions or in formulations. Physiological conditions here are considered an aqueous environment at pH 7.4 and 37 °C. Compound 1 has none of these characteristics and displays prominent chemical instability. Below, we highlight several other concerns regarding the physicochemical properties of 1 that could explain its promiscuous reactivity; these also need to be addressed when studying this molecule in vitro or in vivo.
Physicochemical Properties
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The chemical instability of 1 is most likely the key property responsible for confounding the results of in vitro and in vivo measurements of its bioactivity and for undermining computational predictions of its potential binding and activity in biological assays. Compound 1 also displays undesirable physicochemical properties relative to known drugs. In addition to being unstable, it forms chemical aggregates (colloids) under common biochemical assay conditions. (46) Adding the nonionic detergent Triton X-100 attenuates the activity of 1 versus AmpC β-lactamase (IC50 from 12 μM to >30 μM), malate dehydrogenase (IC50 from 9 μM to >30 μM), and HIV-2 protease (IC50 from 9 μM to >100 μM). This pattern is consistent with chemical aggregation and has been further confirmed by DLS (dynamic light scattering). (46, 78) These studies describe a critical aggregation concentration between 10 and 20 μM for compound 1. This is highly relevant because it corresponds to common compound testing concentrations in many of the investigational assays we encountered. Enzymatic inhibition by colloidal aggregates is stoichiometric, meaning that at a given compound concentration, the real concentration of enzyme is much lower. Once a chemical colloid is saturated with protein (be it enzyme or carrier protein), any unbound enzyme is free to react in the assay system. (79, 80) Consequently, apparent in vitro selectivity can be influenced by the relative protein concentrations in selectivity counterscreens (i.e., all proteins present: enzyme, carrier, and substrate proteins) and does not always reflect selectivity via traditional compound–ligand interactions. This also means that counterscreens with excess enzyme may appear less susceptible to aggregating compounds, helping to identify this circumstance. These phenomena deserve special consideration when designing experiments that include detergent-free assays.
In the event that the observed activity is not found to be due to assay interference, the instability of compound 1 calls into question the identity of the “active” compound. (45) It is important to consider the cellular location of the target protein, as 1 has been shown to perturb cell membranes. This can lead to membrane perturbation being mistaken for specific binding to membrane-associated proteins. (47) This could have significant ramifications for many reported activities, including those for ion channels, transporters, and growth factors. Beyond these factors, the fluorescence properties of 1 must also be taken into account in many biological experiments. The absorbance (∼408–500 nm) and emission (∼450–600 nm) of 1 varies greatly depending on solvent, but largely falls within the range of wavelengths common for many fluorescence-based bioassays. (48, 81)
Other physicochemical properties of 1 are important considerations when developing assays or evaluating druglike properties. Notably, 1 is nearly insoluble in water at room temperature and neutral pH, estimated at 1–10 μg/mL. This can only be viewed as an estimate, however, as the true solubility is confounded by the high propensity for aggregation. (64) Both the estimated ClogP (2.3–3.2) and topological polar surface area (93.1 A2) fall in the range of known chemical aggregators. (78) X-ray crystallography studies with compound 1 also confirm its rapid degradation in aqueous media. Crystallization of 1 with transthyretin revealed both the parent compound and compound 6 (a known degradation product) associated with the protein. (77) When considering molecular modeling, studies based on both the diketone (1a) and enol (1b) forms have been reported but fail to recognize the complete lack of solubility of one form (1a, diketone) and the complete instability of the other (1b, enol).
Beyond the concerns of chemical and physicochemical stability, compounds taken in vivo require appropriate PK/PD properties. Next, we highlight several concerns that should be addressed when using compound 1 in vivo.
ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicology)
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In addition to the poor chemical stability and multiple modes of assay interference displayed by compound 1, it is generally accepted that its pharmacokinetic properties are poor. (7, 82)
Absorption
The absorption of any potential therapeutic is a critical consideration, especially for oral dosing. Several studies, including clinical trials, have been performed using curcumin in a variety of oral dosing formulations. An oral dose of up to 12 g/day has been given with no adverse effects. (83) While this high dose was relatively well tolerated, the absorption of the compound is negligible. All clinical studies reviewed here reported that 1 could not be detected in the serum of the majority of test subjects (including those dosed at 12 g/day). This is not surprising, as the reported oral bioavailability of synthetic 1 in rats is less than 1%. (28) Moreover, compound 1 has displayed poor permeability in the standard Caco-2 model system (Papp = 3.18 × 10–6 ± 1.08 × 10–6 cm/s), (84) which is a widely accepted predictor of cell permeability (poorly permeable compounds have Papp < 5.0 × 10–6 cm/s). (85) Several groups have attempted to improve the absorption and bioavailability of 1 through various formulations. We note that lipid dispersions and nanoparticle systems have been developed for 1, with modest improvement in the absorption and bioavailability of the compound. (82)
Distribution
The extent to which a compound distributes through the body has a large impact on its therapeutic utility. While the distribution of compound 1 has been extensively studied in rats, it has only been sparingly evaluated in humans. Several studies in rodent models have reported variable distribution across tissue types. (9, 82, 86) This high degree of variability is likely due to (1) differences in the preparation of the dose used in the study, (2) differences in extraction, preparation, and detection methods of 1, and (3) lack of specificity in the detection assay. Many assays we analyzed in the literature utilized HPLC-based detection without the added specificity of confirmation of identity by MS. These methods inherently have larger amounts of error as biological impurities, and degraded or transformed compounds could have similar retention times and absorbance properties as the parent compound. In fact, a study comparing the distribution of [3H]-1 to unlabeled 1 found substantially more radioactivity in tissues compared to the amount of unlabeled 1. This result supports the observation that 1 is degraded and/or transformed before and/or after absorption. (87, 88) Together, these studies suggest that the parent compound does not distribute to any specific organs in appreciable levels.
Metabolism
In part due to its reactive structure, any 1 that is absorbed by the body has a high potential to be metabolized. Extensive studies have been done on 1 in human liver microsomes. Phase I metabolism primarily results in reduction of the double bonds in the heptadienedione system, mainly through the action of alcohol dehydrogenase. (82) Phase II metabolic processes rapidly conjugate 1 and its reduced metabolites. The most abundant conjugates are glucuronides and sulfates at the phenolic positions. Unsurprisingly, 1 also interacts readily with glutathione in a nonenzymatic manner, presumably through a Michael-type addition. (89) Some of the formulations investigated to improve the oral bioavailability of 1 also hope to slow down the observed high rate of metabolism upon absorption. Unfortunately, it appears that once 1 is released in vivo, it has a high potential for modification by both first and second phase metabolism.
Excretion
The majority of 1 ingested by oral dosing is excreted in the feces, as determined in multiple studies in rats. Very little is detected in rodent urine; however glucuronide and sulfate metabolites have been identified in rat plasma. (88, 90) There are conflicting reports regarding the excretion of 1 and its metabolites in human subjects. In one study, neither the parent compound nor its metabolites were detected in blood or urine of human subjects after oral dosing, but 1 was recovered from feces. (91) In two other studies, 1 (92) or one of its metabolites (93) was detected in serum of one or three patients from each cohort of 12 or 15 patients, respectively. In a fourth study, 1 was detected in serum of only one subject, but the glucuronide and sulfate conjugates were detected in all subjects. (94) Similar to the reports of absorption, some of this variability in reporting likely comes from variability in the source material and methods of dosing and sample collection, preparation, and detection. Small amounts of compound 1 may be absorbed and excreted unchanged or, if we consider other physicochemical properties (vide supra), may not be absorbed but simply pass directly to the feces. Metabolized 1 is generally excreted in urine as the glucuronide and sulfate conjugates. The remainder of any dose, whether absorbed or not, is likely degraded beyond detection by the time it is excreted.
Toxicology. (7, 95-98)
In addition to the therapeutic targets discussed below, 1 (and its degradation products) shows broad reactivity against a number of human enzymes that are linked to compound toxicity, namely, hERG channels, cytochrome P450s, and glutathione S-transferase (see also Supporting Information Table 3). The reactivity of each of these classes has important implications for potential toxic side effects: hERG channel inhibition is related to cardiotoxicity; (99-101) cytochrome P450 (CYP450) and glutathione S-transferase (GST) inhibition can lead to impaired detoxification and potential toxic drug–drug contraindications. (102) Beyond specific enzyme toxicity, compound 1 has recently been shown to be an active iron chelator in vivo, inducing a state of overt iron deficiency in mice fed diets poor in iron. (44) This suggests that 1 has the potential to affect systemic iron metabolism, particularly in people with a preexisting suboptimal iron status. In studies of therapeutic utility, 1 has been reported as cytotoxic against a number of important cancer cell lines. What is infrequently noted, however, is that it also shows cytotoxicity against normal human lymphocytes. (31) Surprisingly, data on the cytotoxicity of 1 against normal (noncancerous) cell lines are sparse. A recent report demonstrated cytotoxicity of 1 against a murine macrophage cell line and human kidney cells at IC50 values of 31 and 15.2 μM, respectively. (8) These values are at or below those reported for several therapeutic targets or cell lines (see also Supporting Information Tables 1 and 3), suggesting that 1 might be generally cytotoxic and does not show a preference for normal versus cancerous cells.
ADMET Summary
The observed ADMET properties of 1 are not surprising given its chemical structure and physicochemical properties. The numerous papers that suggest 1 has utility as a therapeutic agent have led to a large field of study focusing on the improvement of its PK properties. We would emphasize caution, however, as such improvement in PK may actually lead to exacerbation of the toxicological side effects of 1, given its cytotoxic effects. (8) Fundamental medicinal chemistry principles, and available ADMET evidence, incline us to hypothesize that the observed high tolerance in humans and low rate of adverse events is likely due to its poor absorption and low bioavailability. As an alternative approach, it may be possible for compound 1 to have an effect on human health without being absorbed. Emerging research suggests that 1 could affect the gut microbiota, which has been linked to several chronic diseases. (7) A recent study using a mouse model of colitis-associated colorectal cancer suggests that compound 1 may have a chemopreventive effect that is correlated to changes in the microbiota of these animals. (103) This hypothesis has yet to be fully validated but may ultimately provide focus for studies on the use of 1 as a therapeutic.
Critical Analysis of Some Reported Activities of Curcumin (Real and Virtual) (104, 105)
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Compound 1 is reported to be active at multiple biological targets. What is not typically acknowledged in these focused studies is that it is nonselective for what could be considered “good” versus “bad” targets (vide supra). A comprehensive discussion of the structure–activity (and reactivity) of 1 has been published. (106) In summary, every functional group in 1 probably contributes to its reactivity and its apparent activity. For example, it is not surprising that compound 1 covalently modifies a number of biological proteins given that its two α,β-unsaturated systems are potent Michael acceptors for −SH groups with low pKa values. Additionally, the two phenolic groups are susceptible to redox transformations, and the 1,3-dicarbonyl is an excellent chelator of metal ions. It is important to consider the reported activities of 1 in light of these reactive functional groups in addition to the other properties detailed above. Examples of this critical consideration are presented below as case studies (see also Supporting Information Table 1). One common theme in these reports is particularly disturbing: published bioactivity data of 1 are typically not evaluated critically before it is used to justify further research in an area. This is especially troubling when the original activity reports have been retracted. (107-112)
Activity Case Studies
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p300
Compound 1 is reported to inhibit the histone acetyltransferase (HAT) p300 at low micromolar concentrations in vitro. (11, 113) In one of these original studies, counterscreens failed to show any activity versus the HAT PCAF, the histone methyltransferase G9a, or the histone deacetylase HDAC1. (113) Since the original publication of this bioactivity, there have been dozens of reports that have used 1 as a tool compound to modulate HATs in cell-based and organism-based experiments across many biological systems: (114) mouse neuroblastoma cells, (115) parasites, (116) viruses, (117) and a variety of human cell lines. (118-121) Several points should be made about the original data. (113) First, in vitro testing was performed without detergent and often at compound concentrations above the threshold for colloid formation (vide supra). It is reasonable that aggregates of 1 could have contributed to the in vitro assay readouts and perhaps the apparent selectivity (e.g., enzymatic modulation by chemical aggregation can be mitigated by increased levels of proteins). Second, 1 was allowed to preincubate with the targets in most of the assays. (113) Given its reported instability in aqueous solutions, it is difficult to draw conclusions about the nature of compound–target interactions without additional stability data under these specific testing conditions. Third, another report showed that radiolabeled 1 binds covalently to p300 in a manner consistent with Michael addition, yet failed to inhibit the HATs PCAF or Gcn5 in vitro. (11) The apparent selectivity of 1 for p300 reported nearly a decade ago may be a function of the intrinsic susceptibility of each HAT to thiol-reactive compounds. Selectivity in such a case would be a function of the thiol solvent accessibility, the number of thiols in the target protein (also the overall assay), and the protein conformational changes induced by any thiol modification. As an example, during an investigation of thiol-reactive PAINS, the highly thiol-reactive probe CPM consistently showed less potent inhibition of yeast GCN5 compared to yeast Rtt109 and human p300. (122) Fourth, several kinetic experiments were performed that suggest 1 does not bind to the p300 active site. (113) These experiments appear to be performed without ruling out reversibility or time dependence, and it is possible these kinetic results may be confounded by chemical reactivity as well as compound stability and chemical aggregation. Without question, compound 1 can inhibit p300 HAT activity in vitro based on the published data. Whether or not this inhibition is therapeutically useful, especially in a cellular context, is considerably more controversial. When phenotypes or changes in histone acetylation are observed in cells or whole organisms, these downstream effects are often attributed carte blanche to the inhibition of p300 while downplaying or outright disregarding other potential mediators of cellular histone acetylation such as HDACs or other HATs. This logic is overly simplistic and often flawed when used as supporting evidence for studying specific pathways.
HDAC8
In one report primarily driven by molecular modeling studies, compound 1 was reported to inhibit HDAC8 at midmicromolar compound concentrations (IC50 = 115 μM). (123) On the basis of the title (“potent histone deacetylase inhibitors”), one may be led into thinking 1 could serve as a tool compound for epigenetic studies. As in the p300 example, the relevant in vitro assays omit detergent to mitigate chemical aggregate formation, a potential confounder that is highly likely in this system given the relatively high compound concentrations tested. In addition, the enzyme source from which the IC50 value was derived, HeLa nuclear extracts, should contain multiple HDACs, making it impossible to confidently gauge HDAC8-specific inhibition. No controls were performed to account for readout interference, such as fluorescence quenching or autofluorescence. Orthogonal counterscreens are absent, and there is no evidence presented for direct target engagement (e.g., ITC, X-ray crystallography, or SPR). The heavy reliance on molecular modeling is problematic, including the reporting of theoretical binding constants. Despite these liabilities, subsequent reports cite curcumin for its ability to specifically modulate HDACs. (124-126)
GSK-3β
Compound 1 is reported to be a potent inhibitor of GSK-3β (IC50 = 66 nM). (127) However, detailed analysis of the in vitro testing conditions may help rationalize this level of potency. First, the reported concentration of GSK-3β protein present in the assay was in the femtomolar range, meaning several orders of magnitude stoichiometric excess of compound 1 are still needed to appreciably inhibit GSK-3β activity. Second, the biochemical assay was performed in the absence of thiol-scavenging agents like DTT, meaning 1, or any potential degradation products, could still react with the assay target or substrate. Third, as with previous examples, the assays were performed with incubation times sufficient for compound degradation (30–90 min), (127) without meaningful counterscreens for selectivity and without mechanistic studies to demonstrate therapeutically useful target engagement. In retrospect, the heavy reliance on molecular modeling is problematic without confirmation of compound stability in the assay conditions. Nevertheless, curcumin is still the subject of numerous studies involving GSK-3β. (128-131)
Tau and Amyloid Fibril Formation
Compound 1 was tested as an inhibitor of tau fibril formation as part of the NIH MLPCN (Molecular Libraries Probe Centers Network) campaign. The tested substance showed promising activity in the primary thioflavin T (ThT) fluorescence-based qHTS (IC50 = 3.5 μM). However, it was inactive in a fluorescence polarization (FP) based secondary screen. Compound 1 was still active in a counterscreen for total fluorescence (IC50 = 13 μM), suggesting its activity was due in large part to compound-mediated fluorescence interference. For these reasons, it was not selected for additional follow-up based on these data. This example demonstrates the utility of a well-designed screening tree, complete with secondary assays and assay-specific counterscreens. (132)
Additionally, 1 has been reported as an inhibitor of amyloid-β (Aβ) fibril formation and mediator of Aβ cytotoxicity, also using the ThT assay as a primary readout (IC50 = 1–64 μM). (7, 133) Subsequent publications have shown that 1 is highly absorptive in the same spectral range as ThT. (134) Most recently, transmission electron microscopy has shown that compound 1 does not affect the aggregation of Aβ in vitro. (135) This report attempts to explain the observed cellular protective effects by showing that the oligomers formed by Aβ in the presence of 1 are nontoxic; i.e., the polyclonal antibody A11, which is reported to specifically detect toxic Aβ oligomers, does not detect these oligomers. (136) However, the extremely long incubation times reported here would require follow-up to exclude the likely possibility of aggregation or degradation in the assay conditions. (137)
CFTR (Cystic Fibrosis Transmembrane Conductance Regulator)
In 2004, compound 1 was reported as a calcium-adenosine triphosphatase pump inhibitor for the treatment of cystic fibrosis (CF). (138) The compound was tested in a mouse model based on previously reported in vitro activity (5–15 μM) in a related SERCA (sarcoplasmic/endoplasmic reticulum calcium) pump assay. The assay readout required the release of ΔF508-CFTR protein from the endoplasmic reticulum, which would increase calcium ion flux, a process that is known to be deficient in CF patients. These studies were followed by an investigation using a mouse model that expresses mutant CFTR, which showed that a dose of 45 mg kg–1 day–1 oral administration of 1 ameliorated phenotypic deficits in these mice. However, no orthogonal assay was used to confirm target engagement, and there was no confirmation of 1 in the blood of these animals. The improvement of ion channel conductance in these studies could be largely due to the disruption of cellular membranes by 1 (vide supra), thereby increasing ion release. Follow-up studies by an independent lab were unable to reproduce these in vitro and in vivo results. (139) The measured concentration of 1 in vivo peaked at 60 nM, 30 min after oral dosing at 100 mg/kg, but was not detectable below this dosing level. While publications continue to point to compound 1 as a CFTR modulator as a potential CF treatment, (140) no confirmation of CFTR activity has been published.
CB1
In 2009, compound 1 was reported as a potent, selective inhibitor of human and mouse cannabinoid receptor 1 (CB1). (141) The initial report should raise some concern as the assay had a 90 min incubation time of 1 with the receptor at room temperature, conditions known to result in rapid compound degradation (vide supra). These results are, therefore, confounded minimally by the formation of degradation products. In addition, there is no orthogonal evidence presented of direct target engagement. Approximately six months after the publication of these results, the manuscript was retracted. (142) According to the letter of retraction, both the authors and three external labs were unable to reproduce the original results. In repeated experiments, compound 1 was a low micromolar inhibitor of both CB1 and CB2 and showed no selectivity. The original authors hypothesized that their results were due to sample contamination by their CB1 control compound. Unfortunately, articles are still published that cite the originally reported activity and selectivity of 1 for CB1, without acknowledgment of the subsequent retraction. (143)
Overview of Literature Reports of Curcumin Activity
A critical review of the literature reveals several major themes whenever novel bioactivity has been attributed to 1: (1) bioactivity was often observed at low micromolar to midmicromolar compound concentrations, typically above the critical aggregation concentration threshold for 1; (2) appropriate counterscreens for assay interference were frequently not performed, and target engagement was not confirmed nor was target selectivity; (3) nearly all the manuscripts reviewed failed to consider the stability of the compound; (4) finally, weak yet desired phenotypes, often observed at relatively high compound concentrations, were taken to “validate” specific target engagement but without sufficient evidence to rule out off-target effects. Such critical review of any reported activity requires a thorough understanding of the medicinal chemistry properties of 1 (vide supra).
Critical Evaluation of Clinical Trials
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Most researchers currently consider compound 1 as a dietary supplement, and the FDA does not support claims regarding its therapeutic utility. For it to achieve a level of documented therapeutic utility in the United States, researchers will need to show that it is safe and effective for its intended use. While the essential oils and oleoresins of turmeric are recognized as GRAS substances, (144)1 is not on any readily accessible FDA GRAS list. When one company requested GRAS designation for a proprietary preparation of a mixture of curcuminoids, the FDA responded that it “has no questions at this time regarding (the company’s) conclusion that curcuminoids is [sic] GRAS under the intended conditions” (inclusion in baked goods; soups; snack foods; imitation dairy products; and seasoning and flavors at use levels up to 20 mg curcumin/serving) but that the agency “has not, however, made its own determination regarding the GRAS status of the subject use of curcuminoids”. (34)
Adverse events are rarely observed when curcuminoid preparations are dosed orally in humans, though some adverse reactions have occurred when large doses (8–12 g/day) necessary to provide “adequate systemic exposure” were administered orally. For example, a phase I dose-escalation study was carried out where three subjects in each of eight cohorts were treated with a single dose of a commercial milled curcumin mixture (95% curcuminoids with 70–80% 1, 15–25% 3, and 2.5–6.5% 4), (145) over a range escalating from 500 mg to 12 g. Compound 1 was only detected in the serum of 2/6 subjects taking the single doses of 10 or 12 g. (83) A peak serum level of 57.6 ng/mL (156 nmol/L) was measured at 2 h in the one individual who received the single 12 g dose. (For comparison, the Cmax for a 10 mg dose of atorvastatin is 2.81 ng/mL.) (146) Adverse events in this study were diarrhea, rash, or headache. These events occurred in 30% of the trial participants, but did not appear to be dose related. In a longitudinal Phase I study of curcumin dosing, 15 patients with advanced colorectal cancer were administered 0.45 to 3.6 g daily of the same commercial mixture of curcuminoids described above for up to four months. (147) In this case, 1 was found in the blood of 3/6 of the patients receiving the highest dose (11.1 ± 0.22 ng/mL, converted from the reported 0.6 nmol/L, at the 1 h time point on days 1, 2, 8, and 29), but not in the other nine subjects who received lower doses. Sulfate (8.9 ± 0.7 nmol/L) and glucuronide (15.8 ± 0.9 nmol/L) conjugates were found in all six of the subjects taking the 3.6 g daily dose, though there was no obvious difference in metabolite levels between those high-dose subjects in which 1 was found and in those in which it was not present. Notably “decreases in tumor markers or serum cholesterol were not observed as a result of treatment in any of the patients”, and “three significant changes in quality of life scores were reported: one patient noticed a significant improvement after one month of treatment, and two patients deteriorated after two months of treatment, both of whom were found to have radiologic progressive disease.” Mild diarrhea was the only sign of toxicity observed. In the present discussion, the significance of these phase I studies is two-fold. First, large amounts of 1 appear to be fairly well tolerated, suggesting that the use of curcuminoids or turmeric as an herbal supplement at lower doses is probably benign. Second, even at what might be considered the maximum-tolerated dose from the standpoint of pill consumption, (148) we note that 1 has a variable and extremely low systemic bioavailability when dosed orally.
Beyond these primarily PK in vivo studies, 1 has a long history of being the subject of human PD clinical trials. The first article to report its use as a human therapeutic was in 1937. (149-152) None of these studies have yet led to the approval of 1, curcuminoids, or turmeric as a therapeutic for any disease. According to the United States NIH, (153) currently (from 2001 to the present) there are 135 registered clinical trials that have evaluated or will evaluate the toxicity and efficacy of curcuminoids in the treatment of a broad spectrum of diseases. Of the 135 trials, eight have reported study results. Forty-nine studies are listed as “recruiting” or “not yet recruiting”. It is beyond the scope of this work to compile, categorize, or analyze the results of all of these trials. We will, however, review the results of four archetypical clinical trials that illustrate the lack of significant success in this area. These trials were selected because data were reported on clinicaltrials.gov, and the therapeutic utility of 1 for these diseases is often referenced in manuscripts as validating its continued study.
Radiation Dermatitis
A recent example (2011–2014, NCT01246973) advanced to phase II/III and evaluated the administration of oral curcuminoids for the treatment of radiation-induced dermatitis in 686 women undergoing radiotherapy for the treatment of breast cancer. The objective “was to study the efficacy of curcumin in preventing and/or reducing the severity of dermatitis in radiation treatment site in breast cancer patients”. The treatment group took four commercially produced 500 mg curcuminoid mixture capsules (2.0 g) orally three times daily (6.0 g/day) throughout the course of radiation treatment plus one adjuvant week, while a placebo group received placebo capsules. To summarize, the study results appear inconclusive. The radiation dermatitis score (RDS, 0–4 with higher numbers indicating worse outcome) was used as a measure of the severity of the dermatitis. The RDS for the 283 patients who completed the curcumin arm of the study was 2.02 ± 0.05, while that of the placebo group was 1.99 ± 0.06. This result is perhaps not surprising, given the low oral bioavailability of compound 1. To our knowledge these data have not yet been published.
Colon Cancer
A phase IIa study evaluated the efficacy of curcumin in preventing colon cancer in smokers with aberrant crypt foci (NCT00365209). In stage 1 of this trial, 23 enrolled patients (21 completed the trial) received 2 g/day of a curcumin preparation. In stage 2, 21 additional subjects (19 completed) received 4 g/day of the curcumin preparation. In both cases the trial was continued for 30 days in the absence of unacceptable toxicity or disease progression. One important outcome measure was post-treatment concentration of compound 1 in rectal mucosa. In the stage 1 cohort, 5/21 subjects had detectable levels of 1 (8.2 ± 2.9 μg/g of protein), and in the stage 2 group, 3/18 subjects had detectable levels of 1 (3.8 ± 0.6 μg/g of protein). Additionally, compound 1 was observed in 2/19 subjects in stage 2 (3.8 ± 1.3 μg/mL). One key outcome measure was the change in total aberrant crypt foci number. The median change in stage 1 was 0.0 (range, −18 to 15) and was 6.0 in stage 2 (range, −1 to 14). While no statistical analysis was reported, there was no overall change in the stage 1 group (0.0) and very modest change in the stage 2 group (6.0). For clinical context, a change of 6.0 may move a patient from “normal” to “precancerous” or from “precancerous” to “cancerous”, but this will often result in no change in patient designation. (3, 154) To our knowledge, these data have not yet been published.
Alzheimer’s Disease (AD)
The results of a phase II 24-week, randomized, double-blinded clinical trial (2004–2008) studying the tolerability and efficacy of oral curcumin were reported in 2012. (145) This trial was based on extensive preclinical experiments demonstrating that 1 reduced Aβ-induced toxicity in vitro and reduced markers of central nervous system oxidative stress in Tg2576 APPsw mice. In this study, human subjects (average age 74 years) received placebo, 2 g, or 4 g of a commercial curcuminoid mixture in two daily oral doses. PK sampling was performed using HPLC (lower limit of detection (LLOD), 200 ng/mL of 1) at baseline and 0.5, 1, 2, 3, and 4 h postdose at 24 weeks and by LC/MS/MS (LLOD 1 ng/mL compound 1; 3 ng/mL, tetrahydrocurcumin) at baseline and 3 h postdose at 24 weeks. As might be expected based on our previous ADMET discussion, 1 was not found by HPLC analysis in any patient plasma sample, save one sample taken 4 h after a 4 g dose (6 ng/mL, below the assay LLOD). With more sensitive LC/MS/MS methods, the mean baseline level of 1 at 24 weeks was 2.67 ± 1.69 ng/mL, while that of tetrahydrocurcumin was 6.86 ± 1.69 ng/mL. Three hours post-treatment, the mean plasma levels were as follows: compound 1 (7.76 ± 3.23 ng/mL), tetrahydrocurcumin (3.73 ± 2.0 ng/mL), glucuronidated 1 (96.05 ± 26 ng/mL), and glucuronidated tetrahydrocurcumin (298.2 ± 140.0 ng/mL). After 24 weeks of treatment, there was no observed difference in mental status between the placebo and treated groups based on several measurements of cognitive status such as ADAS-Cog or mini-mental state examination (MMSE) scores. While no serious adverse events were reported, almost all (>90%) of the control and experimental subjects reported adverse events such as diarrhea, joint pain, and complaints attributed to endocrine system effects. The plasma glucose levels in the treated subjects were statistically higher than those of the placebo subjects, though not outside a normal range. The potential of compound 1 as a neurotherapeutic has been extensively reviewed, and it was concluded (our notes italicized):
“It seems debatable to further pursue the supplementation of high concentrations of curcumin in humans. Instead, in line with the concepts of promising alternative mechanisms such as neurohormesis (Note: a mechanism by which the therapeutic effects of low doses of substances are amplified by stimulation of endogenous, beneficial biochemical pathways (155)) and the gut microbiota as primary targets of curcumin to mediate neuroprotection, low doses of curcumin should be considered in future in clinical trial design.” (7)
Another more recent review (156) stated that there is insufficient evidence to recommend the use of curcumin in dementia patients and that its low bioavailability and poor study design could explain the apparent discrepancies between in vitro and human clinical trial results.
The results of an epidemiological study comparing the low incidence of AD in Ballabgarh, a rural community in northern India, to a cohort of subjects in the rural mid-Monongahela Valley of Pennsylvania is often cited as evidence that a diet containing turmeric (of which 1 is a minor component) is beneficial. (157) However, even the authors of the oft-cited study cautioned against overinterpretation of their results given the relatively short duration of the study, the small number of incident cases, and the wide confidence intervals. Diet was not considered as part of the study, and the frequency of the APOE4 allele, a risk factor for AD, was noted as being lower in the Ballabgarh group (0.073) as compared to the Monongahela Valley group (0.11). Another frequently cited study (158) used to support the impact of curcumin on AD measured the cognitive function of 1010 nondemented, elderly subjects (Singapore National Mental Health Survey) compared to their self-reported ingestion of curry (containing turmeric spice; 1–6% curcuminoids). (159) Various ethnic versions of the MMSE were used to compare the cognitive status of those who consumed curry “never or rarely”, “occasionally”, or “often” (Table 1).
| unadjusted (MMSE)b | adjusted (MMSE)c | ||||
|---|---|---|---|---|---|
| curry consumption | no. subjects | mean | 95% CI | mean | 95% CI |
| never or rarely | 163 | 24.9 | 24.2, 25.7 | 23.3 | 21.2, 25.4 |
| occasionally | 411 | 26.2 | 25.8, 26.6 | 24.8 | 22.9, 26.7 |
| often | 436 | 25.0 | 25.6, 26.4 | 24.8 | 22.9, 26.6 |
| ANOVA | p = 0.004 | p = 0.023 | |||
a
Cognitive function was evaluated using various ethnic versions of the MMSE scores for each group.
b
Unweighted sample estimates.
c
Weighted least-squares regression estimates adjusted for age, education, gender, ethnicity, etc. (20 variables total).
According to the study authors, “although the results are suggestive of a biological therapeutic effect, we emphasize that they do not establish a clear and direct causal effect of curry consumption on improving cognitive function.” The difference in MMSE between those who rarely use turmeric and those that often use it is not significant. (160)
Pancreatic Cancer
A phase II study of the use of curcuminoids in patients with advanced pancreatic cancer was reported in 2008. (148) This study used encapsulated curcuminoids in a form that contained 90% compound 1, 8% of 3, and 2% of 4. Patients started at a dose of 8 g/day and took oral curcuminoids daily for at least 8 weeks. The dosing regimen was then continued if their disease had stabilized. Twenty-one of the 25 subjects initially enrolled were evaluable for response at the end of the study. At the time of publication, one patient had remained stable for more than 18 months and another single patient had a brief but marked 73% reduction in tumor size that lasted one month. One other patient remained enrolled in the study for approximately eight months with “stable weight and a feeling of well-being, albeit with progression in non-target lesions”. Only low levels of 1 were detectable in plasma (∼22–41 ng/mL at steady state on day 3). No treatment-related toxic effects were reported.
Clinical Trials Review Summary
The aforementioned clinical trials were discussed because they are representative of many other studies for which outcome data are not (yet) available. Given its low systemic bioavailability, we remain highly skeptical that an oral dose of 1 can ever be effective in human clinical trials that are translated from reports of in vitro activity. Disagreements regarding the importance of alternative therapeutic mechanisms like neurohormesis notwithstanding, it is hard to formulate reasonable justification for studying lower oral doses of curcuminoids given that even at high doses compound 1 is not found in the serum of test subjects. The transformation of 1 to potentially active metabolites in the gut and the related influence on the gut microbiota (vide supra) (103) seems to be reasonable areas of study as no absorption of the parent compound is necessary. Still, the lack of any observed efficacy of oral curcuminoids in clinical trials where it was given in high doses does not bode well for these alternative hypotheses of therapeutic efficacy.
Conclusions: Future Curcumin Research
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The vast number of manuscripts published on the biological activity of curcumin makes it all but impossible for researchers to keep up with the state-of-the-art in the field. Herein, an attempt has been made to present an overview of the medicinal chemistry research that will be helpful for researchers and reviewers to consider in their respective roles. At first, curcumin appeared to offer great potential for the development of a therapeutic from a NP (turmeric) that is classified as a GRAS material. (144) Unfortunately, no form of curcumin, or its closely related analogues, appears to possess the properties required for a good drug candidate (chemical stability, high water solubility, potent and selective target activity, high bioavailability, broad tissue distribution, stable metabolism, and low toxicity). The in vitro interference properties of curcumin do, however, offer many traps that can trick unprepared researchers into misinterpreting the results of their investigations.
The observations of this Miniperspective offer several key points that can help identify potentially problematic research approaches and/or interpretation of outcomes in publications or preliminary data involving curcumin bioactivity. Notably, many of these strategies have been articulated previously: (122, 161)
| 1. | Look for evidence of compound stability in assay buffer/media, including when molecular models are invoked as supporting evidence of target engagement. |
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| 2. | Look for the presence of detergent and thiol-scavenging reagents in biochemical assays to mitigate the impact of chemical aggregation and nonspecific thiol reactivity. Are/were any additional counterscreens performed to rule out these phenomena? |
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| 3. | Examine the selectivity data. What are the magnitudes of any observed selectivity? Are these significant? Can any selectivity be explained by differential target susceptibilities to nonspecific interference modalities like thiol reactivity? Can any apparent selectivity be explained by the assay conditions, such as target or total protein concentration? |
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| 4. | Examine the potency of the compound. At those concentrations, would there be any expected aggregation or off-target effects? And if so, can one make meaningful conclusions about specific pathways and target engagement? Does the stoichiometry make sense? |
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| 5. | Evaluate the methods to confirm target engagement. Look for biophysical orthogonal methods for support of target engagement (e.g., SPR, ITC, CETSA), not solely phenotypic assays. |
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| 6. | Carefully examine the detection method for determining the concentration of 1 present in an assay. What biophysical method is/was used for detection? Can likely degradation products or metabolites have a similar response and/or explain the data/hypothesis? |
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With respect to curcumin/curcuminoids and in vivo studies and clinical trials, we believe there is rather “much ado about nothing”. Certainly, the low systemic exposure levels reported in clinical trials do not support its further investigation as a therapeutic. Circumventing the requirement for systemic circulation, curcumin might provide benefit by acting on gut microbiota. Thus far, there is limited evidence to support this hypothesis, which will also limit the utility of this delivery method. Delivery systems such as lipid vesicles, nanoparticles, and nanofibers might be able to boost the bioavailability of 1, but this could also conceivably narrow its therapeutic window and lead to off-target toxicity by aforementioned processes. Available evidence demonstrates curcumin will ultimately degrade upon release into physiologic media, no matter the delivery mechanism. Analogues of 1 might address some of the delivery challenges but would be new chemical entities and would have to proceed through expensive preclinical work to be approved for clinical trials. In our opinion, analogues of curcumin are based on a fairly weak foundation.
Of course, we do not rule out the possibility that an extract of crude turmeric might have beneficial effects on human health. The large RC of NP extracts, and even of refined NP preparations, makes the identification of the active constituent(s) and evaluation of their efficacy in humans very difficult. (51, 162) Considering the overwhelming evidence showing the weakness of isolated curcumin (almost always a mixture of curcuminoids) as a viable therapeutic, consideration of holistic approaches that take into account the chemical and PD/PK complexity of turmeric and its broad TxM/nutritional foundation appears to be superior directions for future research in the turmeric domain. While the concepts of static and dynamic RC apply equally to synthetically prepared compounds, the development of leads sourced from metabolomic (natural) sources is intrinsically more prone to the impact of purity (and unknown impurities). In some ways, the oversimplification of this complexity has led to complicatedness that makes it difficult to interpret results of curcumin-based studies. (142, 143) In addition, there is increasing evidence that TxM agents cannot be adequately described with reductionist pharmacology models but require consideration of polypharmacology and synergy. (163) The recent recognition of IMPS (4) adds to the uniqueness of natural products by identifying panacea-type substances that establish a new dimension of biological signatures generated by bioactive molecules. Curcumin is not the only potential IMP that has received much attention by the scientific community as a drug lead. Development projects with numerous other prominent plant natural products (e.g., polyphenolics) have experienced similar drawbacks despite major efforts. As shown here for curcumin, the essential medicinal chemistry of natural products that were developed into drugs successfully, and as almost unaltered structures (e.g., artemisinin, camptothecin, taxol, ivermectin, etc.), differs significantly from those of potential IMPS. This orthogonal perspective on the druggability of NPs is further supported by the metabolic feedback hypothesis, (164) which states that bioactivity, especially of many food-borne phytochemicals, can act via weak negative biological feedback mechanisms, escaping in vitro detection and blurring our understanding of mechanisms of action. Collectively, recognition of these factors may remove complicatedness from ongoing research while inspiring the development of out-of-the-box approaches to unraveling the complexity and potential health benefits of turmeric and other NPs.
Supporting Information
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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.6b00975.
Supplemental Tables 1, 2, and 3 of assays, half-lives, and activities, along with a discussion of covalent protein modification by 1 (PDF)
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Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.
Author Information
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Kathryn M. Nelson - Department of Medicinal Chemistry, Institute for Therapeutics Discovery and Development, University of Minnesota, Minneapolis, Minnesota 55414, United States;http://orcid.org/0000-0001-8274-2064
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Guido F. Pauli - Center for Natural Product Technologies, Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, United States; Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, United States;http://orcid.org/0000-0003-1022-4326
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Biographies
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Kathryn M. Nelson
Kathryn M. Nelson is a Research Associate at the Institute for Therapeutics Discovery and Development at the University of Minnesota (UMN) in Minneapolis, MN. She graduated from the UMN College of Pharmacy in 2013, where she received her Ph.D. in Medicinal Chemistry. Her doctoral thesis work focused on the development of novel antitubercular agents and chemical tools for biological target identification. Her current research interests include development of new Alzheimer’s therapeutics, assay development and triage, and the development of new chemical tools for target interrogation.
Jayme L. Dahlin
Jayme L. Dahlin is a Resident Physician in Clinical Pathology at Brigham and Women’s Hospital in Boston, MA. He graduated from the Mayo Clinic Medical Scientist Training Program in 2016, where he received his Ph.D. in Molecular Pharmacology and Experimental Therapeutics from Mayo Graduate School and his M.D. from Mayo Medical School. His doctoral thesis work focused on chemical mechanisms of assay interference in high-throughput screening (HTS) and early drug discovery. His current research interests include HTS and triage, bioassay promiscuity, and assay development.
Jonathan Bisson
Jonathan Bisson obtained an M.S. degree in Structural Biochemistry and started his phytochemistry journey under the mentorship of Dr. Vincent Dumontet at the Institut de Chimie des Substances Naturelles, Gif-sur-Yvette, France. He then obtained a Ph.D. in Science, Technology and Health from the University of Bordeaux, France under the mentorship of Dr. Pierre Waffo-Téguo, specializing in methodology at the chemistry–biology interface. In 2013, he joined the University of Illinois at Chicago, where he is currently a Postdoctoral Research Associate, developing new methods and tools for natural products research in interdisciplinary programs, mainly through data analysis, NMR, and chromatographic approaches related to promiscuous natural products (IMPS). Recently, he has been involved in the redesign of the NAPRALERT database.
James Graham
James Graham received a B.S. in Chemistry in 1994 from the University of Pittsburgh, followed by a Ph.D. in Pharmacognosy in 2001, as a protégé of Norman R. Farnsworth at the University of Illinois at Chicago College of Pharmacy (UIC-COP). Following an NIH postdoctoral fellowship in Miami and a stint as Technical Officer at the World Health Organization in Geneva, he returned to UIC-COP in 2007, where he is currently editor of the NAPRALERT database and Research Associate Professor in the Department of Medicinal Chemistry and Pharmacognosy.
Guido F. Pauli
Guido F. Pauli is a pharmacist with a doctoral degree in Natural Products Chemistry and Pharmacognosy. As Professor and University Scholar at UIC, Chicago (IL), he is PI and collaborator in various interdisciplinary natural-product-centered research projects and Director of the Center for Natural Product Technologies. His research involves metabolome analysis of complex natural products, analytical methodology for bioactive principles, herbal dietary supplements, anti-TB drug discovery, and dental applications of natural agents. His scholarly activities involve the education of the next generation of pharmacognosist, service on pharmacopoeial expert and federal agency panels, and guest professorships. His dissemination portfolio comprises 170+ peer-reviewed journal articles as well as journal coeditorial and board functions.
Michael A. Walters
Michael A. Walters is a Research Associate Professor of Medicinal Chemistry at the University of Minnesota (UMN). He began his academic career in the Department of Chemistry at Dartmouth College and then worked at Parke-Davis and Pfizer. He is currently the Director of the Lead and Probe Discovery Group in the Institute for Therapeutics Discovery and Development at the UMN. This institute serves as a minibiotech for the development of the ideas of biomedical researchers at the UMN and Mayo Clinic. His research interests currently focus on the investigation of compound reactivity as it applies to assay interference mechanisms, the development of Alzheimer’s disease therapeutics, and new compounds to treat heart valve calcification.
Acknowledgment
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J.L.D., J.B., J.G., and G.F.P. acknowledge Dr. Brian Shoichet for helpful discussions. J.B. and G.F.P. acknowledge funding from NCCIH and ODS/NIH through Grant U41AT008706. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The opinions or assertions contained herein belong to the authors and are not necessarily the official views of the funders.
Abbreviations Used
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| AD | Alzheimer’s disease |
| ADMET | absorption, distribution, metabolism, excretion, and toxicology |
| AID | assay identifier |
| CETSA | cellular thermal shift assay |
| CPM | N-[4-(7-diethylamino-4-methylcoumarin-3-yl)phenyl]maleimide |
| DLS | dynamic light scattering |
| DTT | dithiolthreitol |
| FDA | Federal Drug Administration |
| FP | fluorescence polarization |
| GRAS | generally recognized as safe |
| HAT | histone acetyltransferase |
| HDAC | histone deacetylase |
| HPLC | high-performance liquid chromatography |
| HTS | high-throughput screening |
| IC50 | half-maximal inhibitory concentration |
| IMPS | invalid (or improbable) metabolic panaceas |
| ITC | isothermal titration calorimetry |
| LLOD | lower limit of detection |
| ClogP | calculated partition coefficient |
| MLPCN | Molecular Libraries Probe Centers Network |
| MMSE | mini-mental state examination |
| NAPRALERT | natural products alert |
| NP | natural product |
| PAINS | pan assay interference compounds |
| NMR | nuclear magnetic resonance |
| PD | pharmacodynamics |
| PK | pharmacokinetics |
| RDS | radiation dermatitis score |
| RPMI 1640 | Roswell Park Memorial Institute 1640 medium |
| RC | residual complexity |
| SPR | surface plasmon resonance |
| ThT | thioflavin T |
References
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This article references 164 other publications.
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1Yuan, D.; Yang, X.; Guo, J. C. A great honor and a huge challenge for China: You-you tu getting the nobel prize in physiology or medicine J. Zhejiang Univ., Sci., B 2016, 17, 405– 408 DOI: 10.1631/jzus.B1600094Google ScholarThere is no corresponding record for this reference.
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3Baell, J.; Walters, M. A. Chemistry: Chemical con artists foil drug discovery Nature (London, U. K.) 2014, 513, 481– 483 DOI: 10.1038/513481aGoogle Scholar3https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhs1WjsL7M&md5=f5788d81d006460c688e4b78e6200503Chemistry: Chemical con artists foil drug discoveryBaell, Jonathan; Walters, Michael A.Nature (London, United Kingdom) (2014), 513 (7519), 481-483CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)A review. Naivety about promiscuous, assay-duping mols. is polluting the literature and wasting resources, warn Jonathan Baell and Michael A. Walters. Academic drug discoverers must be more vigilant. Mols. that show the strongest activity in screening might not be the best starting points for drugs. PAINS hits should almost always be ignored. Even trained medicinal chemists have to be careful until they become experienced in screening.
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4Bisson, J.; McAlpine, J. B.; Friesen, J. B.; Chen, S.-N.; Graham, J.; Pauli, G. F. Can invalid bioactives undermine natural product-based drug discovery? J. Med. Chem. 2016, 59, 1671– 1690 DOI: 10.1021/acs.jmedchem.5b01009Google Scholar4https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtVChsro%253D&md5=cc3256ccc9a96d61cb9b81bf2a9be9f2Can Invalid Bioactives Undermine Natural Product-Based Drug Discovery?Bisson, Jonathan; McAlpine, James B.; Friesen, J. Brent; Chen, Shao-Nong; Graham, James; Pauli, Guido F.Journal of Medicinal Chemistry (2016), 59 (5), 1671-1690CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)High-throughput biol. has contributed a wealth of data on chems., including natural products (NPs). Recently, attention was drawn to certain, predominantly synthetic, compds. that are responsible for disproportionate percentages of hits but are false actives. Spurious bioassay interference led to their designation as pan-assay interference compds. (PAINS). NPs lack comparable scrutiny, which this study aims to rectify. Systematic mining of 80+ years of the phytochem. and biol. literature, using the NAPRALERT database, revealed that only 39 compds. represent the NPs most reported by occurrence, activity, and distinct activity. Over 50% are not explained by phenomena known for synthetic libraries, and all had manifold ascribed bioactivities, designating them as invalid metabolic panaceas (IMPs). Cumulative distributions of ∼200,000 NPs uncovered that NP research follows power-law characteristics typical for behavioral phenomena. Projection into occurrence-bioactivity-effort space produces the hyperbolic black hole of NPs, where IMPs populate the high-effort base.
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5Burgos-Moron, E.; Calderon-Montano, J. M.; Salvador, J.; Robles, A.; Lopez-Lazaro, M. The dark side of curcumin Int. J. Cancer 2010, 126, 1771– 1775 DOI: 10.1002/ijc.24967Google Scholar5https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtl2itbw%253D&md5=dba8c958325cf5b0b45e888e051c9c04The dark side of curcuminBurgos-Moron, Estefania; Calderon-Montano, Jose Manuel; Salvador, Javier; Robles, Antonio; Lopez-Lazaro, MiguelInternational Journal of Cancer (2010), 126 (7), 1771-1775CODEN: IJCNAW; ISSN:0020-7136. (Wiley-Liss, Inc.)A review, on the therapeutic use and safety of curcumin.
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6Baell, J. B. Feeling nature’s PAINS: Natural products, natural product drugs, and pan assay interference compounds (PAINS) J. Nat. Prod. 2016, 79, 616– 628 DOI: 10.1021/acs.jnatprod.5b00947Google Scholar6https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XivVWktrc%253D&md5=199b040b1f6f3d636521879acae0114dFeeling Nature's PAINS: Natural Products, Natural Product Drugs, and Pan Assay Interference Compounds (PAINS)Baell, Jonathan B.Journal of Natural Products (2016), 79 (3), 616-628CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)We have previously reported on classes of compds. that can interfere with bioassays via a no. of different mechanisms and termed such compds. Pan Assay INterference compds., or PAINS. These compds. were defined on the basis of high-throughput data derived from vendor-supplied synthetics. The question therefore arises whether the concept of PAINS is relevant to compds. of natural origin. Here, it is shown that this is indeed the case, but that the context of the biol. readout is an important factor that must be brought into consideration.
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7Chin, D.; Huebbe, P.; Pallauf, K.; Rimbach, G. Neuroprotective properties of curcumin in Alzheimer’s disease - merits and limitations Curr. Med. Chem. 2013, 20, 3955– 3985 DOI: 10.2174/09298673113209990210Google Scholar7https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsFyms7fP&md5=beaff04bd5c682c35627cb4749ecf389Neuroprotective Properties of Curcumin in Alzheimer's Disease - Merits and LimitationsChin, Dawn; Huebbe, Patricia; Pallauf, Kathrin; Rimbach, GeraldCurrent Medicinal Chemistry (2013), 20 (32), 3955-3985CODEN: CMCHE7; ISSN:0929-8673. (Bentham Science Publishers Ltd.)A review. As demographics in developed nations shift towards an aging population, neurodegenerative pathologies, esp. dementias such as Alzheimer's disease, pose one of the largest challenges to the modern health care system. Since there is yet no cure for dementia, there is great pressure to discover potential therapeutics for these diseases. One popular candidate is curcumin or diferuloylmethane, a polyphenolic compd. that is the main curcuminoid found in Curcuma longa (family Zingiberaceae). In recent years, curcumin has been reported to possess anti-amyloidogenic, antiinflammatory, anti-oxidative, and metal chelating properties that may result in potential neuroprotective effects. Particularly, the hydrophobicity of the curcumin mol. hints at the possibility of blood-brain barrier penetration and accumulation in the brain. However, curcumin exhibits extremely low bioavailability, mainly due to its poor aq. soly., poor stability in soln., and rapid intestinal first-pass and hepatic metab. Despite the many efforts that are currently being made to improve the bioavailability of curcumin, brain concn. of curcumin remains low. Furthermore, although many have reported that curcumin possesses a relatively low toxicity profile, curcumin applied at high doses, which is not uncommon practice in many in vivo and clin. studies, may present certain dangers that in our opinion have not been addressed sufficiently. Herein, the neuroprotective potential of curcumin, with emphasis on Alzheimer's disease, as well as its limitations will be discussed in detail.
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8Glaser, J.; Holzgrabe, U. Focus on PAINS: False friends in the quest for selective anti-protozoal lead structures from nature? MedChemComm 2016, 7, 214– 223 DOI: 10.1039/C5MD00481KGoogle Scholar8https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhvFCrsQ%253D%253D&md5=449fb431ba2964ca31fc19d7b9cbed93Focus on PAINS: false friends in the quest for selective anti-protozoal lead structures from Nature?Glaser, J.; Holzgrabe, U.MedChemComm (2016), 7 (2), 214-223CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)Pan-assay interference compds. (PAINS) are mols. showing promising but deceptive activities in various biochem. screenings mainly due to unselective interactions with the target. Overall awareness of this problem has been raised recently. Many natural products inherently have PAINS characteristics but are nevertheless uncritically acclaimed as new antiprotozoal lead structures. However, a non-selective mode of action may be the cause of obsd. activity. This review describes the most common assay-interfering characteristics of antiprotozoal natural products, discusses significant examples from the recent literature and strategies to deal with these promiscuous structures.
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9Heger, M.; van Golen, R. F.; Broekgaarden, M.; Michel, M. C. The molecular basis for the pharmacokinetics and pharmacodynamics of curcumin and its metabolites in relation to cancers Pharmacol. Rev. 2014, 66, 222– 307 DOI: 10.1124/pr.110.004044Google Scholar9https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsVGnu7fM&md5=519c5283d1a5d0c96421e7a3364cf44eThe molecular basis for the pharmacokinetics and pharmacodynamics of curcumin and its metabolites in relation to cancersHeger, Michal; van Golen, Rowan F.; Broekgaarden, Mans; Michel, Martin C.Pharmacological Reviews (2014), 66 (1), 222-307, 338 pp.CODEN: PAREAQ; ISSN:1521-0081. (American Society for Pharmacology and Experimental Therapeutics)This review addresses the oncopharmacol. properties of curcumin at the mol. level. First, the interactions between curcumin and its mol. targets are addressed on the basis of curcumin's distinct chem. properties, which include H-bond donating and accepting capacity of the β-dicarbonyl moiety and the phenylic hydroxyl groups, H-bond accepting capacity of the methoxy ethers, multivalent metal and nonmetal cation binding properties, high partition coeff., rotamerization around multiple C-C bonds, and the ability to act as a Michael acceptor. Next, the in vitro chem. stability of curcumin is elaborated in the context of its susceptibility to photochem. and chem. modification and degrdn. (e.g., alk. hydrolysis). Specific modification and degradatory pathways are provided, which mainly entail radical-based intermediates, and the in vitro catabolites are identified. The implications of curcumin's (photo) chem. instability are addressed in light of pharmaceutical curcumin prepns., the use of curcumin analogs, and implementation of nanoparticulate drug delivery systems. Furthermore, the pharmacokinetics of curcumin and its most important degrdn. products are detailed in light of curcumin's poor bioavailability. Particular emphasis is placed on xenobiotic phase I and II metab. as well as excretion of curcumin in the intestines (first pass), the liver (second pass), and other organs in addn. to the pharmacokinetics of curcumin metabolites and their systemic clearance. Lastly, a summary is provided of the clin. pharmacodynamics of curcumin followed by a detailed account of curcumin's direct mol. targets, whereby the phenotypical/biol. changes induced in cancer cells upon completion of the curcumin-triggered signaling cascade(s) are addressed in the framework of the hallmarks of cancer. The direct mol. targets include the ErbB family of receptors, protein kinase C, enzymes involved in prostaglandin synthesis, vitamin D receptor, and DNA.
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10Elias, G.; Jacob, P. J.; Hareeshbabu, E.; Mathew, V. B.; Krishnan, B.; Krishnakumar, K. Curcumin: Transforming the spice to a wonder drug Int. J. Pharm. Sci. Res. 2015, 6, 2671– 2680 DOI: 10.13040/IJPSR.0975-8232.6(7).2671-80Google Scholar10https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhs1GnsL3O&md5=0756b8875f65de2e35c1178150c51039Curcumin: transforming the spice to a wonder drugElias, Geetha; Jacob, P. Jaismy; Hareeshbabu, E.; Mathew, V. Baldwin; Krishnan, Bibitha; Krishnakumar, K.International Journal of Pharmaceutical Sciences and Research (2015), 6 (7), 2671-2680CODEN: IJPSTT; ISSN:0975-8232. (International Journal of Pharmaceutical Sciences and Research)A review. Turmeric is a spice obtained from the dried rhizomes of Curcuma longa, family Zingiberaceae. It has been extensively used in traditional Indian (Ayurveda) and Chinese medicine for various ailments such as anti-inflammatory, blood purifier and even as a cosmetic. Curcumin, the chief constituent in turmeric has been isolated centuries ago, has been found to have a wide range of pharmacol. actions such as antioxidant, anti-inflammatory, anticancer, antimicrobial and much more. Thus curcumin and its analogs have immense therapeutic potential for use in rheumatoid arthritis, Crohn's disease, cancer, diabetes, cardiovascular disease, HIV-I and Alzheimer's disease. Phase I clin. studies have shown that high doses of curcumin is well tolerated in man. Despite its safety, curcumin still evades clin. use due to poor bioavailability. Novel formulations of curcumin with piperine, sol. fibers of fenugreek, liposomes, micelles, nanoparticles, cyclodextrin and turmerone have shown enhanced bioavailability to some extent, each one having its own limitations. Recent formulation of curcuminoid with 45% turmerone seems to be promising. Further research in this direction is imperative to realize the clin. use of this promising mol.
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11Neckers, L.; Trepel, J.; Lee, S.; Chung, E.-J.; Lee, M.-J.; Jung, Y.-J.; Marcu, M. G. Curcumin is an inhibitor of p300 histone acetyltransferase Med. Chem. (Sharjah, United Arab Emirates) 2006, 2, 169– 174 DOI: 10.2174/157340606776056133Google Scholar11https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xislyht7w%253D&md5=123a01f4dccf8849f30bd68bbab80024Curcumin is an inhibitor of p300 histone acetyltransferaseMarcu, Monica G.; Jung, Yun-Jin; Lee, Sunmin; Chung, Eun-Joo; Lee, Min-Jung; Trepel, Jane; Neckers, LenMedicinal Chemistry (2006), 2 (2), 169-174CODEN: MCEHAJ; ISSN:1573-4064. (Bentham Science Publishers Ltd.)Histone acetyltransferases (HATs), and p300/CBP in particular, have been implicated in cancer cell growth and survival, and as such, HATs represent novel, therapeutically relevant mol. targets for drug development. In this study, we demonstrate that the small mol. natural product curcumin, whose medicinal properties have long been recognized in India and Southeast Asia, is a selective HAT inhibitor. Furthermore the data indicate that α, β unsatd. carbonyl groups in the curcumin side chain function as Michael reaction sites and that the Michael reaction acceptor functionality of curcumin is required for its HAT-inhibitory activity. In cells, curcumin promoted proteasome-dependent degrdn. of p300 and the closely related CBP protein without affecting the HATs PCAF or GCN5. In addn. to inducing p300 degrdn. curcumin inhibited the acetyltransferase activity of purified p300 as assessed using either histone H3 or p53 as substrate. Radiolabeled curcumin formed a covalent assocn. with p300, and tetrahydrocurcumin displayed no p300 inhibitory activity, consistent with a Michael reaction-dependent mechanism. Finally, curcumin was able to effectively block histone hyperacetylation in both PC3-M prostate cancer cells and peripheral blood lymphocytes induced by the histone deacetylase inhibitor MS-275. These data thus identify the medicinal natural product curcumin as a novel lead compd. for development of possibly therapeutic, p300/CBP-specific HAT inhibitors.
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12Rainey-Smith, S. R.; Brown, B. M.; Sohrabi, H. R.; Shah, T.; Goozee, K. G.; Gupta, V. B.; Martins, R. N. Curcumin and cognition: A randomised, placebo-controlled, double-blind study of community-dwelling older adults Br. J. Nutr. 2016, 115, 2106– 2113 DOI: 10.1017/S0007114516001203Google Scholar12https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtVyiur3J&md5=2b8737b23ff7737c43605c246303f203Curcumin and cognition: a randomised, placebo-controlled, double-blind study of community-dwelling older adultsRainey-Smith, Stephanie R.; Brown, Belinda M.; Sohrabi, Hamid R.; Shah, Tejal; Goozee, Kathryn G.; Gupta, Veer B.; Martins, Ralph N.British Journal of Nutrition (2016), 115 (12), 2106-2113CODEN: BJNUAV; ISSN:0007-1145. (Cambridge University Press)Curcumin therapy in animals has produced pos. cognitive and behavioral outcomes; results of human trials, however, have been inconsistent. In this study, we report the results of a 12-mo, randomized, placebo-controlled, double-blind study that investigated the ability of a curcumin formulation to prevent cognitive decline in a population of community-dwelling older adults. Individuals (n 96) ingested either placebo or 1500 mg/d BiocurcumaxTM for 12 mo. A battery of clin. and cognitive measures was administered at baseline and at the 6-mo and 12-mo follow-up assessments. A significant time×treatment group interaction was obsd. for the Montreal Cognitive Assessment (repeated-measures anal.; time×treatment; F=3·85, P<0·05). Subsequent anal. revealed that this assocn. was driven by a decline in function of the placebo group at 6 mo that was not obsd. in the curcumin treatment group. No differences were obsd. between the groups for all other clin. and cognitive measures. Our findings suggest that further longitudinal assessment is required to investigate changes in cognitive outcome measures, ideally in conjunction with biol. markers of neurodegeneration.
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18Huh, S.; Lee, J.; Jung, E.; Kim, S.-C.; Kang, J.-I.; Lee, J.; Kim, Y.-W.; Sung, Y. K.; Kang, H.-K.; Park, D. A cell-based system for screening hair growth-promoting agents Arch. Dermatol. Res. 2009, 301, 381– 385 DOI: 10.1007/s00403-009-0931-0Google Scholar18https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXmsVOru7w%253D&md5=0ae619cd8cb9f111d91863b722fbef6bA cell-based system for screening hair growth-promoting agentsHuh, Sungran; Lee, Jongsung; Jung, Eunsun; Kim, Sang-Cheol; Kang, Jung-Il; Lee, Jienny; Kim, Yong-Woo; Sung, Young Kwan; Kang, Hee-Kyoung; Park, DeokhoonArchives of Dermatological Research (2009), 301 (5), 381-385CODEN: ADREDL; ISSN:0340-3696. (Springer)Androgen-inducible transforming growth factor β (TGF-β1) derived from dermal papilla cells (DPCs) is a catagen inducer that mediates hair growth suppression in androgenetic alopecia (AGA). In this study, a cell-based assay system was developed to monitor TGF-β1 promoter activity and then used to evaluate the effects of activated TGF-β1 promoter in human epidermal keratinocytes (HaCaT). To accomplish this, a pMetLuc-TGF-β1 promoter plasmid that expresses the luciferase reporter gene in response to TGF-β1 promoter activity was constructed. Treatment of HaCaT with dihydrotestosterone, which is known to be a primary factor of AGA, resulted in a concn.-dependent increase in TGF-β1 promoter activity. However, treatment of HaCaT with the TGF-β1 inhibitor, curcumin, resulted in a concn.-dependant decrease in TGF-β1 expression. Subsequent use of this assay system to screen TGF-β1 revealed that HaCaT that were treated with apigenin showed decreased levels of TGF-β1 expression. In addn., treatment with apigenin also significantly increased the proliferation of both SV40T-DPCs (human DPCs) and HaCaT cells. Furthermore, apigenin stimulated the elongation of hair follicles in a rat vibrissa hair follicle organ culture. Taken together, these findings suggest that apigenin, which is known to have antioxidant, anti-inflammatory, and anti-tumor properties, stimulates hair growth through downregulation of the TGF-β1 gene. In addn., these results suggest that this assay system could be used to quant. measure TGF-β1 promoter activity in HaCaT, thereby facilitating the screening of agents promoting hair growth.
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19Ahluwalia, G. S.; Shander, D.; Styczynski, P. Inhibition of hair growth with protein kinase C inhibitors. WO9609806A2, 1996.Google ScholarThere is no corresponding record for this reference.
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20Jana, S.; Paul, S.; Swarnakar, S. Curcumin as anti-endometriotic agent: Implication of MMP-3 and intrinsic apoptotic pathway Biochem. Pharmacol. (Amsterdam, Neth.) 2012, 83, 797– 804 DOI: 10.1016/j.bcp.2011.12.030Google ScholarThere is no corresponding record for this reference.
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21Naz, R. K.; Lough, M. L. Curcumin as a potential non-steroidal contraceptive with spermicidal and microbicidal properties Eur. J. Obstet. Gynecol. Reprod. Biol. 2014, 176, 142– 148 DOI: 10.1016/j.ejogrb.2014.01.024Google Scholar21https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXltl2ms7k%253D&md5=be6b73ddbb9d17c3b3aba2b213034fa9Curcumin as a potential non-steroidal contraceptive with spermicidal and microbicidal propertiesNaz, R. K.; Lough, M. L.European Journal of Obstetrics & Gynecology and Reproductive Biology (2014), 176 (), 142-148CODEN: EOGRAL; ISSN:0301-2115. (Elsevier Ireland Ltd.)Curcumin, a component of the curry powder turmeric, has immense biol. properties, including anticancer effects. The objective of this study was to det. if curcumin can provide a novel non-steroidal contraceptive having both spermicidal and microbicidal properties. The effect of curcumin, with and without photosensitization, was examd. on human sperm forward motility and growth of several aerobic (n = 8) and anaerobic bacteria (n = 4) and yeast (n = 7) strains implicated in vaginosis, vaginitis, and vaginal infections in women. The effect of various concns. of curcumin on human sperm and microbes (aerobic and anaerobic bacteria and yeast) was tested. The effect on sperm was examd. by counting the sperm forward motility, and on microbes by agar and broth dilns. and colony counting. Each expt. was repeated using different semen specimens, and bacteria and yeast stocks. Curcumin caused a concn.-dependent inhibition of sperm forward motility with a total block at ≥250 μM concn. After photosensitization, the effective concn. to completely block sperm forward motility decreased 25-fold, now requiring only 10 μM concn. for total inhibition. Curcumin concns. between 100 and 500 μM completely blocked the growth of all the bacteria and yeast strains tested. After photosensitization, the effective concn. to completely inhibit microbial growth decreased 10-fold for aerobic bacteria and yeast, and 5-fold for anaerobic bacteria. These findings suggest that curcumin can block sperm function and bacteria/yeast growth. It can potentially provide an ideal non-steroidal contraceptive having both spermicidal and microbicidal properties against vaginal infections.
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22Data pertaining to these claims are easily accessible by any Internet search engine, e.g., https://www.google.com/#q=curcumin+AND+health+benefitsGoogle ScholarThere is no corresponding record for this reference.
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23Goel, A.; Kunnumakkara, A. B.; Aggarwal, B. B. Curcumin as "curecumin": From kitchen to clinic Biochem. Pharmacol. (Amsterdam, Neth.) 2008, 75, 787– 809 DOI: 10.1016/j.bcp.2007.08.016Google ScholarThere is no corresponding record for this reference.
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24Kumar, A.; Chetia, H.; Sharma, S.; Kabiraj, D.; Talukdar, N. C.; Bora, U. Curcumin resource database Database 2015, 2015, bav070 DOI: 10.1093/database/bav070Google ScholarThere is no corresponding record for this reference.
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25Wang, J.; Zhang, C.-J.; Chia, W. N.; Loh, C. C. Y.; Li, Z.; Lee, Y. M.; He, Y.; Yuan, L.-X.; Lim, T. K.; Liu, M.; Liew, C. X.; Lee, Y. Q.; Zhang, J.; Lu, N.; Lim, C. T.; Hua, Z.-C.; Liu, B.; Shen, H.-M.; Tan, K. S. W.; Lin, Q. Haem-activated promiscuous targeting of artemisinin in Plasmodium falciparum Nat. Commun. 2015, 6, 10111 DOI: 10.1038/ncomms10111Google Scholar25https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXitVynsLjO&md5=a532a76cdd2f33b0ca23e733e6247a0cHaem-activated promiscuous targeting of artemisinin in Plasmodium falciparumWang, Jigang; Zhang, Chong-Jing; Chia, Wan Ni; Loh, Cheryl C. Y.; Li, Zhengjun; Lee, Yew Mun; He, Yingke; Yuan, Li-Xia; Lim, Teck Kwang; Liu, Min; Liew, Chin Xia; Lee, Yan Quan; Zhang, Jianbin; Lu, Nianci; Lim, Chwee Teck; Hua, Zi-Chun; Liu, Bin; Shen, Han-Ming; Tan, Kevin S. W.; Lin, QingsongNature Communications (2015), 6 (), 10111CODEN: NCAOBW; ISSN:2041-1723. (Nature Publishing Group)The mechanism of action of artemisinin and its derivs., the most potent of the anti-malarial drugs, is not completely understood. Here we present an unbiased chem. proteomics anal. to directly explore this mechanism in Plasmodium falciparum. We use an alkyne-tagged artemisinin analog coupled with biotin to identify 124 artemisinin covalent binding protein targets, many of which are involved in the essential biol. processes of the parasite. Such a broad targeting spectrum disrupts the biochem. landscape of the parasite and causes its death. Furthermore, using alkyne-tagged artemisinin coupled with a fluorescent dye to monitor protein binding, we show that haem, rather than free ferrous iron, is predominantly responsible for artemisinin activation. The haem derives primarily from the parasite's haem biosynthesis pathway at the early ring stage and from Hb digestion at the latter stages. Our results support a unifying model to explain the action and specificity of artemisinin in parasite killing.
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26Medhi, B.; Patyar, S.; Rao, R. S.; Byrav, D. S. P.; Prakash, A. Pharmacokinetic and toxicological profile of artemisinin compounds: An update Pharmacology 2009, 84, 323– 332 DOI: 10.1159/000252658Google Scholar26https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhsFaqt7nO&md5=005201fe4409b98be94d9c8615ec6859Pharmacokinetic and Toxicological Profile of Artemisinin Compounds: An UpdateMedhi, Bikash; Patyar, Sazal; Rao, Ramya S.; Byrav DS, Prasad; Prakash, AjayPharmacology (2009), 84 (6), 323-332CODEN: PHMGBN; ISSN:0031-7012. (S. Karger AG)A review. Artemisinin has been used effectively in malaria treatment. With the emerging resistance to malaria, the optimum and judicial use of the drug has become important. The drug metab. and toxicol. can have an impact on the therapeutic profile and clin. use of this antimalarial agent. In this review, we discuss the pharmacokinetics and toxicol. aspects of artemisinin and its therapeutic implications. Artemisinins have several dosing routes including oral, i.m., i.v. and rectal. With repeated dosing, artemisinin has propensity for autoinduction, leading to decreased plasma levels on repeated dosing. Combination with other antimalarials in most cases did not influence the pharmacokinetics of artemisinins. Interactions with cytochrome P450 inhibitors are known but these neither affect the efficacy nor the toxicity of the resp. deriv. Artemisinins are generally regarded to be of low toxicity. Two major problems assocd. with them are neurotoxicity and reproductive toxicity. But the extent of this neurotoxicity is dependent on the nature of the compd., on the route of administration, and on the nature of the formulation. Moreover, it occurs in humans at very high doses. However, as a matter of precaution, the use of artemisinins in the first trimester of pregnancy has been contraindicated.
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27Wang, Y.-J.; Pan, M.-H.; Cheng, A.-L.; Lin, L.-I.; Ho, Y.-S.; Hsieh, C.-Y.; Lin, J.-K. Stability of curcumin in buffer solutions and characterization of its degradation products J. Pharm. Biomed. Anal. 1997, 15, 1867– 1876 DOI: 10.1016/S0731-7085(96)02024-9Google Scholar27https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXlvVejtbo%253D&md5=15cd834a8238d9d1f71e5ea74e3d40d5Stability of curcumin in buffer solutions and characterization of its degradation productsWang, Ying-Jan; Pan, Min-Hsiung; Cheng, Ann-Lii; Lin, Liang-In; Ho, Yuan-Soon; Hsieh, Chang-Yao; Lin, Jen-KunJournal of Pharmaceutical and Biomedical Analysis (1997), 15 (12), 1867-1876CODEN: JPBADA; ISSN:0731-7085. (Elsevier)The degrdn. kinetics of curcumin under various pH conditions and the stability of curcumin in physiol. matrixes were investigated. When curcumin was incubated in 0.1 M phosphate buffer and serum-free medium, pH 7.2 at 37°C, about 90% decompd. within 30 min. A series of pH conditions ranging from 3 to 10 were tested and the result showed that decompn. was pH-dependent and occurred faster at neutral-basic conditions. It is more stable in cell culture medium contg. 10% fetal calf serum and in human blood; less than 20% of curcumin decompd. within 1 h, and after incubation for 8 h, about 50% of curcumin is still remained. Trans-6-(4'-hydroxy-3'-methoxyphenyl)-2,4-dioxo-5-hexenal was predicted as major degrdn. product and vanillin, ferulic acid, feruloyl methane were identified as minor degrdn. products. The amt. of vanillin increased with incubation time.
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28Yang, K. Y.; Lin, L. C.; Tseng, T. Y.; Wang, S. C.; Tsai, T. H. Oral bioavailability of curcumin in rat and the herbal analysis from Curcuma longa by LC-MS/MS J. Chromatogr. B: Anal. Technol. Biomed. Life Sci. 2007, 853, 183– 189 DOI: 10.1016/j.jchromb.2007.03.010Google Scholar28https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXmsFKkt74%253D&md5=91dea0673d30e9917a903ba8c984c2e0Oral bioavailability of curcumin in rat and the herbal analysis from Curcuma longa by LC-MS/MSYang, Kuo-Yi; Lin, Lei-Chwen; Tseng, Ting-Yu; Wang, Shau-Chun; Tsai, Tung-HuJournal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences (2007), 853 (1-2), 183-189CODEN: JCBAAI; ISSN:1570-0232. (Elsevier B.V.)This study presents a validated liq. chromatog. technique coupled with tandem mass spectrometry (LC-MS/MS) to measure curcumin in rat plasma and provide curcuminoids anal. from the ext. of Curcumin longa L. This method was applied to investigate the pharmacokinetics of curcumin in a freely moving rat. The analytes were sepd. by a reversed phase C18 column (150 × 4.6 mm I.D., particle size 5 μm) and eluted with acetonitrile-1 mM HCOOH mobile phase (70:30, vol./vol.) with a flow rate of 0.8 mL/min in rat plasma and herbal exts. Multiple reaction monitoring (MRM) was used to monitor the transition of the deprotonated mol. m/z of 367 [M - H]- to the product ion 217 for curcumin, a m/z of 337-217 for demethoxycurcumin and a m/z of 265-224 for honokiol (internal std.) anal. The limit of detection (LOD) and quantification (LOQ) of curcumin in the rat plasma were 1 and 5 ng/mL, resp. The method was linear in the range of 5-1000 ng/mL with a coeff. of correlation greater than 0.996 in the rat plasma. After curcumin (500 mg/kg, p.o.) administration, the max. concn. (C max) and the time to reach max. concn. (T max) were 0.06 ± 0.01 μg/mL and 41.7 ± 5.4 min, resp. The elimination half-life (t 1/2,β) were 28.1 ± 5.6 and 44.5 ± 7.5 min for curcumin (500 mg/kg, p.o.) and curcumin (10 mg/kg, i.v.), resp. The oral bioavailability was about 1%.
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29Chow, S.-C.; Chiu, S.-T. A note on design and analysis of clinical trials Drug Des.: Open Access 2013, 2, 102 DOI: 10.4172/2169-0138.1000102Google ScholarThere is no corresponding record for this reference.
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30National Institutes of Health. NIH RePORTER. Research portfolio online reporting tools. Reports, data, and analysis of NIH research activities. http://projectreporter.nih.gov/reporter.cfm (accessed October 6, 2016) .Google ScholarThere is no corresponding record for this reference.
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31Kuttan, R.; Bhanumathy, P.; Nirmala, K.; George, M. C. Potential anticancer activity of turmeric (Curcuma longa) Cancer Lett. (N. Y., NY, U. S.) 1985, 29, 197– 202 DOI: 10.1016/0304-3835(85)90159-4Google Scholar31https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL28XmtFKmtg%253D%253D&md5=8bcbde767c97604f0d99e296064f718bPotential anticancer activity of turmeric (Curcuma longa)Kuttan, Ramadasan; Bhanumathy, P.; Nirmala, K.; George, M. C.Cancer Letters (Shannon, Ireland) (1985), 29 (2), 197-202CODEN: CALEDQ; ISSN:0304-3835.Anticancer activity of the rhizomes of turmeric was evaluated in vitro using tissue culture methods and in vivo in mice using Dalton's lymphoma cells grown as ascites form. Turmeric ext. inhibited the cell growth in Chinese Hamster Ovary (CHO) cell culture at a concn. of 0.4 mg/mL and was cytotoxic to lymphocytes and Dalton's lymphoma cells at the same concn. Cytotoxic effect was found within 30 min at room temp. The active constituent was found to be curcumin [458-37-7] which showed cytotoxicity to lymphocytes and Dalton's lymphoma cells at a concn. of 4 μg/mL. Initial expts. indicated that turmeric ext. and curcumin reduced the development of animal tumors.
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32Niranjan, A.; Singh, S.; Dhiman, M.; Tewari, S. K. Biochemical composition of Curcuma longa l. Accessions Anal. Lett. 2013, 46, 1069– 1083 DOI: 10.1080/00032719.2012.751541Google Scholar32https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhvVeku7vL&md5=074030903fba86cfb0c939073d2a9dd4Biochemical Composition of Curcuma longa L. AccessionsNiranjan, Abhishek; Singh, Shweta; Dhiman, Manjul; Tewari, S. K.Analytical Letters (2013), 46 (7), 1069-1083CODEN: ANALBP; ISSN:0003-2719. (Taylor & Francis, Inc.)The essential oil compn. and total phenolic content (TPC) of curcuminoids were studied in rhizomes of nine Curcuma longa L. accessions. Curcuminoids, present in com. available turmeric rhizomes, play vital roles in various pharmacol. activities. A simple, rapid, and sensitive high performance liq. chromatog. photodiode array (HPLC-PDA) method was optimized for simultaneous detn. of curcuminoids, namely, a mixt. of curcumin, demethoxy curcumin (DMC), and bisdemethoxy curcumin (BDMC) in rhizomes of C. longa. Chromatog. sepn. was performed on an RP C18 column within 13 min (11.4 to 12.95 min). Elution was accomplished by the application of acetonitrile and 1.5% acetic acid in water in a gradient system with flow rate of 2.0 mL min-1. PDA was employed for qual. and quant. anal. The calibration curves were found linear (0.99) for all cucuminoids; the limit of detection and quantification ranged between 1.01 μ g mL-1 to 1.16 μ g mL-1 and 2.30 μ g mL-1 to 3.05 μ g mL-1, resp., while recovery values ranged between 97.97% to 98.32%. The amt. of curcumin varied from 0.46% to 2.17%, DMC from 0.13% to 0.92% and BDMC from 0.06% to 0.52%. The validated method was successively used to det. the above compds. in C. longa rhizomes. The TPC in rhizomes ranged from 14.12 mg g-1 to 27.72 mg g-1. The chem. compn. of rhizome essential oil, analyzed by gas chromatog. mass spectrometry (GCMS) showed large variations in major compds. like ar-tumerone (7.31-38.66%), β-curcumene (1.58-24.53%), and curlone (1.55-15.97%).
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33Priyadarsini, K. I. The chemistry of curcumin: From extraction to therapeutic agent Molecules 2014, 19, 20091– 20112 DOI: 10.3390/molecules191220091Google Scholar33https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitFOksLzE&md5=905dd120d7b649acf106858f980af304The chemistry of curcumin: from extraction to therapeutic agentPriyadarsini, Kavirayani IndiraMolecules (2014), 19 (12), 20091-20112, 22 pp.CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)A review. Curcumin, a pigment from turmeric, is one of the very few promising natural products that has been extensively investigated by researchers from both the biol. and chem. point of view. While there are several reviews on the biol. and pharmacol. effects of curcumin, chem. reviews are comparatively scarcer. In this article, an overview of different aspects of the unique chem. research on curcumin will be discussed. These include methods for the extn. from turmeric, lab. synthesis methods, chem. and photochem. degrdn. and the chem. behind its metab. Addnl. other chem. reactions that have biol. relevance like nucleophilic addn. reactions, and metal chelation will be discussed. Recent advances in the prepn. of new curcumin nanoconjugates with metal and metal oxide nanoparticles will also be mentioned. Directions for future investigations to be undertaken in the chem. of curcumin have also been suggested.
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34Food and Drug Administration Office of Food Additive Safety. Agency Response Letter GRAS Notice No. Grn 000460. U.S. Food and Drug Administration, 2013.Google ScholarThere is no corresponding record for this reference.
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35Majeed, S. The state of the curcumin market. Natural Products Insider; Informa Exhibitions, 2015; http://www.naturalproductsinsider.com/articles/2015/12/the-state-of-the-curcumin-market.aspx.Google ScholarThere is no corresponding record for this reference.
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36Niranjan, A.; Prakash, D. Chemical constituents and biological activities of turmeric (Curcuma longa l.) - a review J. Food Sci. Technol. (New Delhi, India) 2008, 45, 109– 116Google ScholarThere is no corresponding record for this reference.
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37Panahi, Y.; Hosseini, M. S.; Khalili, N.; Naimi, E.; Majeed, M.; Sahebkar, A. Antioxidant and anti-inflammatory effects of curcuminoid-piperine combination in subjects with metabolic syndrome: A randomized controlled trial and an updated meta-analysis Clin. Nutr. 2015, 34, 1101– 1108 DOI: 10.1016/j.clnu.2014.12.019Google Scholar37https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXosFGqsA%253D%253D&md5=ab3ebfedd8e61e8516196e53653f0522Antioxidant and anti-inflammatory effects of curcuminoid-piperine combination in subjects with metabolic syndrome: A randomized controlled trial and an updated meta-analysisPanahi, Yunes; Hosseini, Mahboobeh Sadat; Khalili, Nahid; Naimi, Effat; Majeed, Muhammed; Sahebkar, AmirhosseinClinical Nutrition (2015), 34 (6), 1101-1108CODEN: CLNUDP; ISSN:0261-5614. (Elsevier Ltd.)Oxidative stress and inflammation have been proposed as emerging components of metabolic syndrome (MetS). Curcuminoids are natural polyphenols with strong antioxidant and anti-inflammatory properties. To study the effectiveness of supplementation with a bioavailable curcuminoid prepn. on measures of oxidative stress and inflammation in patients with MetS. Our secondary aim was to perform a meta-anal. of data from all randomized controlled trials in order to est. the effect size of curcuminoids on plasma C-reactive protein (CRP) concns. In this randomized double-blind placebo-controlled trial, 117 subjects with MetS (according to the NCEP-ATPIII diagnostic criteria) were randomly assigned to curcuminoids (n = 59; drop-outs = 9) or placebo (n = 58; drop-outs = 8) for eight weeks. Curcuminoids were administered at a daily dose of 1 g, and were co-supplemented with piperine (10 mg/day) in order to boost oral bioavailability. Serum activities of superoxide dismutase (SOD) and concns. of malondialdehyde (MDA) and CRP were measured at baseline and at study end. Regarding the importance of CRP as a risk marker and risk factor of cardiovascular disease, a random-effects meta-anal. of clin. trials was performed to est. the overall impact of curcuminoid therapy on circulating concns. of CRP. The robustness of estd. effect size was evaluated using leave-one-out sensitivity anal. Supplementation with curcuminoid-piperine combination significantly improved serum SOD activities (p < 0.001) and reduced MDA (p < 0.001) and CRP (p < 0.001) concns. compared with placebo. Quant. data synthesis revealed a significant effect of curcuminoids vs. placebo in reducing circulating CRP concns. (weighed mean difference: -2.20 mg/L; 95% confidence interval [CI]: -3.96, -0.44; p = 0.01). This effect was robust in sensitivity anal. Short-term supplementation with curcuminoid-piperine combination significantly improves oxidative and inflammatory status in patients with MetS. Curcuminoids could be regarded as natural, safe and effective CRP-lowering agents.
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38Yue, G. G.; Chan, B. C.; Hon, P. M.; Lee, M. Y.; Fung, K. P.; Leung, P. C.; Lau, C. B. Evaluation of in vitro anti-proliferative and immunomodulatory activities of compounds isolated from Curcuma longa Food Chem. Toxicol. 2010, 48, 2011– 2020 DOI: 10.1016/j.fct.2010.04.039Google Scholar38https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXptlGiurs%253D&md5=cdbd6f10972ac4a0067941309fc758aeEvaluation of in vitro anti-proliferative and immunomodulatory activities of compounds isolated from Curcuma longaYue, Grace G. L.; Chan, Ben C. L.; Hon, Po-Ming; Lee, Mavis Y. H.; Fung, Kwok-Pui; Leung, Ping-Chung; Lau, Clara B. S.Food and Chemical Toxicology (2010), 48 (8-9), 2011-2020CODEN: FCTOD7; ISSN:0278-6915. (Elsevier Ltd.)The rhizome of Curcuma longa (CL) has been commonly used in Asia as a potential candidate for the treatment of different diseases, including inflammatory disorders and cancers. The present study evaluated the anti-proliferative activities of the isolated compds. (three curcuminoids and two turmerones) from CL, using human cancer cell lines HepG2, MCF-7 and MDA-MB-231. The immunomodulatory activities of turmerones (α and arom.) isolated from CL were also examd. using human peripheral blood mononuclear cells (PBMC). Our results showed that the curcuminoids (curcumin, demethoxycurcumin and bisdemethoxycurcumin) and α-turmerone significantly inhibited proliferation of cancer cells in dose-dependent manner. The IC50 values of these compds. in cancer cells ranged from 11.0 to 41.8 μg/mL. α-Turmerone induced MDA-MB-231 cells to undergo apoptosis, which was confirmed by annexin-V and propidium iodide staining, and DNA fragmentation assay. The caspase cascade was activated as shown by a significant decrease of procaspases-3, -8 and -9 in α-turmerone treated cells. Both α-turmerone and arom.-turmerone showed stimulatory effects on PBMC proliferation and cytokine prodn. The anti-proliferative effect of α-turmerone and immunomodulatory activities of ar-turmerone was shown for the first time. The findings revealed the potential use of CL crude ext. (contg. curcuminoids and volatile oil including turmerones) as chemopreventive agent.
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39Hu, S.; Maiti, P.; Ma, Q.; Zuo, X.; Jones, M. R.; Cole, G. M.; Frautschy, S. A. Clinical development of curcumin in neurodegenerative disease Expert Rev. Neurother. 2015, 15, 629– 637 DOI: 10.1586/14737175.2015.1044981Google Scholar39https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXpt1Kmsbw%253D&md5=463b61b79a9c1f33b39cb7a066ec4dd5Clinical development of curcumin in neurodegenerative diseaseHu, Shuxin; Maiti, Panchanan; Ma, Qiulan; Zuo, Xiaohong; Jones, Mychica R.; Cole, Greg M.; Frautschy, Sally A.Expert Review of Neurotherapeutics (2015), 15 (6), 629-637CODEN: ERNXAR; ISSN:1473-7175. (Informa Healthcare)A review. Curcumin, a polyphenolic antioxidant derived from the turmeric root has undergone extensive preclin. development, showing remarkable efficacy in wound repair, cancer and inflammatory disorders. This review addresses the rationale for its use in neurodegenerative disease, particularly Alzheimer's disease. Curcumin is a pleiotropic mol., which not only directly binds to and limits aggregation of the β-sheet conformations of amyloid characteristic of many neurodegenerative diseases but also restores homeostasis of the inflammatory system, boosts the heat shock system to enhance clearance of toxic aggregates, scavenges free radicals, chelates iron and induces anti-oxidant response elements. Although curcumin corrects dysregulation of multiple pathways, it may exert many effects via a few mol. targets. Pharmaceutical development of natural compds. like curcumin and synthetic derivs. have strong scientific rationale, but will require overcoming various hurdles including; high cost of trials, concern about profitability and misconceptions about drug specificity, stability, and bioavailability.
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40Baell, J. B.; Holloway, G. A. New substructure filters for removal of pan assay interference compounds (PAINS) from screening libraries and for their exclusion in bioassays J. Med. Chem. 2010, 53, 2719– 2740 DOI: 10.1021/jm901137jGoogle Scholar40https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhsF2qsLw%253D&md5=fbf397aa4910753c550425708c866fd2New Substructure Filters for Removal of Pan Assay Interference Compounds (PAINS) from Screening Libraries and for Their Exclusion in BioassaysBaell, Jonathan B.; Holloway, Georgina A.Journal of Medicinal Chemistry (2010), 53 (7), 2719-2740CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)This report describes a no. of substructural features which can help to identify compds. that appear as frequent hitters (promiscuous compds.) in many biochem. high throughput screens. The compds. identified by such substructural features are not recognized by filters commonly used to identify reactive compds. Even though these substructural features were identified using only one assay detection technol., such compds. have been reported to be active from many different assays. In fact, these compds. are increasingly prevalent in the literature as potential starting points for further exploration, whereas they may not be.
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41Fang, J.; Lu, J.; Holmgren, A. Thioredoxin reductase is irreversibly modified by curcumin: A novel molecular mechanism for its anticancer activity J. Biol. Chem. 2005, 280, 25284– 25290 DOI: 10.1074/jbc.M414645200Google Scholar41https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXlsFyqtbw%253D&md5=373d0ddf866fdab1c60f811c75a200d7Thioredoxin Reductase Is Irreversibly Modified by Curcumin: a novel molecular mechanism for its anticancer activityFang, Jianguo; Lu, Jun; Holmgren, ArneJournal of Biological Chemistry (2005), 280 (26), 25284-25290CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)The thioredoxin reductase (TrxR) isoenzymes, TrxR1 in cytosol or nucleus and TrxR2 in mitochondria, are essential mammalian selenocysteine (Sec)-contg. flavoenzymes with a -Gly-Cys-Sec-Gly active site. TrxRs are the only enzymes catalyzing the NADPH-dependent redn. of the active site disulfide in thioredoxins (Trxs), which play essential roles in substrate redns., defense against oxidative stress, and redox regulation by thiol redox control. TrxRs have been found to be overexpressed by a no. of human tumors. Curcumin, which is consumed daily by millions of people, is a polyphenol derived from the plant Curcuma longa. This phytochem. has well known anticancer and antiangiogenic properties. In this study we report that rat TrxR1 activity in Trx-dependent disulfide redn. was inhibited by curcumin. The IC50 value for the enzyme was 3.6 μM after incubation at room temp. for 2 h in vitro. The inhibition occurred with enzyme only in the presence of NADPH and persisted after removal of curcumin. By using mass spectrometry and blotting anal., we proved that this irreversible inhibition by curcumin was caused by alkylation of both residues in the catalytically active site (Cys496/Sec497) of the enzyme. However, the curcumin-modified enzyme showed a strongly induced NADPH oxidase activity to produce reactive oxygen species. Inhibition of TrxR by curcumin added to cultured HeLa cells was also obsd. with an IC50 of around 15 μM. Modification of TrxR by curcumin provides a possible mechanistic explanation for its cancer preventive activity, shifting the enzyme from an antioxidant to a prooxidant.
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42Jurrmann, N.; Birgelius-Flohe, R.; Boel, G.-F. Curcumin blocks interleukin-1 (IL-1) signaling by inhibiting the recruitment of the IL-1 receptor-associated kinase IRAK in murine thymoma EL-4 cells J. Nutr. 2005, 135, 1859– 1864Google Scholar42https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXnvVSmtbw%253D&md5=4f1d09035024b3143e88516145eed14eCurcumin blocks interleukin-1 (IL-1) signaling by inhibiting the recruitment of the IL-1 receptor-associated kinase IRAK in murine thymoma EL-4 cellsJurrmann, Nadine; Birgelius-Flohe, Regina; Boel, Gaby-FleurJournal of Nutrition (2005), 135 (8), 1859-1864CODEN: JONUAI; ISSN:0022-3166. (American Society for Nutritional Sciences)Curcumin is a dietary compd. with diverse anti-inflammatory and anticarcinogenic effects in several exptl. models. A mechanism by which curcumin exerts these actions might be the direct modification of protein thiols, thereby altering the activity of the affected proteins. An early event in inflammatory signaling cascades is the recruitment of the interleukin-1 (IL-1) receptor-assocd. kinase (IRAK) to the IL-1 receptor (IL-1RI) upon stimulation with IL-1. IRAK recruitment was shown recently to be inhibited by agents that modify thiols of IRAK. We asked, therefore, whether IRAK is also a target for curcumin. Curcumin indeed blocked IRAK thiols in a murine T-cell line stably overexpressing IRAK (EL-4IRAK), which resulted in the inhibition of IRAK recruitment to the IL-1RI and phosphorylation of IRAK and IL-1RI-assocd. proteins. Inhibitory effects were not reversible by thiol-reducing agents. Thus, modification by curcumin did not occur by oxidn. but rather by alkylation, as is typical for electrophilic compds. reacting as Michael addn. acceptors. The block in one of the earliest events in the IL-1 signaling cascade can explain the often obsd. inhibition of IL-1-mediated signaling steps by curcumin further downstream. Hence, thiol modification might be a crucial step in the anti-inflammatory functions of curcumin.
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43Jung, Y.; Xu, W.; Kim, H.; Ha, N.; Neckers, L. Curcumin-induced degradation of ErbB2: A role for the E3 ubiquitin ligase CHIP and the Michael reaction acceptor activity of curcumin Biochim. Biophys. Acta, Mol. Cell Res. 2007, 1773, 383– 390 DOI: 10.1016/j.bbamcr.2006.11.004Google Scholar43https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXitFOhs7g%253D&md5=f683d493b87afaad168bc86c7d90c319Curcumin-induced degradation of ErbB2: A role for the E3 ubiquitin ligase CHIP and the Michael reaction acceptor activity of curcuminJung, Yunjin; Xu, Wanping; Kim, Heejung; Ha, Namchul; Neckers, LenBiochimica et Biophysica Acta, Molecular Cell Research (2007), 1773 (3), 383-390CODEN: BBAMCO; ISSN:0167-4889. (Elsevier Ltd.)We investigated the mol. mechanism underlying curcumin depletion of ErbB2 protein. Curcumin induced ErbB2 ubiquitination but pretreatment with proteasome inhibitors neither prevented curcumin depletion of ErbB2 protein nor further accumulated ubiquitinated ErbB2. Curcumin increased assocn. of endogenous and ectopically expressed CHIP, a chaperone-dependent ubiquitin ligase, with ErbB2. In COS7 cells cotransfected with ErbB2 and various CHIP plasmids followed by curcumin treatment, CHIP-H260Q (a mutant lacking ubiquitin ligase activity) promoted less curcumin-induced ErbB2 ubiquitination than did wild type CHIP, and CHIP-K30A (a mutant incapable of binding Hsp90 and Hsp70) neither assocd. with ErbB2 nor promoted its ubiquitination. ErbB2 mutants lacking the kinase domain failed to assoc. with CHIP and were completely resistant to ubiquitination and depletion induced by curcumin. Finally, curcumin's Michael reaction acceptor functionality was required for both covalent assocn. of curcumin with ErbB2 and curcumin-mediated ErbB2 depletion. These data suggest (1) that CHIP-dependent ErbB2 ubiquitination is implicated in curcumin-stimulated ErbB2 depletion, and (2) that covalent modification of ErbB2 by curcumin is the proximal signal which initiates this process.
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44Chin, D.; Huebbe, P.; Frank, J.; Rimbach, G.; Pallauf, K. Curcumin may impair iron status when fed to mice for six months Redox Biol. 2014, 2, 563– 569 DOI: 10.1016/j.redox.2014.01.018Google Scholar44https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXht1Kqt7nL&md5=341aef7f9099bc467e28d37266d50f97Curcumin may impair iron status when fed to mice for six monthsChin, Dawn; Huebbe, Patricia; Frank, Jan; Rimbach, Gerald; Pallauf, KathrinRedox Biology (2014), 2 (), 563-569CODEN: RBEIB3; ISSN:2213-2317. (Elsevier B.V.)Curcumin has been shown to have many potentially health beneficial properties in vitro and in animal models with clin. studies on the toxicity of curcumin reporting no major side effects. However, curcumin may chelate dietary trace elements and could thus potentially exert adverse effects. Here, we investigated the effects of a 6 mo dietary supplementation with 0.2% curcumin on iron, zinc, and copper status in C57BL/6J mice. Compared to non-supplemented control mice, we obsd. a significant redn. in iron, but not zinc and copper stores, in the liver and the spleen, as well as strongly suppressed liver hepcidin and ferritin expression in the curcumin-supplemented mice. The expression of the iron-importing transport proteins divalent metal transporter 1 and transferrin receptor 1 was induced, while hepatic and splenic inflammatory markers were not affected in the curcumin-fed mice. The mRNA expression of other putative target genes of curcumin, including the nuclear factor (erythroid-derived 2)-like 2 and haem oxygenase 1 did not differ between the groups. Most of the published animal trials with curcumin-feeding have not reported adverse effects on iron status or the spleen. However, it is possible that long-term curcumin supplementation and a Western-type diet may aggravate iron deficiency. Therefore, our findings show that further studies are needed to evaluate the effect of curcumin supplementation on iron status.
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45Schneider, C.; Gordon, O. N.; Edwards, R. L.; Luis, P. B. Degradation of curcumin: From mechanism to biological implications J. Agric. Food Chem. 2015, 63, 7606– 7614 DOI: 10.1021/acs.jafc.5b00244Google Scholar45https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXlsVShtbk%253D&md5=aa5e9f46a4065b3ec8d86b19cb95538dDegradation of Curcumin: From Mechanism to Biological ImplicationsSchneider, Claus; Gordon, Odaine N.; Edwards, Rebecca L.; Luis, Paula B.Journal of Agricultural and Food Chemistry (2015), 63 (35), 7606-7614CODEN: JAFCAU; ISSN:0021-8561. (American Chemical Society)Curcumin is the main bioactive ingredient in turmeric ext. and widely consumed as part of the spice mix curry or as a dietary supplement. Turmeric has a long history of therapeutic application in traditional Asian medicine. Biomedical studies conducted in the past two decades have identified a large no. of cellular targets and effects of curcumin. In vitro curcumin rapidly degrades in an autoxidative transformation to diverse chem. species, the formation of which has only recently been appreciated. This paper discusses how the degrdn. and metab. of curcumin, through products and their mechanism of formation, provide a basis for the interpretation of preclin. data and clin. studies. It is suggested that the previously unrecognized diversity of its degrdn. products could be an important factor in explaining the polypharmacol. of curcumin.
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46Duan, D.; Doak, A. K.; Nedyalkova, L.; Shoichet, B. K. Colloidal aggregation and the in vitro activity of traditional Chinese medicines ACS Chem. Biol. 2015, 10, 978– 988 DOI: 10.1021/cb5009487Google Scholar46https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtFCntLg%253D&md5=04d107e8f0350ca38afd0131c4322fe6Colloidal Aggregation and the in Vitro Activity of Traditional Chinese MedicinesDuan, Da; Doak, Allison K.; Nedyalkova, Lyudmila; Shoichet, Brian K.ACS Chemical Biology (2015), 10 (4), 978-988CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)Traditional Chinese Medicines (TCMs) have been the sole source of therapeutics in China for two millennia. In recent drug discovery efforts, purified components of TCM formulations have shown activity in many in vitro assays, raising concerns of promiscuity. Here, we investigated 14 bioactive small mols. isolated from TCMs for colloidal aggregation. At concns. commonly used in cell-based or biochem. assay conditions, eight of these compds. formed particles detectable by dynamic light scattering and showed detergent-reversible inhibition against β-lactamase and malate dehydrogenase, two counter-screening enzymes. When three of these compds. were tested against their literature-reported mol. targets, they showed similar reversal of their inhibitory activity in the presence of detergent. For three of the most potent aggregators, contributions to promiscuity via oxidative cycling were investigated; addn. of 1 mM DTT had no effect on their activity, which is inconsistent with an oxidative mechanism. TCMs are often active at micromolar concns.; this study suggests that care must be taken to control for artifactual activity when seeking their primary targets. Implications for the formulation of these mols. are considered.
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47Ingolfsson, H. I.; Thakur, P.; Herold, K. F.; Hobart, E. A.; Ramsey, N. B.; Periole, X.; de Jong, D. H.; Zwama, M.; Yilmaz, D.; Hall, K.; Maretzky, T.; Hemmings, H. C., Jr.; Blobel, C.; Marrink, S. J.; Kocer, A.; Sack, J. T.; Andersen, O. S. Phytochemicals perturb membranes and promiscuously alter protein function ACS Chem. Biol. 2014, 9, 1788– 1798 DOI: 10.1021/cb500086eGoogle Scholar47https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXptlyqt7s%253D&md5=b61876239e926b652adea2e130627bc3Phytochemicals Perturb Membranes and Promiscuously Alter Protein FunctionIngolfsson, Helgi I.; Thakur, Pratima; Herold, Karl F.; Hobart, E. Ashley; Ramsey, Nicole B.; Periole, Xavier; de Jong, Djurre H.; Zwama, Martijn; Yilmaz, Duygu; Hall, Katherine; Maretzky, Thorsten; Hemmings, Hugh C.; Blobel, Carl; Marrink, Siewert J.; Kocer, Armagan; Sack, Jon T.; Andersen, Olaf S.ACS Chemical Biology (2014), 9 (8), 1788-1798CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)A wide variety of phytochems. are consumed for their perceived health benefits. Many of these phytochems. have been found to alter numerous cell functions, but the mechanisms underlying their biol. activity tend to be poorly understood. Phenolic phytochems. are particularly promiscuous modifiers of membrane protein function, suggesting that some of their actions may be due to a common, membrane bilayer-mediated mechanism. To test whether bilayer perturbation may underlie this diversity of actions, we examd. five bioactive phenols reported to have medicinal value: capsaicin from chili peppers, curcumin from turmeric, EGCG from green tea, genistein from soybeans, and resveratrol from grapes. We find that each of these widely consumed phytochems. alters lipid bilayer properties and the function of diverse membrane proteins. Mol. dynamics simulations show that these phytochems. modify bilayer properties by localizing to the bilayer/soln. interface. Bilayer-modifying propensity was verified using a gramicidin-based assay, and indiscriminate modulation of membrane protein function was demonstrated using four proteins: membrane-anchored metalloproteases, mechanosensitive ion channels, and voltage-dependent potassium and sodium channels. Each protein exhibited similar responses to multiple phytochems., consistent with a common, bilayer-mediated mechanism. Our results suggest that many effects of amphiphilic phytochems. are due to cell membrane perturbations, rather than specific protein binding.
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48Priyadarsini, K. I. Photophysics, photochemistry and photobiology of curcumin: Studies from organic solutions, bio-mimetics and living cells J. Photochem. Photobiol., C 2009, 10, 81– 95 DOI: 10.1016/j.jphotochemrev.2009.05.001Google Scholar48https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXptlektL8%253D&md5=1356fe80bacb33742766c7fad061a991Photophysics, photochemistry and photobiology of curcumin: Studies from organic solutions, bio-mimetics and living cellsPriyadarsini, K. IndiraJournal of Photochemistry and Photobiology, C: Photochemistry Reviews (2009), 10 (2), 81-95CODEN: JPPCAF; ISSN:1389-5567. (Elsevier B.V.)A review. Curcumin, with its recent success as an antitumor agent, has been attracting researchers from wide ranging fields of physics, chem., biol. and medicine. The chem. structure of curcumin has two o-methoxy phenols attached sym. through α,β-unsatd. β-diketone linker, which also induces keto-enol tautomerism. Due to this, curcumin exhibits many interesting photophys. and photochem. properties. The absorption max. of curcumin is ∼408-430 nm in most of the org. solvents, while the emission max. is very sensitive to the surrounding solvent medium (460-560 nm) and the Stokes' shift varied from 2000 to 6000 cm-1. The fluorescence quantum yield in most of the solvents is low and reduced significantly in presence of water. The fluorescence lifetime is short (<1 ns) and displayed multi-exponential decay profile. The singlet excited states of curcumin decay by non-radiative processes contributed mainly by intra- and intermol. proton transfer with very low intersystem crossing efficiency. Polarity, π-bonding nature, hydrogen bond donating and accepting properties of the solvent influence the excited state photophysics of curcumin in a complex manner. The triplet excited states of curcumin absorb at 720 nm and react with oxygen to produce singlet mol. oxygen. The photodegrdn. of curcumin produces smaller phenols and the photobiol. activity of curcumin is due to the generation of reactive oxygen species. Being lipophilic in nature, the water soly. of curcumin could be enhanced upon the addn. of surfactants, polymers, cyclodextrins, lipids and proteins. Changes in the absorption and fluorescence properties of curcumin have been found useful to follow its interaction and site of binding in these systems. Curcumin fluorescence could be employed to follow the unfolding pattern and structural changes in proteins. The intracellular curcumin showed more fluorescence in tumor cells than in normal cells and fluorescence spectroscopy could be used to monitor its preferential localization in the membrane of tumor cells. This review, presents the current status of research on the photophys., photochem. and photobiol. processes of curcumin in homogeneous solns., bio-mimetics and living cells. Based on these studies, the possibility of developing curcumin, as a bimol. sensitive fluorescent probe is also discussed.
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49Esatbeyoglu, T.; Ulbrich, K.; Rehberg, C.; Rohn, S.; Rimbach, G. Thermal stability, antioxidant, and anti-inflammatory activity of curcumin and its degradation product 4-vinyl guaiacol Food Funct. 2015, 6, 887– 893 DOI: 10.1039/C4FO00790EGoogle Scholar49https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXotVKhsA%253D%253D&md5=1a16da1ec4ac5e7b7a5e351ad8f274dbThermal stability, antioxidant, and anti-inflammatory activity of curcumin and its degradation product 4-vinyl guaiacolEsatbeyoglu, Tuba; Ulbrich, Katrin; Rehberg, Clemens; Rohn, Sascha; Rimbach, GeraldFood & Function (2015), 6 (3), 887-893CODEN: FFOUAI; ISSN:2042-6496. (Royal Society of Chemistry)Curcumin is a secondary plant metabolite present in Curcuma longa L. Since curcumin is widely used as a food colorant in thermally processed food it may undergo substantial chem. changes which in turn could affect its biol. activity. In the current study, curcumin was roasted at 180 °C up to 70 min and its kinetic of degrdn. was analyzed by means of HPLC-PDA and LC-MS, resp. Roasting of curcumin resulted in the formation of the degrdn. products vanillin, ferulic acid, and 4-vinyl guaiacol. In cultured hepatocytes roasted curcumin as well as 4-vinyl guaiacol enhanced the transactivation of the redox-regulated transcription factor Nrf2, known to be centrally involved in cellular stress response and antioxidant defense mechanisms. The antioxidant enzyme paraoxonase 1 was induced by roasted curcumin and 4-vinyl guaiacol. Furthermore, roasted curcumin and 4-vinyl guaiacol decreased interleukin-6 gene expression in lipopolysaccharide stimulated murine macrophages. Current data suggest that curcumin undergoes degrdn. due to roasting and its degrdn. product exhibit significant biol. activity in cultured cells.
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50Avonto, C.; Taglialatela-Scafati, O.; Pollastro, F.; Minassi, A.; Di Marzo, V.; De Petrocellis, L.; Appendino, G. An NMR spectroscopic method to identify and classify thiol-trapping agents: Revival of Michael acceptors for drug discovery? Angew. Chem., Int. Ed. 2011, 50, 467– 471 DOI: 10.1002/anie.201005959Google Scholar50https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXitlGiuw%253D%253D&md5=8fd61bce5e0dfeb9209a6572516fd583An NMR Spectroscopic Method to Identify and Classify Thiol-Trapping Agents: Revival of Michael Acceptors for Drug Discovery?Avonto, Cristina; Taglialatela-Scafati, Orazio; Pollastro, Federica; Minassi, Alberto; Di Marzo, Vincenzo; De Petrocellis, Luciano; Appendino, GiovanniAngewandte Chemie, International Edition (2011), 50 (2), 467-471, S467/1-S467/30CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)We have developed a simple and quick NMR spectroscopic method to identify Michael acceptor sites in complex multifunctional compds. The method sorts them out in reversible and irreversible thiol sinks, and predicts their potential to modify proteins, as validated by the identification of several new chemotypes of TRPA1 activators. These include well-known anti-inflammatory agents, such as curcumin and parthenolide, which had been overlooked as ligands for this druggable end point of inflammation.
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51Pauli, G. F.; Chen, S. N.; Friesen, J. B.; McAlpine, J. B.; Jaki, B. U. Analysis and purification of bioactive natural products: The AnaPurNa study J. Nat. Prod. 2012, 75, 1243– 1255 DOI: 10.1021/np300066qGoogle Scholar51https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XnsVeru70%253D&md5=15d145c2988692d26558d6d4361337d9Analysis and Purification of Bioactive Natural Products: The AnaPurNa StudyPauli, Guido F.; Chen, Shao-Nong; Friesen, J. Brent; McAlpine, James B.; Jaki, Birgit U.Journal of Natural Products (2012), 75 (6), 1243-1255CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)A review on the survey of anal. methodol. such as chromatog. and spectroscopy used for isolation and purity assessment of bioactive natural products (NPs), which have been employed in the almost 2000 publications in the recent years.
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52Simmler, C.; Hajirahimkhan, A.; Lankin, D. C.; Bolton, J. L.; Jones, T.; Soejarto, D. D.; Chen, S. N.; Pauli, G. F. Dynamic residual complexity of the isoliquiritigenin-liquiritigenin interconversion during bioassay J. Agric. Food Chem. 2013, 61, 2146– 2157 DOI: 10.1021/jf304445pGoogle Scholar52https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXivFCgtrk%253D&md5=3e1d3de79750615a80d04164d8f6c429Dynamic Residual Complexity of the Isoliquiritigenin-Liquiritigenin Interconversion During BioassaySimmler, Charlotte; Hajirahimkhan, Atieh; Lankin, David C.; Bolton, Judy L.; Jones, Tristesse; Soejarto, Djaja D.; Chen, Shao-Nong; Pauli, Guido F.Journal of Agricultural and Food Chemistry (2013), 61 (9), 2146-2157CODEN: JAFCAU; ISSN:0021-8561. (American Chemical Society)Bioactive components in food plants can undergo dynamic processes that involve multiple chem. species. For example, 2'-hydroxychalcones can readily isomerize into flavanones. Although chem. well documented, this reaction has barely been explored in the context of cell-based assays. The present time-resolved study fills this gap by investigating the isomerization of isoliquiritigenin (a 2'-hydroxychalcone) and liquiritigenin (a flavanone) in two culture media (Dulbecco's modified eagle medium and Roswell Park Memorial Institute medium) with and without MCF-7 cells, using high-performance liq. chromatog.-diode array detector-electrospray ionization/atm. pressure chem. ionization-mass spectrometry for anal. Both compds. were isomerized and epimerized under all investigated biol. conditions, leading to mixts. of isoliquiritigenin and R/S-liquiritigenin, with 19.6% R enantiomeric excess. Consequently, all three species can potentially modulate the biol. responses. This exemplifies dynamic residual complexity and demonstrates how both nonchiral reactions and enantiomeric discrimination can occur in bioassay media, with or without cells. The findings highlight the importance of controlling in situ chem. reactivity, influenced by biol. systems when evaluating the mode of action of bioactives.
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53Gordon, O. N.; Luis, P. B.; Sintim, H. O.; Schneider, C. Unraveling curcumin degradation: Autoxidation proceeds through spiroepoxide and vinylether intermediates en route to the main bicyclopentadione J. Biol. Chem. 2015, 290, 4817– 4828 DOI: 10.1074/jbc.M114.618785Google Scholar53https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXjtlGju74%253D&md5=55623efe8a52f2763ea949a89b82063cUnraveling Curcumin DegradationGordon, Odaine N.; Luis, Paula B.; Sintim, Herman O.; Schneider, ClausJournal of Biological Chemistry (2015), 290 (8), 4817-4828CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)Curcumin is a dietary anti-inflammatory and chemopreventive agent consisting of two methoxyphenol rings connected by a conjugated heptadienedione chain. Curcumin is unstable at physiol. pH and rapidly degrades in an autoxidn. reaction to a major bicyclopentadione product in which the 7-carbon chain has undergone oxygenation and double cyclization. Early degrdn. products (but not the final bicyclopentadione) mediate topoisomerase poisoning and possibly many other activities of curcumin, but it is not known how many and what autoxidn. products are formed, nor their mechanism of formation. Here, using [14C2]curcumin as a tracer, seven novel autoxidn. products, including two reaction intermediates, were isolated and identified using one- and two-dimensional NMR and mass spectrometry. The unusual spiroepoxide and vinylether reaction intermediates are precursors to the final bicyclopentadione product. A mechanism for the autoxidn. of curcumin is proposed that accounts for the addn. and exchange of oxygen that have been detd. using 18O2 and H218O. Several of the byproducts are formed from an endoperoxide intermediate via reactions that are well precedented in lipid peroxidn. The electrophilic spiroepoxide intermediate formed a stable adduct with N-acetylcysteine, suggesting that oxidative transformation is required for biol. effects mediated by covalent adduction to protein thiols. The spontaneous autoxidn. distinguishes curcumin among natural polyphenolic compds. of therapeutic interest; the formation of chem. diverse reactive and electrophilic products provides a novel paradigm for understanding the polypharmacol. effects of curcumin.
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54Workman, P.; Collins, I. Probing the probes: Fitness factors for small molecule tools Chem. Biol. (Oxford, U. K.) 2010, 17, 561– 577 DOI: 10.1016/j.chembiol.2010.05.013Google Scholar54https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXotVWqs78%253D&md5=16be01da2339173aae8207030bf83c12Probing the Probes: Fitness Factors For Small Molecule ToolsWorkman, Paul; Collins, IanChemistry & Biology (Cambridge, MA, United States) (2010), 17 (6), 561-577CODEN: CBOLE2; ISSN:1074-5521. (Cell Press)A review. Chem. probes for interrogating biol. processes are of considerable current interest. Cell permeable small mol. tools have a major role in facilitating the functional annotation of the human genome, understanding both physiol. and pathol. processes, and validating new mol. targets. To be valuable, chem. tools must satisfy necessary criteria and recent publications have suggested objective guidelines for what makes a useful chem. probe. Although recognizing that such guidelines may be valuable, we caution against overly restrictive rules that may stifle innovation in favor of a "fit-for-purpose" approach. Reviewing the literature and providing examples from the cancer field, we recommend a series of "fitness factors" to be considered when assessing chem. probes. We hope this will encourage innovative chem. biol. research while minimizing the generation of poor quality and misleading biol. data, thus increasing understanding of the particular biol. area, to the benefit of basic research and drug discovery.
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55Singh, J.; Petter, R. C.; Baillie, T. A.; Whitty, A. The resurgence of covalent drugs Nat. Rev. Drug Discovery 2011, 10, 307– 317 DOI: 10.1038/nrd3410Google Scholar55https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXktVGmu7g%253D&md5=2190289081e151416c097be4a5b04460The resurgence of covalent drugsSingh, Juswinder; Petter, Russell C.; Baillie, Thomas A.; Whitty, AdrianNature Reviews Drug Discovery (2011), 10 (4), 307-317CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)A review. Covalent drugs haveproved to be successful therapies for various indications, but largely owing to safety concerns, they are rarely considered when initiating a target-directed drug discovery project. There is a need to reassess this important class of drugs, and to reconcile the discordance between the historic success of covalent drugs and the reluctance of most drug discovery teams to include them in their armamentarium. This Review surveys the prevalence and pharmacol. advantages of covalent drugs, discusses how potential risks and challenges may be addressed through innovative design, and presents the broad opportunities provided by targeted covalent inhibitors.
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56Kalgutkar, A. S.; Dalvie, D. K. Drug discovery for a new generation of covalent drugs Expert Opin. Drug Discovery 2012, 7, 561– 581 DOI: 10.1517/17460441.2012.688744Google Scholar56https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XptFWmt7k%253D&md5=b7fc8e60b263dda5765dd8380f52df17Drug discovery for a new generation of covalent drugsKalgutkar, Amit S.; Dalvie, Deepak K.Expert Opinion on Drug Discovery (2012), 7 (7), 561-581CODEN: EODDBX; ISSN:1746-0441. (Informa Healthcare)A review. Introduction: The design of target-specific covalent inhibitors is conceptually attractive because of increased biochem. efficiency through covalency and increased duration of action that outlasts the pharmacokinetics of the agent. Although many covalent inhibitors have been approved or are in advanced clin. trials to treat indications such as cancer and hepatitis C, there is a general tendency to avoid them as drug candidates because of concerns regarding immune-mediated toxicity that can arise from indiscriminate reactivity with off-target proteins.Areas covered: The review examines potential reason(s) for the excellent safety record of marketed covalent agents and advanced clin. candidates for emerging therapeutic targets. A significant emphasis is placed on proteomic techniques and chem./biochem. reactivity assays that aim to provide a systematic rank ordering of pharmacol. selectivity relative to off-target protein reactivity of covalent inhibitors.Expert opinion: While tactics to examine selective covalent modification of the pharmacol. target are broadly applicable in drug discovery, it is unclear whether the output from such studies can prospectively predict idiosyncratic immune-mediated drug toxicity. Opinions regarding an acceptable threshold of protein reactivity/body burden for a toxic electrophile and a non-toxic electrophilic covalent drug have not been defined. Increasing confidence in proteomic and chem./biochem. reactivity screens will require a retrospective side-by-side profiling of marketed covalent drugs and electrophiles known to cause deleterious toxic effects via non-selective covalent binding.
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57Schröder, J.; Klinger, A.; Oellien, F.; Marhoefer, R. J.; Duszenko, M.; Selzer, P. M. Docking-based virtual screening of covalently binding ligands: An orthogonal lead discovery approach J. Med. Chem. 2013, 56, 1478– 1490 DOI: 10.1021/jm3013932Google Scholar57https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3szisFyhtA%253D%253D&md5=a5186da21cd91e5bbe05c3cd96701258Docking-based virtual screening of covalently binding ligands: an orthogonal lead discovery approachSchroder Jorg; Klinger Anette; Oellien Frank; Marhofer Richard J; Duszenko Michael; Selzer Paul MJournal of medicinal chemistry (2013), 56 (4), 1478-90 ISSN:.In pharmaceutical industry, lead discovery strategies and screening collections have been predominantly tailored to discover compounds that modulate target proteins through noncovalent interactions. Conversely, covalent linkage formation is an important mechanism for a quantity of successful drugs in the market, which are discovered in most cases by hindsight instead of systematical design. In this article, the implementation of a docking-based virtual screening workflow for the retrieval of covalent binders is presented considering human cathepsin K as a test case. By use of the docking conditions that led to the best enrichment of known actives, 44 candidate compounds with unknown activity on cathepsin K were finally selected for experimental evaluation. The most potent inhibitor, 4-(N-phenylanilino)-6-pyrrolidin-1-yl-1,3,5-triazine-2-carbonitrile (CP243522), showed a K(i) of 21 nM and was confirmed to have a covalent reversible mechanism of inhibition. The presented approach will have great potential in cases where covalent inhibition is the desired drug discovery strategy.
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58Davids, M. S.; Brown, J. R. Ibrutinib: A first in class covalent inhibitor of Bruton’s tyrosine kinase Future Oncol. 2014, 10, 957– 967 DOI: 10.2217/fon.14.51Google Scholar58https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXpvFCrtbc%253D&md5=345b4e839a830be822d474f62755a022Ibrutinib: a first in class covalent inhibitor of Bruton's tyrosine kinaseDavids, Matthew S.; Brown, Jennifer R.Future Oncology (2014), 10 (6), 957-967CODEN: FOUNBN; ISSN:1479-6694. (Future Medicine Ltd.)A review. Ibrutinib (formerly PCI-32765) is a potent, covalent inhibitor of Bruton's tyrosine kinase, a kinase downstream of the B-cell receptor that is crit. for B-cell survival and proliferation. In preclin. studies, ibrutinib bound to Bruton's tyrosine kinase with high affinity, leading to inhibition of B-cell receptor signaling, decreased B-cell activation and induction of apoptosis. In clin. studies, ibrutinib has been well-tolerated and has demonstrated profound anti-tumor activity in a variety of hematol. malignancies, most notably chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), leading to US FDA approval for relapsed CLL and MCL. Ongoing studies are evaluating ibrutinib in other types of non-Hodgkin's lymphoma, such as diffuse large B-cell lymphoma and Waldenstroem's macrogobulinemia, in larger Phase III studies in CLL and MCL, and in combination studies with monoclonal antibodies and chemotherapy. Future studies will combine ibrutinib with other promising novel agents currently in development in hematol. malignancies.
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59Flanagan, M. E.; Abramite, J. A.; Anderson, D. P.; Aulabaugh, A.; Dahal, U. P.; Gilbert, A. M.; Li, C.; Montgomery, J.; Oppenheimer, S. R.; Ryder, T.; Schuff, B. P.; Uccello, D. P.; Walker, G. S.; Wu, Y.; Brown, M. F.; Chen, J. M.; Hayward, M. M.; Noe, M. C.; Obach, R. S.; Philippe, L.; Shanmugasundaram, V.; Shapiro, M. J.; Starr, J.; Stroh, J.; Che, Y. Chemical and computational methods for the characterization of covalent reactive groups for the prospective design of irreversible inhibitors J. Med. Chem. 2014, 57, 10072– 10079 DOI: 10.1021/jm501412aGoogle Scholar59https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvVyjtLbM&md5=3ccf59ab7a494655185e5eb5becf8c48Chemical and Computational Methods for the Characterization of Covalent Reactive Groups for the Prospective Design of Irreversible InhibitorsFlanagan, Mark E.; Abramite, Joseph A.; Anderson, Dennis P.; Aulabaugh, Ann; Dahal, Upendra P.; Gilbert, Adam M.; Li, Chao; Montgomery, Justin; Oppenheimer, Stacey R.; Ryder, Tim; Schuff, Brandon P.; Uccello, Daniel P.; Walker, Gregory S.; Wu, Yan; Brown, Matthew F.; Chen, Jinshan M.; Hayward, Matthew M.; Noe, Mark C.; Obach, R. Scott; Philippe, Laurence; Shanmugasundaram, Veerabahu; Shapiro, Michael J.; Starr, Jeremy; Stroh, Justin; Che, YeJournal of Medicinal Chemistry (2014), 57 (23), 10072-10079CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Interest in drugs that covalently modify their target is driven by the desire for enhanced efficacy that can result from the silencing of enzymic activity until protein resynthesis can occur, along with the potential for increased selectivity by targeting uniquely positioned nucleophilic residues in the protein. However, covalent approaches carry addnl. risk for toxicities or hypersensitivity reactions that can result from covalent modification of unintended targets. Here we describe methods for measuring the reactivity of covalent reactive groups (CRGs) with a biol. relevant nucleophile, glutathione (GSH), along with kinetic data for a broad array of electrophiles. We also describe a computational method for predicting electrophilic reactivity, which taken together can be applied to the prospective design of thiol-reactive covalent inhibitors.
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60Jost, C.; Nitsche, C.; Scholz, T.; Roux, L.; Klein, C. D. Promiscuity and selectivity in covalent enzyme inhibition: A systematic study of electrophilic fragments J. Med. Chem. 2014, 57, 7590– 7599 DOI: 10.1021/jm5006918Google ScholarThere is no corresponding record for this reference.
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61Mah, R.; Thomas, J. R.; Shafer, C. M. Drug discovery considerations in the development of covalent inhibitors Bioorg. Med. Chem. Lett. 2014, 24, 33– 39 DOI: 10.1016/j.bmcl.2013.10.003Google Scholar61https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvFOlsr3O&md5=9407bcb76e83065f5a56a97b63547edeDrug discovery considerations in the development of covalent inhibitorsMah, Robert; Thomas, Jason R.; Shafer, Cynthia M.Bioorganic & Medicinal Chemistry Letters (2014), 24 (1), 33-39CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)A review. In recent years, the no. of drug candidates with a covalent mechanism of action progressing through clin. trials or being approved by the FDA has increased significantly. And as interest in covalent inhibitors has increased, the tech. challenges for characterizing and optimizing these inhibitors have become evident. A no. of new tools have been developed to aid this process, but these have not gained wide-spread use. This review will highlight a no. of methods and tools useful for prosecuting covalent inhibitor drug discovery programs.
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62Moghaddam, M. F.; Tang, Y.; O’Brien, Z.; Richardson, S. J.; Bacolod, M.; Chaturedi, P.; Apuy, J.; Kulkarni, A. A proposed screening paradigm for discovery of covalent inhibitor drugs Drug Metab. Lett. 2014, 8, 19– 30 DOI: 10.2174/1872312808666140317151735Google Scholar62https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhslGqur%252FF&md5=97ff5ba47e9547cbae3e5d10ec35112eA Proposed Screening Paradigm for Discovery of Covalent Inhibitor DrugsMoghaddam, Mehran F.; Tang, Yang; O'Brien, Zhihong; Richardson, Samantha J.; Bacolod, Maria; Chaturedi, Prasoon; Apuy, Julius; Kulkarni, AshutoshDrug Metabolism Letters (2014), 8 (1), 19-30CODEN: DMLRBM; ISSN:1872-3128. (Bentham Science Publishers Ltd.)The in vitro and in vivo preclin. ADME properties of 10 clin. late stage or marketed covalent inhibitors were evaluated in order to define advancement criteria for discovery of future drugs in this arena. Our studies revealed the following: After incubating with S9 fractions for 30 min, the rat and human in vitro stability for these compds. ranged from 1% to 100%. The blood stability ranged from 30% to 100%. There was a broad range of CYP inhibition with prevalence for time-dependent inhibition of at least one enzyme. The Caco-2 permeability (A→B) ranged from negligible (0.6 x 10-6 cm/s) to highly permeable (31 x 10-6 cm/s) and the efflux ratio also varied widely (0.2-30). Most of the compds. were highly protein bound in both rat and human with binding ≥ 90%. Rat plasma clearance for the 10 compds. ranged from slow (11 mL/min/kg) to very rapid (350 mL/min/kg). The Vss ranged from low (0.67 L/kg) to very high (115 L/kg). MRT's also ranged from short (0.5 h) to long (7.4 h). The oral exposures also showed a very broad range with Cmax's ranging from 0.01-77 μM and exposure levels ranging from 0.03-106 μM.hr. In conclusion, the wide range in in vitro and in vivo ADME data makes these particular ADME assays non-discriminatory in the selection of promising compds. In our opinion, non-traditional assays such as target mass modification, target confirmation by amino acid sequencing, cellular target occupancy, and target turnover rate data in combination with the pharmacokinetic profiles are the crit. considerations for progression of irreversible compds. in early discovery. ; <b>Biog.</b>: Mehran Moghaddam, PhD, is.
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63Payton, F.; Sandusky, P.; Alworth, W. L. NMR study of the solution structure of curcumin J. Nat. Prod. 2007, 70, 143– 146 DOI: 10.1021/np060263sGoogle Scholar63https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXmsVylsg%253D%253D&md5=256dfb68d48c05c70b191b1ad4c9f5e7NMR Study of the Solution Structure of CurcuminPayton, Florastina; Sandusky, Peter; Alworth, William L.Journal of Natural Products (2007), 70 (2), 143-146CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)Curcumin [1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione (I)] is derived from the rhizomes of Curcuma longa. Although early studies concluded that curcumin exists predominantly as a keto-enol tautomer, II, in several recent articles the soln. structure of curcumin has been represented as a β-diketone tautomer, I. We have investigated the structure of curcumin in solvents ranging in polarity from CDCl3 to mixts. of DMSO-d6 in water, and in buffered aq. DMSO-d6 solns. with pH values varying from 3 to 9. The soln. structure of curcumin was detd. on the basis of NMR techniques, including DEPT, HMQC, HMBC, and COSY. The results of the NMR studies show definitely that curcumin exists in soln. as keto-enol tautomers, II.
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64Jagannathan, R.; Abraham, P. M.; Poddar, P. Temperature-dependent spectroscopic evidences of curcumin in aqueous medium: A mechanistic study of its solubility and stability J. Phys. Chem. B 2012, 116, 14533– 14540 DOI: 10.1021/jp3050516Google Scholar64https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhslKhsrrO&md5=63b9c38eaf6b4ff167901c50441b5c5aTemperature-Dependent Spectroscopic Evidences of Curcumin in Aqueous Medium: A Mechanistic Study of Its Solubility and StabilityJagannathan, Ramya; Abraham, Priya Mary; Poddar, PankajJournal of Physical Chemistry B (2012), 116 (50), 14533-14540CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)In curcumin, keto-enol-enolate equil. of the heptadiene-dione moiety dets. its physiochem. and antioxidant properties. However, its poor soly. in water at neutral pH and room temp. decreases its bioavailability. Potential therapeutic applications have triggered an interest in manipulating the soly. of curcumin in water as its stability and soly. in water remains poorly understood. Here, the mechanism behind its soly. at various temps. and the influence of interplay of temp., intramol. H-bonding, and intermol. forces is reported, which leads to aggregation-disaggregation at various temps. Remarkable change is obsd. in temp.-dependent electronic transition behavior of curcumin, however, the absorption spectra after cooling and heating cycles remain unchanged, hinting much better thermal stability of curcumin in water than previously thought. This study indicates that it is perhaps the breaking of intramol. hydrogen bonding which leads to exposure of polar groups and hence responsible for the dissoln. of curcumin at higher temp. The formation of intermol. aggregates might be responsible behind a better room temp. stability of the mols. after cooling its aq. suspension from 90 to 25 °C. These curcumin soly. studies have great application in biol. research with ref. to bioavailability and to understand target oriented mode of action of curcumin.
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65Takagi, T.; Ramachandran, C.; Bermejo, M.; Yamashita, S.; Yu, L. X.; Amidon, G. L. A provisional biopharmaceutical classification of the top 200 oral drug products in the United States, Great Britain, Spain, and Japan Mol. Pharmaceutics 2006, 3, 631– 643 DOI: 10.1021/mp0600182Google Scholar65https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhtVagsr%252FN&md5=fab640e0a7885c72de8022ef1cdf0e72A Provisional Biopharmaceutical Classification of the Top 200 Oral Drug Products in the United States, Great Britain, Spain, and JapanTakagi, Toshihide; Ramachandran, Chandrasekharan; Bermejo, Marival; Yamashita, Shinji; Yu, Lawrence X.; Amidon, Gordon L.Molecular Pharmaceutics (2006), 3 (6), 631-643CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)Orally administered, immediate-release (IR) drug products in the top 200 drug product lists from the United States (US), Great Britain (GB), Spain (ES), and Japan (JP) were provisionally classified based on the Biopharmaceutics Classification System (BCS). The provisional classification is based on the aq. soly. of the drugs reported in readily available ref. literature and a correlation of human intestinal membrane permeability for a set of 29 ref. drugs with their calcd. partition coeffs. Oral IR drug products constituted more that 50% of the top 200 drug products on all four lists, and ranged from 102 to 113 in no. Drugs with dose nos. less than or equal to unity are defined as high-soly. drugs. More than 50% of the oral IR drug products on each list were detd. to be high-soly. drugs (55-59%). The provisional classification of permeability is based on correlations of the human intestinal permeabilities of 29 ref. drugs with the calcd. Log P or CLogP lipophilicity values for the uncharged chem. form. The Log P and CLogP ests. were linearly correlated (r2 = 0.79) for 187 drugs. Metoprolol was chosen as the ref. compd. for permeability and Log P or CLogP. A total of 62-69.0% and 56-60% of the drugs on the four lists exhibited CLogP and Log P ests., resp., greater than or equal to the corresponding metoprolol value and are provisionally classified as high-permeability drugs. We have compared the BCS classification in this study with the recently proposed BDDCS classification based on fraction dose metab. Although the two approaches are based on different in vivo processes, fraction dose metabolized and fraction dose absorbed are highly correlated and, while depending on the choice of ref. drug for permeability classification, e.g., metoprolol vs. cimetidine or atenolol, show excellent agreement in drug classification. In summary, more than 55% of the drug products were classified as high-soly. (Class 1 and Class 3) drugs in the four lists, suggesting that in vivo bioequivalence (BE) may be assured with a less expensive and more easily implemented in vitro dissoln. test.
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66Griesser, M.; Pistis, V.; Suzuki, T.; Tejera, N.; Pratt, D. A.; Schneider, C. Autoxidative and cyclooxygenase-2 catalyzed transformation of the dietary chemopreventive agent curcumin J. Biol. Chem. 2011, 286, 1114– 1124 DOI: 10.1074/jbc.M110.178806Google Scholar66https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXjtFaqtw%253D%253D&md5=297d642ba6a73eac6ff4028a30486048Autoxidative and Cyclooxygenase-2 Catalyzed Transformation of the Dietary Chemopreventive Agent CurcuminGriesser, Markus; Pistis, Valentina; Suzuki, Takashi; Tejera, Noemi; Pratt, Derek A.; Schneider, ClausJournal of Biological Chemistry (2011), 286 (2), 1114-1124CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)The efficacy of the diphenol curcumin as a cancer chemopreventive agent is limited by its chem. and metabolic instability. Non-enzymic degrdn. has been described to yield vanillin, ferulic acid, and feruloylmethane through cleavage of the heptadienone chain connecting the phenolic rings. Here we provide evidence for an alternative mechanism, resulting in autoxidative cyclization of the heptadienone moiety as a major pathway of degrdn. Autoxidative transformation of curcumin was pH-dependent with the highest rate at pH 8 (2.2 μM/min) and assocd. with stoichiometric uptake of O2. Oxidn. was also catalyzed by recombinant cyclooxygenase-2 (COX-2) (50 nM; 7.5 μM/min), and the rate was increased ≈10-fold by the addn. of 300 μM H2O2. The COX-2 catalyzed transformation was inhibited by acetaminophen but not indomethacin, suggesting catalysis occurred by the peroxidase activity. We propose a mechanism of enzymic or autoxidative hydrogen abstraction from a phenolic hydroxyl to give a quinone methide and a delocalized radical in the heptadienone chain that undergoes 5-exo cyclization and oxygenation. Hydration of the quinone methide (measured by the incorporation of O-18 from H[Formula: see text]O) and rearrangement under loss of water gives the final dioxygenated bicyclopentadione product. When curcumin was added to RAW264.7 cells, the bicyclopentadione was increased 1.8-fold in cells activated by LPS; vanillin and other putative cleavage products were negligible. Oxidn. to a reactive quinone methide is the mechanistic basis of many phenolic anti-cancer drugs. It is possible, therefore, that oxidative transformation of curcumin, a prominent but previously unrecognized reaction, contributes to its cancer chemopreventive activity.
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67Gordon, O. N.; Schneider, C. Vanillin and ferulic acid: Not the major degradation products of curcumin Trends Mol. Med. 2012, 18, 361– 363DOI: 10.1016/j.molmed.2012.04.011
(author reply, pp 363–364)
Google Scholar67https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtVShsb7K&md5=c47a9a41885123b2c24a6876164b88b5Vanillin and ferulic acid: not the major degradation products of curcuminGordon, Odaine N.; Schneider, ClausTrends in Molecular Medicine (2012), 18 (7), 361-363CODEN: TMMRCY; ISSN:1471-4914. (Elsevier Ltd.)A polemic in response to Shen and Ji (Trends Mol. Med. 2012, 18, 138-144) is given. In their study, Shen and Ji described the hypothesis that metabolites of curcumin, specifically vanillin and ferulic acid, could account for its striking polypharmacol. as well as for the enigmatically low levels of curcumin in animal and human plasma upon dietary administration. The authors believed that testing of this hypothesis requires that the degrdn. products are pos. identified, such that the correct products are considered for activity. They also contested the widely held notion that vanillin, ferulic acid, and feruloylmethane are abundant products of the nonenzymic degrdn. of curcumin. -
68Khurana, A.; Ho, C. T. High-performance liquid-chromatographic analysis of curcuminoids and their photo-oxidative decomposition compounds in Curcuma longa l J. Liq. Chromatogr. 1988, 11, 2295– 2304 DOI: 10.1080/01483918808067200Google Scholar68https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL1MXhtlWntb8%253D&md5=f4d2b7c5ba26ff53372351af286c9098High performance liquid chromatographic analysis of curcuminoids and their photo-oxidative decomposition compounds in Curcuma longa LKhurana, Amrik; Ho, Chi TangJournal of Liquid Chromatography (1988), 11 (11), 2295-304CODEN: JLCHD8; ISSN:0148-3919.Photochem. oxidn. of curcuminoids such as curcumin, bisdemethoxycurcumin, and demethoxycurcumin in dry powder of Curcuma longa (zingiberaceae) root and in EtOH and MeOH exts. has been studied following sunlight exposure for 120 h. Whatman PartiSphere-5 NH2 and Whatman PartiSphere-5 WCX columns were used to analyze curcuminoids and their degrdn. products. The curcuminoids were found to be more stable in the dry powder of C. longa root than in EtOH and MeOH exts. Vanillin, p-hydroxybenzaldehyde, ferulic aldehyde, p-hydroxybenzoic acid, vanillic acid, and ferulic acid were identified as the oxidn. products.
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69Tønnesen, H. H.; Karlsen, J.; van Henegouwen, G. B. Studies on curcumin and curcuminoids. VIII. Photochemical stability of curcumin Z. Lebensm.-Unters. Forsch. 1986, 183, 116– 122 DOI: 10.1007/BF01041928Google Scholar69https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaL2s%252FitFGisw%253D%253D&md5=df5990866da489cef1a76a237c02659bStudies on curcumin and curcuminoids. VIII. Photochemical stability of curcuminTonnesen H H; Karlsen J; van Henegouwen G BZeitschrift fur Lebensmittel-Untersuchung und -Forschung (1986), 183 (2), 116-22 ISSN:0044-3026.The photodecomposition of curcumin when exposed to UV/visible radiation is studied. The main degradation products are identified. The reaction mechanisms are investigated and the order of the over-all degradation reactions and the half-lives of curcumin in different solvents and in the solid state are determined.
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70Ghosh, M.; Singh, A. T.; Xu, W.; Sulchek, T.; Gordon, L. I.; Ryan, R. O. Curcumin nanodisks: Formulation and characterization Nanomedicine 2011, 7, 162– 167 DOI: 10.1016/j.nano.2010.08.002Google Scholar70https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXltFGjsL4%253D&md5=34d7bc2edf1aa1cbd50482aabe80a2d1Curcumin nanodisks: formulation and characterizationGhosh, Mistuni; Singh, Amareshwar T. K.; Xu, Wenwei; Sulchek, Todd; Gordon, Leo I.; Ryan, Robert O.Nanomedicine (Philadelphia, PA, United States) (2011), 7 (2), 162-167CODEN: NANOBF; ISSN:1549-9634. (Elsevier Inc.)Nanodisks (NDs) are nanoscale, disk-shaped phospholipid bilayers whose edge is stabilized by apolipoproteins. In the present study, NDs were formulated with the bioactive polyphenol curcumin at a 6:1 phospholipid-to-curcumin molar ratio. At. force microscopy revealed that curcumin-NDs are particles with diams. <50 nm and the thickness of a phospholipid bilayer. When formulated in NDs, curcumin is water sol. and gives rise to a characteristic absorbance spectrum with a peak centered at 420 nm. Fluorescence spectroscopy of curcumin-NDs provided evidence of self-quenching. Incubation of curcumin-NDs with empty NDs relieved the self-quenching, indicating redistribution of curcumin between curcumin-loaded and empty NDs. In HepG2 cells, curcumin-NDs mediated enhanced cell growth inhibition as compared with free curcumin. In a cell culture model of mantle cell lymphoma, curcumin-NDs were a more potent inducer of apoptosis than free curcumin. The nanoscale size of the complexes, combined with their ability to solubilize curcumin, indicates NDs may have in vivo therapeutic applications.
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71Sun, M.; Su, X.; Ding, B.; He, X.; Liu, X.; Yu, A.; Lou, H.; Zhai, G. Advances in nantoechnology-based delivery systems for curcumin Nanomedicine (London, U. K.) 2012, 7, 1085– 1100 DOI: 10.2217/nnm.12.80Google Scholar71https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtFWjsrrN&md5=40a117c92bc233432ec7fe287272195bAdvances in nanotechnology-based delivery systems for curcuminSun, Min; Su, Xun; Ding, Buyun; He, Xiuli; Liu, Xiuju; Yu, Aihua; Lou, Hongxiang; Zhai, GuangxiNanomedicine (London, United Kingdom) (2012), 7 (7), 1085-1100CODEN: NLUKAC; ISSN:1743-5889. (Future Medicine Ltd.)A review. Curcumin (CUR), a bioactive component of turmeric, which is a commonly used spice and nutritional supplement, is isolated from the rhizomes of Curcuma longa Linn. (Zingiberaceae). In recent years, the potential pharmacol. actions of CUR in inflammatory disorders, cardiovascular disease, cancer, Alzheimer's disease and neurol. disorders were shown. However, the clin. application of CUR is severely limited by its main drawbacks such as instability, low soly., poor bioavailability and rapid metab. Multifarious nanotechnol.-based delivery approaches were used to enhance the oral bioavailability, biol. activity or tissue-targeting ability of CUR. This article reviews potential novel drug delivery systems for CUR including liposomes, polymeric nanoparticles, solid lipid nanoparticles, micelles, nanogels, nanosuspensions, nanoemulsions, complexes and dendrimer/dimer, which provide promising results for CUR to improve its biol. activities.
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72Tamvakopoulos, C.; Dimas, K.; Sofianos, Z. D.; Hatziantoniou, S.; Han, Z.; Liu, Z. L.; Wyche, J. H.; Pantazis, P. Metabolism and anticancer activity of the curcumin analogue, dimethoxycurcumin Clin. Cancer Res. 2007, 13, 1269– 1277 DOI: 10.1158/1078-0432.CCR-06-1839Google Scholar72https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhvF2htr0%253D&md5=1df697514606695d2121e226e413fbbcMetabolism and Anticancer Activity of the Curcumin Analogue, DimethoxycurcuminTamvakopoulos, Constantin; Dimas, Konstantinos; Sofianos, Zacharias D.; Hatziantoniou, Sophia; Han, Zhiyong; Liu, Zhong-Li; Wyche, James H.; Pantazis, PanayotisClinical Cancer Research (2007), 13 (4), 1269-1277CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)Purpose: The plant-derived compd. curcumin has shown promising abilities as a cancer chemoprevention and chemotherapy agent in vitro and in vivo but exhibits poor bioavailability. Therefore, there is a need to investigate modified curcumin congeners for improved anticancer activity and pharmacokinetic properties. Exptl. Design: The synthetic curcumin analog dimethoxycurcumin was compared with curcumin for ability to inhibit proliferation and apoptosis of human HCT116 colon cancer cells in vitro by estg. the GI50 and LC50 values and detecting the extent of apoptosis by flow cytometry anal. of the cell cycle. Metabolic stability and/or identification of metabolites were evaluated by recently developed mass spectrometric approaches after incubation with mouse and human liver microsomes and cancer cells in vitro. Addnl., circulating levels of dimethoxycurcumin and curcumin were detd. in mice following i.p. administration. Results: Dimethoxycurcumin is significantly more potent than curcumin in inhibiting proliferation and inducing apoptosis in HCT116 cells treated for 48 h. Nearly 100% of curcumin but <30% of dimethoxycurcumin was degraded in cells treated for 48 h, and incubation with liver microsomes confirmed the limited metab. of dimethoxycurcumin. Both compds. were rapidly degraded in vivo but dimethoxycurcumin was more stable. Conclusions: Compared with curcumin, dimethoxycurcumin is (a) more stable in cultured cells, (b) more potent in the ability to kill cancer cells by apoptosis, (c) less extensively metabolized in microsomal systems, and (d) more stable in vivo. It is likely that the differential extent of apoptosis induced by curcumin and dimethoxycurcumin in vitro is assocd. with the metabolite profiling and/or the extent of stability.
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73Robinson, T. P.; Hubbard, R. B. t.; Ehlers, T. J.; Arbiser, J. L.; Goldsmith, D. J.; Bowen, J. P. Synthesis and biological evaluation of aromatic enones related to curcumin Bioorg. Med. Chem. 2005, 13, 4007– 4013 DOI: 10.1016/j.bmc.2005.03.054Google ScholarThere is no corresponding record for this reference.
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74Liang, G.; Shao, L.; Wang, Y.; Zhao, C.; Chu, Y.; Xiao, J.; Zhao, Y.; Li, X.; Yang, S. Exploration and synthesis of curcumin analogues with improved structural stability both in vitro and in vivo as cytotoxic agents Bioorg. Med. Chem. 2009, 17, 2623– 2631 DOI: 10.1016/j.bmc.2008.10.044Google Scholar74https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXjsFajsrk%253D&md5=c723d921647ac6ad129e2935e22f8260Exploration and synthesis of curcumin analogues with improved structural stability both in vitro and in vivo as cytotoxic agentsLiang, Guang; Shao, Lili; Wang, Yi; Zhao, Chengguang; Chu, Yanhui; Xiao, Jian; Zhao, Yu; Li, Xiaokun; Yang, ShulinBioorganic & Medicinal Chemistry (2009), 17 (6), 2623-2631CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)Curcumin has a surprisingly wide range of chemo-preventive and chemo-therapeutic activities and is under investigation for the treatment of various human cancers. However, the clin. application of curcumin has been significantly limited by its instability and poor metabolic property. Although a no. of synthetic modifications of curcumin have been studied intensively in order to develop a mol. with enhanced bioactivities, few synthetic studies were done for the improvement of pharmacokinetic profiles. In the present study, a series of mono-carbonyl analogs of curcumin were designed and synthesized by deleting the reactive β-diketone moiety, which was considered to be responsible for the pharmacokinetic limitation of curcumin. The results of the in vitro stability studies and in vivo pharmacokinetic studies indicated that the stability of these mono-carbonyl analogs was greatly enhanced in vitro and their pharmacokinetic profiles were also significantly improved in vivo. Furthermore, the cytotoxic activities of mono-carbonyl analogs were evaluated in seven different tumor cell lines by MTT assay and the structure-activity relation (SAR) was discussed and concluded. The results suggest that the five-carbon linker-contg. analogs of curcumin may be favorable for the curcumin-based drug development both pharmacokinetically and pharmacol.
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75Lim, T.-G.; Lee, S.-Y.; Huang, Z.; Lim, D. Y.; Chen, H.; Jung, S. K.; Bode, A. M.; Lee, K. W.; Dong, Z. Curcumin suppresses proliferation of colon cancer cells by targeting CDK2 Cancer Prev. Res. 2014, 7, 466– 474 DOI: 10.1158/1940-6207.CAPR-13-0387Google Scholar75https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXlslSmt70%253D&md5=a609b37581ee658cbbfed899768c9cb1Curcumin Suppresses Proliferation of Colon Cancer Cells by Targeting CDK2Lim, Tae-Gyu; Lee, Sung-Young; Huang, Zunnan; Lim, Do Young; Chen, Hanyong; Jung, Sung Keun; Bode, Ann M.; Lee, Ki Won; Dong, ZigangCancer Prevention Research (2014), 7 (4), 466-474CODEN: CPRACC; ISSN:1940-6207. (American Association for Cancer Research)Curcumin, the yellow pigment of turmeric found in Southeast Indian food, is one of the most popular phytochems. for cancer prevention. Numerous reports have demonstrated modulation of multiple cellular signaling pathways by curcumin and its mol. targets in various cancer cell lines. To identify a new mol. target of curcumin, we used shape screening and reverse docking to screen the Protein Data Bank against curcumin. Cyclin-dependent kinase 2 (CDK2), a major cell-cycle protein, was identified as a potential mol. target of curcumin. Indeed, in vitro and ex vivo kinase assay data revealed a dramatic suppressive effect of curcumin on CDK2 kinase activity. Furthermore, curcumin induced G1 cell-cycle arrest, which is regulated by CDK2 in HCT116 cells. Although the expression levels of CDK2 and its regulatory subunit, cyclin E, were not changed, the phosphorylation of retinoblastoma (Rb), a well-known CDK2 substrate, was reduced by curcumin. Because curcumin induced cell-cycle arrest, we investigated the antiproliferative effect of curcumin on HCT116 colon cancer cells. In this expt., curcumin suppressed HCT116 cell proliferation effectively. To det. whether CDK2 is a direct target of curcumin, CDK2 expression was knocked down in HCT116 cells. As expected, HCT116 sh-CDK2 cells exhibited G1 arrest and reduced proliferation. Because of the low levels of CDK2 in HCT116 sh-CDK2 cells, the effects of curcumin on G1 arrest and cell proliferation were not substantially relative to HCT116 sh-control cells. From these results, we identified CDK2 as a direct target of curcumin in colon cancer cells. Cancer Prev Res; 7(4); 466-74. ©2014 AACR.
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76Balasubramanian, K. Molecular orbital basis for yellow curry spice curcumin’s prevention of Alzheimer’s disease J. Agric. Food Chem. 2006, 54, 3512– 3520 DOI: 10.1021/jf0603533Google Scholar76https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XjsFOitrk%253D&md5=c8bdb36531df9ab157271d6eebdf2169Molecular Orbital Basis for Yellow Curry Spice Curcumin's Prevention of Alzheimer's DiseaseBalasubramanian, KrishnanJournal of Agricultural and Food Chemistry (2006), 54 (10), 3512-3520CODEN: JAFCAU; ISSN:0021-8561. (American Chemical Society)It is demonstrated by using high-level ab initio computations that the yellow curcumin pigment, bis(4-hydroxy-3-methoxyphenyl)-1,6-diene-3,5-dione, in the east Indian root plant turmeric (Curcuma longa) exhibits unique charge and bonding characteristics that facilitate penetration into the blood-brain barrier and binding to amyloid β (Aβ). Alzheimer's disease is caused by Aβ accumulation in the brain cells combined with oxidative stress and inflammation. Consistent with the recent exptl. work by Cole and co-workers (Yang, F., et al. J. Biol. Chem. 2004, 280, 5892-5901) that demonstrates curcumin pigment's binding ability to Aβ both in vivo and in vitro, it is shown here that curcumin possesses suitable charge and bonding features to facilitate the binding to Aβ. In addn., curcumin's anti-inflammatory and antioxidant properties are also attributed to electronic and structural features. It is shown that the presence of an enolic center and two phenolic polar groups sepd. by an essentially hydrophobic bridge of a conjugated network provides both hydrophobic and hydrophilic features to the curcumin pigment, thereby facilitating penetration into the blood-brain barrier through the former property and then binding to Aβ oligomer through the latter property. Both d. functional and Moller-Plesset perturbation (MP2) computations have been carried out on the curcumin pigment to obtain fully optimized geometries in the gas phase and aq. soln. and also the at. charges. Different isomers (keto and enol forms) have been considered to show that the enol form is the most favored and has all of the properties for an ideal antioxidant with also features to penetrate the blood-brain barrier and to bind to Aβ. This is demonstrated with natural bond charges, highest occupied and lowest unoccupied MOs, dipole moments, and Laplacian plots. The computed ionization potential and electron affinity show that curcumin has a low mol. hardness and thus has a propensity to dissoc. its phenolic -OH, and the resulting charge undergoes delocalization throughout the structure, resulting in excitonic features. This feature seems to be also important for its binding capability to human proteins such as human serum albumin and Aβ.
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77Ciccone, L.; Tepshi, L.; Nencetti, S.; Stura, E. A. Transthyretin complexes with curcumin and bromo-estradiol: Evaluation of solubilizing multicomponent mixtures New Biotechnol. 2015, 32, 54– 64 DOI: 10.1016/j.nbt.2014.09.002Google Scholar77https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsFyltLfM&md5=66f2e8289d2c9135727f307f523325ebTransthyretin complexes with curcumin and bromo-estradiol: evaluation of solubilizing multicomponent mixturesCiccone, Lidia; Tepshi, Livia; Nencetti, Susanna; Stura, Enrico A.New Biotechnology (2015), 32 (1), 54-64CODEN: NBEIBR; ISSN:1871-6784. (Elsevier B.V.)Crystallog. structure detn. of protein-ligand complexes of transthyretin (TTR) has been hindered by the low affinity of many compds. that bind to the central cavity of the tetramer. Because crystn. trials are carried out at protein and ligand concn. that approach the millimolar range, low affinity is less of a problem than the poor soly. of many compds. that have been shown to inhibit amyloid fibril formation. To achieve complete occupancy in co-crystn. expts., the minimal requirement is one ligand for each of the two sites within the TTR tetramer. Here we present a new strategy for the co-crystn. of TTR using high mol. wt. polyethylene glycol instead of high ionic strength precipitants, with ligands solubilized in multicomponent mixts. of compds. This strategy is applied to the crystn. of TTR complexes with curcumin and 16α-bromo-estradiol. Here we report the crystal structures with these compds. and with the ferulic acid that results from curcumin degrdn.
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78Irwin, J. J.; Duan, D.; Torosyan, H.; Doak, A. K.; Ziebart, K. T.; Sterling, T.; Tumanian, G.; Shoichet, B. K. An aggregation advisor for ligand discovery J. Med. Chem. 2015, 58, 7076– 7087 DOI: 10.1021/acs.jmedchem.5b01105Google Scholar78https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtlOqu7zM&md5=d3112f9f3a57a2ac61a4b32f31778b1dAn Aggregation Advisor for Ligand DiscoveryIrwin, John J.; Duan, Da; Torosyan, Hayarpi; Doak, Allison K.; Ziebart, Kristin T.; Sterling, Teague; Tumanian, Gurgen; Shoichet, Brian K.Journal of Medicinal Chemistry (2015), 58 (17), 7076-7087CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Colloidal aggregation of org. mols. is the dominant mechanism for artifactual inhibition of proteins, and controls against it are widely deployed. Notwithstanding an increasingly detailed understanding of this phenomenon, a method to reliably predict aggregation has remained elusive. Correspondingly, active mols. that act via aggregation continue to be found in early discovery campaigns and remain common in the literature. Over the past decade, over 12 thousand aggregating org. mols. have been identified, potentially enabling a precedent-based approach to match known aggregators with new mols. that may be expected to aggregate and lead to artifacts. We investigate an approach that uses lipophilicity, affinity, and similarity to known aggregators to advise on the likelihood that a candidate compd. is an aggregator. In prospective exptl. testing, five of seven new mols. with Tanimoto coeffs. (Tc's) between 0.95 and 0.99 to known aggregators aggregated at relevant concns. Ten of 19 with Tc's between 0.94 and 0.90 and three of seven with Tc's between 0.89 and 0.85 also aggregated. Another three of the predicted compds. aggregated at higher concns. This method finds that 61 827 or 5.1% of the ligands acting in the 0.1 to 10 μM range in the medicinal chem. literature are at least 85% similar to a known aggregator with these phys. properties and may aggregate at relevant concns. Intriguingly, only 0.73% of all drug-like com. available compds. resemble the known aggregators, suggesting that colloidal aggregators are enriched in the literature. As a percentage of the literature, aggregator-like compds. have increased 9-fold since 1995, partly reflecting the advent of high-throughput and virtual screens against mol. targets. Emerging from this study is an aggregator advisor database and tool (http://advisor.bkslab.org), free to the community, that may help distinguish between fruitful and artifactual screening hits acting by this mechanism.
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79Coan, K. E.; Shoichet, B. K. Stoichiometry and physical chemistry of promiscuous aggregate-based inhibitors J. Am. Chem. Soc. 2008, 130, 9606– 9612 DOI: 10.1021/ja802977hGoogle Scholar79https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXnvF2gsL8%253D&md5=6bb7b0d190db00bd872a2ba86a5d56efStoichiometry and Physical Chemistry of Promiscuous Aggregate-Based InhibitorsCoan, Kristin E. D.; Shoichet, Brian K.Journal of the American Chemical Society (2008), 130 (29), 9606-9612CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Many false positives in early drug discovery owe to nonspecific inhibition by colloid-like aggregates of org. mols. Despite their prevalence, little is known about aggregate concn., structure, or dynamic equil.; the binding mechanism, stoichiometry with, and affinity for enzymes remain uncertain. To investigate the elementary question of concn., we counted aggregate particles using flow cytometry. For seven aggregate-forming mols., aggregates were not obsd. until the concn. of monomer crossed a threshold, indicating a "crit. aggregation concn." (CAC). Above the CAC, aggregate count increased linearly with added org. material, while the particles dispersed when dild. below the CAC. The concn. of monomeric org. mol. is const. above the CAC, as is the size of the aggregate particles. For two compds. that form large aggregates, nicardipine and miconazole, we measured particle nos. directly by flow cytometry, detg. that the aggregate concn. just above the CAC ranged from 5 to 30 fM. By correlating inhibition of an enzyme with aggregate count for these two drugs, we detd. that the stoichiometry of binding is about 10 000 enzyme mols. per aggregate particle. Using measured vols. for nicardipine and miconazole aggregate particles (2.1 × 1011 and 4.7 × 1010 Å3, resp.), computed monomer vols., and the observation that past the CAC all addnl. monomer forms aggregate particles, we find that aggregates are densely packed particles. Finally, given their size and enzyme stoichiometry, all sequestered enzyme can be comfortably accommodated on the surface of the aggregate.
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80Coan, K. E. D.; Maltby, D. A.; Burlingame, A. L.; Shoichet, B. K. Promiscuous aggregate-based inhibitors promote enzyme unfolding J. Med. Chem. 2009, 52, 2067– 2075 DOI: 10.1021/jm801605rGoogle Scholar80https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXjtFKlsL4%253D&md5=d771ee54b647cf93efe5085c7977bb42Promiscuous Aggregate-Based Inhibitors Promote Enzyme UnfoldingCoan, Kristin E. D.; Maltby, David A.; Burlingame, Alma L.; Shoichet, Brian K.Journal of Medicinal Chemistry (2009), 52 (7), 2067-2075CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)One of the leading sources of false positives in early drug discovery is the formation of org. small mol. aggregates, which inhibit enzymes nonspecifically at micromolar concns. in aq. soln. The mol. basis for this widespread problem remains hazy. To investigate the mechanism of inhibition at a mol. level, we detd. changes in solvent accessibility that occur when an enzyme binds to an aggregate using hydrogen-deuterium exchange mass spectrometry. For AmpC β-lactamase, binding to aggregates of the small mol. rottlerin increased the deuterium exchange of all 10 reproducibly detectable peptides, which covered 41% of the sequence of β-lactamase. This suggested a global increase in proton accessibility upon aggregate binding, consistent with denaturation. We then investigated whether enzyme-aggregate complexes were more susceptible to proteolysis than uninhibited enzyme. For five aggregators, trypsin degrdn. of β-lactamase increased substantially when β-lactamase was inhibited by aggregates, whereas uninhibited enzyme was generally stable to digestion. Combined, these results suggest that the mechanism of action of aggregate-based inhibitors proceeds via partial protein unfolding when bound to an aggregate particle.
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81Winter, S.; Tortik, N.; Kubin, A.; Krammer, B.; Plaetzer, K. Back to the roots: Photodynamic inactivation of bacteria based on water-soluble curcumin bound to polyvinylpyrrolidone as a photosensitizer Photochem. Photobiol. Sci. 2013, 12, 1795– 1802 DOI: 10.1039/c3pp50095kGoogle Scholar81https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsVyqsLbM&md5=70702ca399d2d0d8395840f1dbc9ff53Back to the roots: photodynamic inactivation of bacteria based on water-soluble curcumin bound to polyvinylpyrrolidone as a photosensitizerWinter, Sandra; Tortik, Nicole; Kubin, Andreas; Krammer, Barbara; Plaetzer, KristjanPhotochemical & Photobiological Sciences (2013), 12 (10), 1795-1802CODEN: PPSHCB; ISSN:1474-905X. (Royal Society of Chemistry)Photodynamic inactivation (PDI), the light-induced and photosensitizer-mediated overprodn. of reactive oxygen species in microorganisms, represents a convincing approach to treat infections with (multi-resistant) pathogens. Due to its favorable photoactive properties combined with excellent biocompatibility, curcumin derived from the roots of turmeric (Curcuma longa) has been identified as an advantageous photosensitizer for PDI. To overcome the poor water soly. and the rapid decay of the natural substance at physiol. pH, we examd. the applicability of polyvinylpyrrolidone curcumin (PVP-C) in an acidified aq. soln. (soly. of PVP-C up to 2.7 mM) for photoinactivation of Gram(+) and Gram(-) bacteria. Five micromolar PVP-C incubated for 5 min and illuminated using a blue light LED array (435 ± 10 nm, 33.8 J cm-2) resulted in a >6 log10 redn. of the no. of viable Staphylococcus aureus. At this concn., longer incubation periods result in a lower phototoxicity, most likely due to degeneration of curcumin. Upon an increase of the PVP-C concn. to 50 μM (incubation for 15 or 25 min) a complete eradication of Staphylococcus aureus can be achieved. As expected for a non-cationic photosensitizer, cell wall permeabilization with CaCl2 prior to addn. of 50 μM PVP-C for 15 min is necessary to induce a drop in the count of the Gram(-) Escherichia coli for more than 3 log10. As both constituents of the formulation, curcumin (E no. E100) and polyvinylpyrrolidone (E1201), have been approved as food additives, a PDI based on PCP-C might allow for a very sparing clin. application (e.g. for disinfection of wounds) or even for employment in aseptic prodn. of foodstuffs.
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82Siviero, A.; Gallo, E.; Maggini, V.; Gori, L.; Mugelli, A.; Firenzuoli, F.; Vannacci, A. Curcumin, a golden spice with a low bioavailability Journal of Herbal Medicine 2015, 5, 57– 70 DOI: 10.1016/j.hermed.2015.03.001Google ScholarThere is no corresponding record for this reference.
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83Lao, C. D.; Ruffin, M. T. I. V.; Normolle, D.; Heath, D. D.; Murray, S. I.; Bailey, J. M.; Boggs, M. E.; Crowell, J.; Rock, C. L.; Brenner, D. E. Dose escalation of a curcuminoid formulation BMC Complementary Altern. Med. 2006, 6, 10 DOI: 10.1186/1472-6882-6-10Google Scholar83https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD287ps12ksg%253D%253D&md5=468c392b27b48969ee5505e1bb5c059eDose escalation of a curcuminoid formulationLao Christopher D; Ruffin Mack T 4th; Normolle Daniel; Heath Dennis D; Murray Sandra I; Bailey Joanne M; Boggs Martha E; Crowell James; Rock Cheryl L; Brenner Dean EBMC complementary and alternative medicine (2006), 6 (), 10 ISSN:.BACKGROUND: Curcumin is the major yellow pigment extracted from turmeric, a commonly-used spice in India and Southeast Asia that has broad anticarcinogenic and cancer chemopreventive potential. However, few systematic studies of curcumin's pharmacology and toxicology in humans have been performed. METHODS: A dose escalation study was conducted to determine the maximum tolerated dose and safety of a single dose of standardized powder extract, uniformly milled curcumin (C3 Complextrade mark, Sabinsa Corporation). Healthy volunteers were administered escalating doses from 500 to 12,000 mg. RESULTS: Seven of twenty-four subjects (30%) experienced only minimal toxicity that did not appear to be dose-related. No curcumin was detected in the serum of subjects administered 500, 1,000, 2,000, 4,000, 6,000 or 8,000 mg. Low levels of curcumin were detected in two subjects administered 10,000 or 12,000 mg. CONCLUSION: The tolerance of curcumin in high single oral doses appears to be excellent. Given that achieving systemic bioavailability of curcumin or its metabolites may not be essential for colorectal cancer chemoprevention, these findings warrant further investigation for its utility as a long-term chemopreventive agent.
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84Wahlang, B.; Pawar, Y. B.; Bansal, A. K. Identification of permeability-related hurdles in oral delivery of curcumin using the Caco-2 cell model Eur. J. Pharm. Biopharm. 2011, 77, 275– 282 DOI: 10.1016/j.ejpb.2010.12.006Google Scholar84https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtlSktro%253D&md5=a948f9008184ecdefaa37c62b7ffb320Identification of permeability-related hurdles in oral delivery of curcumin using the Caco-2 cell modelWahlang, Banrida; Pawar, Yogesh B.; Bansal, Arvind K.European Journal of Pharmaceutics and Biopharmaceutics (2011), 77 (2), 275-282CODEN: EJPBEL; ISSN:0939-6411. (Elsevier B.V.)Curcumin a poly-phenolic compd. possesses diverse pharmacol. activities; however, its development as a drug has been severely impeded by extremely poor oral bioavailability. Poor aq. soly. and extensive metab. have been implicated for this but the role of membrane permeability has not been investigated. In the present study, permeability of curcumin was assessed using the Caco-2 cell line. Curcumin was poorly permeable with a Papp (A → B) value of 2.93 ± 0.94 × 10-6 cm/s. Papp value in (B → A) study was found out to be 2.55 ± 0.02 × 10-6 cm/s, thus ruling out the role of efflux pathways in poor oral bioavailability of curcumin. Studies using verapamil, a P-gp inhibitor, further confirmed this finding. Detailed mass balance studies showed loss of curcumin during transport. Further expts. using lysed cells revealed that 11.78% of curcumin was metabolized during transport. Studies using itraconazole, a CYP3A4 inhibitor, established its role in curcumin metab. Curcumin was also found to accumulate in cells as revealed by CLSM studies. Sorption and desorption kinetic studies further confirmed accumulation of curcumin inside the cells. Amt. accumulated was quantitated by HPLC and found to be >20%. Thus, intestinal first-pass metab. and intracellular accumulation played a role in poor permeability of curcumin. Based on its poor aq. soly. and intestinal permeability, curcumin can be classified as a BCS Class IV mol. This information can facilitate designing of drug delivery systems for enhancement of oral bioavailability of curcumin.
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85Volpe, D. A.; Faustino, P. J.; Ciavarella, A. B.; Asafu-Adjaye, E. B.; Ellison, C. D.; Yu, L. X.; Hussain, A. S. Classification of drug permeability with a Caco-2 cell monolayer assay Clin. Res. Regul. Aff. 2007, 24, 39– 47 DOI: 10.1080/10601330701273669Google ScholarThere is no corresponding record for this reference.
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86Suresh, D.; Srinivasan, K. Tissue distribution & elimination of capsaicin, piperine & curcumin following oral intake in rats Indian J. Med. Res. 2010, 131, 682– 691Google Scholar86https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXpt1Olsbg%253D&md5=e7a1d76dfdb45452d86dc07357c12fc6Tissue distribution & elimination of capsaicin, piperine & curcumin following oral intake in ratsSuresh, D.; Srinivasan, K.Indian Journal of Medical Research (2010), 131 (5), 682-691CODEN: IMIREV; ISSN:0971-5916. (Indian Council of Medical Research)Curcumin, capsaicin and piperine, the bioactive compds. present in spices-turmeric (Curcuma longa), red pepper (Capsicum annuum), and black pepper (Piper nigrum) resp., have a considerable portion of structural homol. Tissue distribution and elimination of these three structurally similar bioactive compds. was examd. following their oral intake in rats. Sep. sets of animals (150-160 g) were orally administered the three spice principles at dosages of 30 mg (capsaicin), 170 mg (piperine) and 500 mg (curcumin)/kg body wt. The tissue concns. of administered spice compds. were detd. by HPLC. Maximum distribution of 24.4% of administered capsaicin was seen at 1 h, while no intact capsaicin was detectable after 4 days. Absorption of capsaicin was about 94% and very rapid relative to other two compds. A max. of 10.8% of administered piperine was seen in tissues at 6 h. Absorption of the administered piperine was about 96%. Curcumin concn. was max. in the intestine at 1 h; max. in blood at 6 h and remained at significantly higher level even at 24 h. About 63.5% of the curcumin dose was absorbed. Only a small portion of the administered dose of capsaicin (<0.1%) and curcumin (0.173%) was excreted in urine, whereas piperine was not detectable in urine. Enhanced bioavailability of curcumin was evidenced when the same was orally administered concomitant with piperine. Intestinal absorption of curcumin was relatively higher when administered concomitantly with piperine, and it stayed significantly longer in the body tissues. Intact curcumin was detected in brain at 24, 48, and 96 h with a max. at 48 h. Considerable difference exists in the bioavailability of the three test compds. Curcumin could be traced in the brain following its administration. Bioavailability of curcumin can be improved by co-administration with piperine.
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87Ravindranath, V.; Chandrasekhara, N. Absorption and tissue distribution of curcumin in rats Toxicology 1980, 16, 259– 265 DOI: 10.1016/0300-483X(80)90122-5Google Scholar87https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL3cXmtFKhsL4%253D&md5=e28fca7f02c9bb9e5f5aa1cca65c9d7cAbsorption and tissue distribution of curcumin in ratsRavindranath, Vijayalakshmi; Chandrasekhara, NanjundiahToxicology (1980), 16 (3), 259-65CODEN: TXCYAC; ISSN:0300-483X.After oral administration of 400 mg curcumin [458-37-7] to rats, ∼60% of the dose was absorbed. No curcumin was detectable in urine. The urinary excretion of conjugated glucuronides and sulfates significantly increased. No curcumin was present in heart blood. Only traces (<5 μg/mL) in portal blood and negligible quantities in liver and kidney (<20 μg/tissue) were obsd. from 15 min up to 24 h after administration of curcumin. At the end of 24 h, the concn. of curcumin remaining in the lower part of the gut namely caecum and large intestine amounted to 38% of the quantity administered.
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88Ravindranath, V.; Chandrasekhara, N. Metabolism of curcumin - studies with [3H]curcumin Toxicology 1982, 22, 337– 344 DOI: 10.1016/0300-483X(81)90027-5Google ScholarThere is no corresponding record for this reference.
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89Mathews, S.; Rao, M. N. A. Interaction of curcumin with glutathione Int. J. Pharm. (Amsterdam, Neth.) 1991, 76, 257– 259 DOI: 10.1016/0378-5173(91)90278-VGoogle Scholar89https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK38XjsVGitw%253D%253D&md5=a5a248a8d194eccf433182195de12007Interaction of curcumin with glutathioneMathews, Susan; Rao, M. N. A.International Journal of Pharmaceutics (1991), 76 (3), 257-9CODEN: IJPHDE; ISSN:0378-5173.Curcumin interacts with glutathione spontaneously and more rapidly in the presence of glutathione S-transferase. The interaction may involve Michael-type addn. reaction between the α,β-unsatd. chromophore of curcumin and the nucleophilic glutathione.
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90Asai, A.; Miyazawa, T. Occurrence of orally administered curcuminoid as glucuronide and glucuronide/sulfate conjugates in rat plasma Life Sci. 2000, 67, 2785– 2793 DOI: 10.1016/S0024-3205(00)00868-7Google ScholarThere is no corresponding record for this reference.
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91Sharma, R. A.; McLelland, H. R.; Hill, K. A.; Ireson, C. R.; Euden, S. A.; Manson, M. M.; Pirmohamed, M.; Marnett, L. J.; Gescher, A. J.; Steward, W. P. Pharmacodynamic and pharmacokinetic study of oral Curcuma extract in patients with colorectal cancer Clin. Cancer Res. 2001, 7, 1894– 1900Google Scholar91https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXlslaltbg%253D&md5=fbe43c34f827739bcbb6050824051cbbPharmacodynamic and pharmacokinetic study of oral Curcuma extract in patients with colorectal cancerSharma, Ricky A.; McLelland, Heather R.; Hill, Kirsti A.; Ireson, Christopher R.; Euden, Stephanie A.; Manson, Margaret M.; Pirmohamed, Munir; Marnett, Lawrence J.; Gescher, Andreas J.; Steward, William P.Clinical Cancer Research (2001), 7 (7), 1894-1900CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)Curcuma spp. exts., particularly the dietary polyphenol curcumin, prevent colon cancer in rodents. In view of the sparse information on the pharmacodynamics and pharmacokinetics of curcumin in humans, a dose-escalation pilot study of a novel standardized Curcuma ext. in proprietary capsule form was performed at doses between 440 and 2200 mg/day, contg. 36-180 mg of curcumin. Fifteen patients with advanced colorectal cancer refractory to std. chemotherapies received Curcuma ext. daily for up to 4 mo. Activity of glutathione S-transferase and levels of a DNA adduct (M1G) formed by malondialdehyde, a product of lipid peroxidn. and prostaglandin biosynthesis, were measured in patients' blood cells. Oral Curcuma ext. was well tolerated, and dose-limiting toxicity was not obsd. Neither curcumin nor its metabolites were detected in blood or urine, but curcumin was recovered from feces. Curcumin sulfate was identified in the feces of one patient. Ingestion of 440 mg of Curcuma ext. for 29 days was accompanied by a 59% decrease in lymphocytic glutathione S-transferase activity. At higher dose levels, this effect was not obsd. Leukocytic M1G levels were const. within each patient and unaffected by treatment. Radiol. stable disease was demonstrated in five patients for 2-4 mo of treatment. The results suggest that (a) Curcuma ext. can be administered safely to patients at doses of up to 2.2 g daily, equiv. to 180 mg of curcumin; (b) curcumin has low oral bioavailability in humans and may undergo intestinal metab.; and (c) larger clin. trials of Curcuma ext. are merited.
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92Garcea, G.; Berry, D. P.; Jones, D. J. L.; Singh, R.; Dennison, A. R.; Farmer, P. B.; Sharma, R. A.; Steward, W. P.; Gescher, A. J. Consumption of the putative chemopreventative agent curcumin by cancer patients: Assessment of curcumin levels in the colorectum and their pharmacodynamic consequences Cancer Epidemiol., Biomarkers Prev. 2005, 14, 120– 125Google Scholar92https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXmsVOntw%253D%253D&md5=d0e08edefda4f7529f22f6de0ab1a29fConsumption of the Putative Chemopreventive Agent Curcumin by Cancer Patients: Assessment of Curcumin Levels in the Colorectum and their Pharmacodynamic ConsequencesGarcea, Giuseppe; Berry, David P.; Jones, Donald J. L.; Singh, Raj; Dennison, Ashley R.; Farmer, Peter B.; Sharma, Ricky A.; Steward, William P.; Gescher, Andreas J.Cancer Epidemiology, Biomarkers & Prevention (2005), 14 (1), 120-125CODEN: CEBPE4; ISSN:1055-9965. (American Association for Cancer Research)Curcumin, a constituent of the spice turmeric, has been shown to reduce the adenoma burden in rodent models of colorectal cancer accompanied by a redn. of levels of the oxidative DNA adduct 3-(2-deoxy-β-di-erythro-pentafuranosyl)-pyr[1,2-α]-purin-10(3H)one (M1G) and of expression of the enzyme cyclooxygenase-2 (COX-2). We tested the hypothesis that pharmacol. active levels of curcumin can be achieved in the colorectum of humans as measured by effects on levels of M1G and COX-2 protein. Patients with colorectal cancer ingested curcumin capsules (3,600, 1,800, or 450 mg daily) for 7 days. Biopsy samples of normal and malignant colorectal tissue, resp., were obtained at diagnosis and at 6 to 7 h after the last dose of curcumin. Blood was taken 1 h after the last dose of curcumin. Curcumin and its metabolites were detected and quantitated by high-performance liq. chromatog. with detection by UV spectrophotometry or mass spectrometry. M1G levels and COX-2 protein expression were measured by immunoslot blot and Western blotting, resp. The concns. of curcumin in normal and malignant colorectal tissue of patients receiving 3,600 mg of curcumin were 12.7 ± 5.7 and 7.7 ± 1.8 nmol/g, resp. Curcumin sulfate and curcumin glucuronide were identified in the tissue of these patients. Trace levels of curcumin were found in the peripheral circulation. M1G levels were 2.5-fold higher in malignant tissue as compared with normal tissue (P < 0.05 by ANOVA). Administration of curcumin (3,600 mg) decreased M1G levels from 4.8 ± 2.9 adducts per 107 nucleotides in malignant colorectal tissue to 2.0 ± 1.8 adducts per 107 nucleotides (P < 0.05 by ANOVA). COX-2 protein levels in malignant colorectal tissue were not affected by curcumin. The results suggest that a daily dose of 3.6 g curcumin achieves pharmacol. efficacious levels in the colorectum with negligible distribution of curcumin outside the gut.
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93Johnson, J. J.; Mukhtar, H. Curcumin for chemoprevention of colon cancer Cancer Lett. (N. Y., NY, U. S.) 2007, 255, 170– 181 DOI: 10.1016/j.canlet.2007.03.005Google Scholar93https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXpsFKqurk%253D&md5=7dd80d117bf89bbcca9124a1616e3c7cCurcumin for chemoprevention of colon cancerJohnson, Jeremy James; Mukhtar, HasanCancer Letters (Amsterdam, Netherlands) (2007), 255 (2), 170-181CODEN: CALEDQ; ISSN:0304-3835. (Elsevier B.V.)A review. The most practical approach to reduce the morbidity and mortality of cancer is to delay the process of carcinogenesis through the use of chemopreventive agents. This necessitates that safer compds., esp. those derived from natural sources must be critically examd. for chemoprevention. A spice common to India and the surrounding regions, is turmeric, derived from the rhizome of Curcuma longa. Pre-clin. studies in a variety of cancer cell lines including breast, cervical, colon, gastric, hepatic, leukemia, oral epithelial, ovarian, pancreatic, and prostate have consistently shown that curcumin possesses anti-cancer activity in vitro and in pre-clin. animal models. The robust activity of curcumin in colorectal cancer has led to five phase I clin. trials being completed showing the safety and tolerability of curcumin in colorectal cancer patients. To date clin. trials have not identified a max. tolerated dose of curcumin in humans with clin. trials using doses up to 8000 mg per day. The success of these trials has led to the development of phase II trials that are currently enrolling patients. Overwhelming in vitro evidence and completed clin. trials suggests that curcumin may prove to be useful for the chemoprevention of colon cancer in humans. This review will focus on describing the pre-clin. and clin. evidence of curcumin as a chemopreventive compd. in colorectal cancer.
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94Vareed, S. K.; Kakarala, M.; Ruffin, M. T.; Crowell, J. A.; Normolle, D. P.; Djuric, Z.; Brenner, D. E. Pharmacokinetics of curcumin conjugate metabolites in healthy human subjects Cancer Epidemiol., Biomarkers Prev. 2008, 17, 1411– 1417 DOI: 10.1158/1055-9965.EPI-07-2693Google Scholar94https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXnsVKgtL0%253D&md5=1176c76f0880b803c08a5ebceb10994aPharmacokinetics of Curcumin Conjugate Metabolites in Healthy Human SubjectsVareed, Shaiju K.; Kakarala, Madhuri; Ruffin, Mack T.; Crowell, James A.; Normolle, Daniel P.; Djuric, Zora; Brenner, Dean E.Cancer Epidemiology, Biomarkers & Prevention (2008), 17 (6), 1411-1417CODEN: CEBPE4; ISSN:1055-9965. (American Association for Cancer Research)Curcumin is a polyphenol, found in the spice turmeric, that has promising anticancer properties, but previous studies suggest that absorption of curcumin may be limited. This study examd. the pharmacokinetics of a curcumin prepn. in healthy human volunteers 0.25 to 72 h after a single oral dose. Curcumin was administered at doses of 10 g (n = 6) and 12 g (n = 6). Subjects were randomly allocated to dose level for a total of six subjects at each dose level. Serum samples were assayed for free curcumin, for its glucuronide, and for its sulfate conjugate. The data were fit to a one-compartment absorption and elimination model. Using a high-performance liq. chromatog. assay with a limit of detection of 50 ng/mL, only one subject had detectable free curcumin at any of the 14 time points assayed, but curcumin glucuronides and sulfates were detected in all subjects. Based on the pharmacokinetic model, the area under the curve for the 10 and 12 g doses was estd. (mean ± SE) to be 35.33 ± 3.78 and 26.57 ± 2.97 μg/mL x h, resp., whereas Cmax was 2.30 ± 0.26 and 1.73 ± 0.19 μg/mL. The Tmax and t1/2 were estd. to be 3.29 ± 0.43 and 6.77 ± 0.83 h. The ratio of glucuronide to sulfate was 1.92:1. The curcumin conjugates were present as either glucuronide or sulfate, not mixed conjugates. Curcumin is absorbed after oral dosing in humans and can be detected as glucuronide and sulfate conjugates in plasma. (Cancer Epidemiol Biomarkers Prev 2008;17(6):1411-7).
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95Chan, E.; Tan, M.; Xin, J.; Sudarsanam, S.; Johnson, D. E. Interactions between traditional Chinese medicines and western therapeutics Curr. Opin. Drug Discovery Dev. 2010, 13, 50– 65Google Scholar95https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXntVOqug%253D%253D&md5=dfc350826ee988f9a3cd84167f1581edInteractions between traditional Chinese medicines and Western therapeuticsChan, Elena; Tan, Marisela; Xin, Jianni; Sudarsanam, Sucha; Johnson, Dale E.Current Opinion in Drug Discovery & Development (2010), 13 (1), 50-65CODEN: CODDFF; ISSN:2040-3437. (BioMed Central Ltd.)A review. Traditional Chinese medicine (TCM) is a holistic approach to health that attempts to bring the body, mind and spirit into harmony. TCM is an essential part of the healthcare system in several Asian countries, and is considered a complementary or alternative medical system in most Western countries. An integration of the traditional Chinese and Western systems of medicine has begun in multiple medical centers internationally, and there is increasing evidence that several herbs and combinations of herbs used in TCM impart important pharmacol. effects. The no. of databases and compilations of herbs, herbal formulations, phytochem. constituents and mol. targets is increasing, primarily because of the widespread use of TCM in combination with Western drugs. The continued popularity of herbal remedies worldwide suggests that evidence-based research in this field, as well as information regarding the potential efficacy and safety of phytochem. constituents in herbs and TCM formulations, are essential, particularly when TCM is used in combination with other drugs. Herb-drug interactions are similar to drug-drug interactions in terms of their effects on ADME properties. Improvements in the knowledge of the mol. targets and metabolic pathways, as well as of the synergistic and inhibitory effects assocd. with important phytochems. from herbs and herbal formulations, will lead to the development of rational approaches for the safe combination of healthcare systems from different cultures.
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96Hong, D. H.; Son, Y. K.; Choi, I.-W.; Park, W. S. The inhibitory effect of curcumin on voltage-dependent K+ channels in rabbit coronary arterial smooth muscle cells Biochem. Biophys. Res. Commun. 2013, 430, 307– 312 DOI: 10.1016/j.bbrc.2012.10.132Google ScholarThere is no corresponding record for this reference.
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97Bamba, Y.; Yun, Y. S.; Kunugi, A.; Inoue, H. Compounds isolated from Curcuma aromatica Salisb. inhibit human P450 enzymes J. Nat. Med. 2011, 65, 583– 587 DOI: 10.1007/s11418-011-0507-0Google Scholar97https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXns12msLs%253D&md5=8f6641223031d7037ad50e134df2f8dbCompounds isolated from Curcuma aromatica Salisb. inhibit human P450 enzymesBamba, Yoshinori; Yun, Young Sook; Kunugi, Akira; Inoue, HideshiJournal of Natural Medicines (2011), 65 (3-4), 583-587CODEN: JNMOBN; ISSN:1861-0293. (Springer Japan)Curcuma species (Zingiberaceae) are used as both food and medicine in Asia. 10 Sesquiterpenes (1-10) and two curcuminoids (11 and 12) were isolated from the rhizomes of Curcuma aromatica Salisb. and identified. The compds. were evaluated for their ability to inhibit cytochrome P 450 (CYP). Among them, the sesquiterpene (4S,5S)-(+)-germacrone-4,5-epoxide (7) inhibited certain subtypes of CYP more potently than or at levels comparable to the curcuminoids curcumin (11) and demethoxycurcumin (12); 7 (IC50 = 1.0 ± 0.2 μM) > 12 (IC50 = 7.0 ± 1.7 μM) > 11 (IC50 = 14.9 ± 1.4 μM) for CYP3A4 inhibition; 12 (IC50 = 1.4 ± 0.2 μM) > 11 (IC50 = 6.0 ± 1.4 μM) > 7 (IC50 = 7.6 ± 2.5 μM) for CYP2C9 inhibition; and 7 (IC50 = 33.2 ± 3.6 μM) = 12 (IC50 = 34.0 ± 14.2 μM) > 11 (IC50 > 100 μM) for CYP1A2 inhibition. These results suggest the possibility that Curcuma aromatica Salisb. may cause food-drug interactions via cytochrome P 450 inhibition by sesquiterpene 7 and curcuminoids 11 and 12.
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98Gupta, S. C.; Kismali, G.; Aggarwal, B. B. Curcumin, a component of turmeric: From farm to pharmacy BioFactors 2013, 39, 2– 13 DOI: 10.1002/biof.1079Google ScholarThere is no corresponding record for this reference.
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99Schramm, A.; Jahne, E. A.; Baburin, I.; Hering, S.; Hamburger, M. Natural products as potential human ether-a-go-go-related gene channel inhibitors - outcomes from a screening of widely used herbal medicines and edible plants Planta Med. 2014, 80, 1045– 1050 DOI: 10.1055/s-0034-1382907Google ScholarThere is no corresponding record for this reference.
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100Xia, M.; Shahane, S. A.; Huang, R.; Titus, S. A.; Shum, E.; Zhao, Y.; Southall, N.; Zheng, W.; Witt, K. L.; Tice, R. R.; Austin, C. P. Identification of quaternary ammonium compounds as potent inhibitors of hERG potassium channels Toxicol. Appl. Pharmacol. 2011, 252, 250– 258 DOI: 10.1016/j.taap.2011.02.016Google Scholar100https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXkvVGhsLY%253D&md5=4f5007d47bd7d0ab8300e29c3ef0725cIdentification of quaternary ammonium compounds as potent inhibitors of hERG potassium channelsXia, Menghang; Shahane, Sampada A.; Huang, Ruili; Titus, Steven A.; Shum, Enoch; Zhao, Yong; Southall, Noel; Zheng, Wei; Witt, Kristine L.; Tice, Raymond R.; Austin, Christopher P.Toxicology and Applied Pharmacology (2011), 252 (3), 250-258CODEN: TXAPA9; ISSN:0041-008X. (Elsevier B.V.)The human ether-a-go-go-related gene (hERG) channel, a member of a family of voltage-gated potassium (K+) channels, plays a crit. role in the repolarization of the cardiac action potential. The redn. of hERG channel activity as a result of adverse drug effects or genetic mutations may cause QT interval prolongation and potentially leads to acquired long QT syndrome. Thus, screening for hERG channel activity is important in drug development. Cardiotoxicity assocd. with the inhibition of hERG channels by environmental chems. is also a public health concern. To assess the inhibitory effects of environmental chems. on hERG channel function, we screened the National Toxicol. Program (NTP) collection of 1408 compds. by measuring thallium influx into cells through hERG channels. Seventeen compds. with hERG channel inhibition were identified with IC50 potencies ranging from 0.26 to 22 μM. Twelve of these compds. were confirmed as hERG channel blockers in an automated whole cell patch clamp expt. In addn., we investigated the structure-activity relationship of seven compds. belonging to the quaternary ammonium compd. (QAC) series on hERG channel inhibition. Among four active QAC compds., tetra-n-octylammonium bromide was the most potent with an IC50 value of 260 nM in the thallium influx assay and 80 nM in the patch clamp assay. The potency of this class of hERG channel inhibitors appears to depend on the no. and length of their aliph. side-chains surrounding the charged nitrogen. Profiling environmental compd. libraries for hERG channel inhibition provides information useful in prioritizing these compds. for cardiotoxicity assessment in vivo.
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101Hu, C.-W.; Sheng, Y.; Zhang, Q.; Liu, H.-B.; Xie, X.; Ma, W.-C.; Huo, R.; Dong, D.-L. Curcumin inhibits hERG potassium channels in vitro Toxicol. Lett. 2012, 208, 192– 196 DOI: 10.1016/j.toxlet.2011.11.005Google Scholar101https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhs1CitrnF&md5=53ec4e92c26b06df45ae21abc9840565Curcumin inhibits hERG potassium channels in vitroHu, Chao-Wei; Sheng, Yue; Zhang, Qin; Liu, Hui-Bin; Xie, Xin; Ma, Wen-Chao; Huo, Rong; Dong, De-LiToxicology Letters (2012), 208 (2), 192-196CODEN: TOLED5; ISSN:0378-4274. (Elsevier Ireland Ltd.)Curcumin is reported to exert antioxidant, anti-inflammatory, antiviral, antibacterial, antifungal, and anti-tumor activities. The human ether-a-go-go related gene (hERG) encodes the rapid component of the delayed rectifier K+ currents. Inhibition of hERG K+ channels leads to cardiac repolarization prolongation, which contributes to either the anti-arrhythmic effects of anti-arrhythmic drugs, or the pro-arrhythmic effects (induction of long QT syndrome) of some drugs not used for anti-arrhythmias. Since curcumin shows multiple beneficial effects and clin. significance, the aim of the present study is to investigate the effect of curcumin on hERG K+ channels, elucidating its potential cardiac therapeutic or toxic effects. In whole-cell patch-clamp expts., we found that curcumin inhibited hERG K+ currents in HEK293 cells stably expressing hERG channels in a dose-dependent manner, with IC50 value of 5.55 μM. The deactivation, inactivation, and the recovery time from inactivation of hERG channels were significantly changed by acute treatment of 10 μM curcumin. Incubation of 20 μM curcumin for 24 h reduced the HEK293 cell viability. I.v. injection of maximal amt. of curcumin in rabbits (20 mg/animal) did not affect the cardiac repolarization manifested with QTc value. We conclude that curcumin inhibits hERG K+ channels in vitro.
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102Zhang, G.; Nitteranon, V.; Chan, L. Y.; Parkin, K. L. Glutathione conjugation attenuates biological activities of 6-dehydroshogaol from ginger Food Chem. 2013, 140, 1– 8 DOI: 10.1016/j.foodchem.2013.02.073Google ScholarThere is no corresponding record for this reference.
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103McFadden, R.-M. T.; Larmonier, C. B.; Shehab, K. W.; Midura-Kiela, M.; Ramalingam, R.; Harrison, C. A.; Besselsen, D. G.; Chase, J. H.; Caporaso, J. G.; Jobin, C.; Ghishan, F. K.; Kiela, P. R. The role of curcumin in modulating colonic microbiota during colitis and colon cancer prevention Inflamm Bowel Dis. 2015, 21, 2483– 2494 DOI: 10.1097/MIB.0000000000000522Google Scholar103https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28%252Fnt1Kjug%253D%253D&md5=8b5ee2d67cfb8334eb405c0804af37b9The Role of Curcumin in Modulating Colonic Microbiota During Colitis and Colon Cancer PreventionMcFadden Rita-Marie T; Larmonier Claire B; Shehab Kareem W; Midura-Kiela Monica; Ramalingam Rajalakshmy; Harrison Christy A; Besselsen David G; Chase John H; Caporaso J Gregory; Jobin Christian; Ghishan Fayez K; Kiela Pawel RInflammatory bowel diseases (2015), 21 (11), 2483-94 ISSN:.BACKGROUND: Intestinal microbiota influences the progression of colitis-associated colorectal cancer. With diet being a key determinant of the gut microbial ecology, dietary interventions are an attractive avenue for the prevention of colitis-associated colorectal cancer. Curcumin is the most active constituent of the ground rhizome of the Curcuma longa plant, which has been demonstrated to have anti-inflammatory, antioxidative, and antiproliferative properties. METHODS: Il10 mice on 129/SvEv background were used as a model of colitis-associated colorectal cancer. Starting at 10 weeks of age, wild-type or Il10 mice received 6 weekly intraperitoneal injections of azoxymethane (AOM) or phosphate-buffered saline (PBS) and were started on either a control or a curcumin-supplemented diet. Stools were collected every 4 weeks for microbial community analysis. Mice were killed at 30 weeks of age. RESULTS: Curcumin-supplemented diet increased survival, decreased colon weight/length ratio, and, at 0.5%, entirely eliminated tumor burden. Although colonic histology indicated improvement with curcumin, no effects of mucosal immune responses have been observed in PBS/Il10 mice and limited effects were seen in AOM/Il10 mice. In wild-type and in Il10 mice, curcumin increased bacterial richness, prevented age-related decrease in alpha diversity, increased the relative abundance of Lactobacillales, and decreased Coriobacterales order. Taxonomic profile of AOM/Il10 mice receiving curcumin was more similar to those of wild-type mice than those fed control diet. CONCLUSIONS: In AOM/Il10 model, curcumin reduced or eliminated colonic tumor burden with limited effects on mucosal immune responses. The beneficial effect of curcumin on tumorigenesis was associated with the maintenance of a more diverse colonic microbial ecology.
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104Gupta, S. C.; Prasad, S.; Kim, J. H.; Patchva, S.; Webb, L. J.; Priyadarsini, I. K.; Aggarwal, B. B. Multitargeting by curcumin as revealed by molecular interaction studies Nat. Prod. Rep. 2011, 28, 1937– 1955 DOI: 10.1039/c1np00051aGoogle Scholar104https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsVOjt7rF&md5=0b57191439e921d89a2695aa49b602e5Multitargeting by curcumin as revealed by molecular interaction studiesGupta, Subash C.; Prasad, Sahdeo; Kim, Ji Hye; Patchva, Sridevi; Webb, Lauren J.; Priyadarsini, Indira K.; Aggarwal, Bharat B.Natural Product Reports (2011), 28 (12), 1937-1955CODEN: NPRRDF; ISSN:0265-0568. (Royal Society of Chemistry)A review. Curcumin (diferuloylmethane), the active ingredient in turmeric (Curcuma longa), is a highly pleiotropic mol. with anti-inflammatory, anti-oxidant, chemopreventive, chemosensitization, and radiosensitization activities. The pleiotropic activities attributed to curcumin come from its complex mol. structure and chem., as well as its ability to influence multiple signaling mols. Curcumin has been shown to bind by multiple forces directly to numerous signaling mols., such as inflammatory mols., cell survival proteins, protein kinases, protein reductases, histone acetyltransferase, histone deacetylase, glyoxalase I, xanthine oxidase, proteasome, HIV1 integrase, HIV1 protease, sarco (endo) plasmic reticulum Ca2+ ATPase, DNA methyltransferases 1, FtsZ protofilaments, carrier proteins, and metal ions. Curcumin can also bind directly to DNA and RNA. Owing to its β-diketone moiety, curcumin undergoes keto-enol tautomerism that has been reported as a favorable state for direct binding. The functional groups on curcumin found suitable for interaction with other macromols. include the α, β-unsatd. β-diketone moiety, carbonyl and enolic groups of the β-diketone moiety, methoxy and phenolic hydroxyl groups, and the Ph rings. Various biophys. tools have been used to monitor direct interaction of curcumin with other proteins, including absorption, fluorescence, Fourier transform IR (FTIR) and CD (CD) spectroscopy, surface plasmon resonance, competitive ligand binding, Forster type fluorescence resonance energy transfer (FRET), radiolabeling, site-directed mutagenesis, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), immunopptn., phage display biopanning, electron microscopy, 1-anilino-8-naphthalene-sulfonate (ANS) displacement, and co-localization. Mol. docking, the most commonly employed computational tool for calcg. binding affinities and predicting binding sites, has also been used to further characterize curcumin's binding sites. Furthermore, the ability of curcumin to bind directly to carrier proteins improves its soly. and bioavailability. In this review, we focus on how curcumin directly targets signaling mols., as well as the different forces that bind the curcumin-protein complex and how this interaction affects the biol. properties of proteins. We will also discuss various analogs of curcumin designed to bind selective targets with increased affinity.
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105Ghosh, S.; Banerjee, S.; Sil, P. C. The beneficial role of curcumin on inflammation, diabetes and neurodegenerative disease: A recent update Food Chem. Toxicol. 2015, 83, 111– 124 DOI: 10.1016/j.fct.2015.05.022Google Scholar105https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtVWgu7fJ&md5=f8e58560062b009bf029808ca161750aThe beneficial role of curcumin on inflammation, diabetes and neurodegenerative disease: A recent updateGhosh, Shatadal; Banerjee, Sharmistha; Sil, Parames C.Food and Chemical Toxicology (2015), 83 (), 111-124CODEN: FCTOD7; ISSN:0278-6915. (Elsevier Ltd.)The concept of using phytochems. has ushered in a new revolution in pharmaceuticals. Naturally occurring polyphenols (like curcumin, morin, resveratrol, etc.) have gained importance because of their minimal side effects, low cost and abundance. Curcumin (diferuloylmethane) is a component of turmeric isolated from the rhizome of Curcuma longa. Research for more than two decades has revealed the pleiotropic nature of the biol. effects of this mol. More than 7000 published articles have shed light on the various aspects of curcumin including its antioxidant, hypoglycemic, anti-inflammatory and anti-cancer activities. Apart from these well-known activities, this natural polyphenolic compd. also exerts its beneficial effects by modulating different signalling mols. including transcription factors, chemokines, cytokines, tumor suppressor genes, adhesion mols., microRNAs, etc. Oxidative stress and inflammation play a pivotal role in various diseases like diabetes, cancer, arthritis, Alzheimer's disease and cardiovascular diseases. Curcumin, therefore, could be a therapeutic option for the treatment of these diseases, provided limitations in its oral bioavailability can be overcome. The current review provides an updated overview of the metab. and mechanism of action of curcumin in various organ pathophysiologies. The review also discusses the potential for multifunctional therapeutic application of curcumin and its recent progress in clin. biol.
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106Oliveira, A. S.; Sousa, E.; Vasconcelos, M. H.; Pinto, M. Curcumin: A natural lead for potential new drug candidates Curr. Med. Chem. 2015, 22, 4196– 4232 DOI: 10.2174/0929867322666151029104611Google Scholar106https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXitVagur3K&md5=195c850b38a74c1f86c80819cfd88f48Curcumin: A Natural Lead for Potential New Drug CandidatesOliveira, Ana Sofia; Sousa, Emilia; Vasconcelos, Maria Helena; Pinto, MadalenaCurrent Medicinal Chemistry (2015), 22 (36), 4196-4232CODEN: CMCHE7; ISSN:0929-8673. (Bentham Science Publishers Ltd.)Curcumin (1) is a secondary metabolite of turmeric, derived from Curcuma longa L. and was shown to have many biol. activities. One of the most interesting properties of curcumin (1) is the antitumor activity allied with the ability to act as a multidrug resistance (MDR) modulator. Several curcumin derivs. have been synthesized with the purpose of discovering more information about the mechanisms of action, to establish structure-activity relationships (SAR), and to overcome pharmacokinetic problems. Over the past few decades, more potent and more stable curcumin derivs. have emerged with potential as drug candidates. Some important SAR studies pointed out that the unstable ,-unsatd. diketone linker present in curcumin (1) may not be necessary for the antitumor activity; generally, shorter linkers result in more potent compds. than curcumin (1); the type of substituents and their substitution pattern are crucial regarding the biol. activities of interest. Overall, the structure of curcumin (1) may represent an important basis for the development of more effective therapeutic agents, particularly in chemotherapy, as reflected by ongoing clin. trials. This article aims to review the synthesis and biol. activities of curcumin (1) and derivs., highlighting the MDR modulation properties of curcumin (1), since these effects makes this natural product a promising lead compd. for the development of new anticancer drugs.
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107Kundu, P.; Mohanty, C.; Sahoo, S. K. Antiglioma activity of curcumin-loaded lipid nanoparticles and its enhanced bioavailability in brain tissue for effective glioblastoma therapy Acta Biomater. 2012, 8, 2670– 2687 DOI: 10.1016/j.actbio.2012.03.048Google ScholarThere is no corresponding record for this reference.
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108Dilnawaz, F.; Singh, A.; Sahoo, S. K. Transferrin-conjugated curcumin-loaded superparamagnetic iron oxide nanoparticles induce augmented cellular uptake and apoptosis in K562 cells Acta Biomater. 2012, 8, 704– 719 DOI: 10.1016/j.actbio.2011.10.022Google ScholarThere is no corresponding record for this reference.
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109Ni, Z.; Xing, F.; Wang, P.; Cao, G. Retracted: Synthesis, characterization and release of curcumin-intercalated Mg–Al-layered double hydroxides Appl. Clay Sci. 2008, 40, 72– 80 DOI: 10.1016/j.clay.2007.07.008Google ScholarThere is no corresponding record for this reference.
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110Tomita, M.; Kawakami, H.; Uchihara, J. N.; Okudaira, T.; Masuda, M.; Takasu, N.; Matsuda, T.; Ohta, T.; Tanaka, Y.; Mori, N. Curcumin suppresses constitutive activation of AP-1 by downregulation of Jund protein in HTLV-1-infected T-cell lines Leuk. Res. 2006, 30, 313– 321 DOI: 10.1016/j.leukres.2005.08.004Google Scholar110https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XksFGhtw%253D%253D&md5=a6652fe29782705ee5b39fe42d2f7f73Curcumin suppresses constitutive activation of AP-1 by downregulation of JunD protein in HTLV-1-infected T-cell linesTomita, Mariko; Kawakami, Hirochika; Uchihara, Jun-Nosuke; Okudaira, Taeko; Masuda, Masato; Takasu, Nobuyuki; Matsuda, Takehiro; Ohta, Takao; Tanaka, Yuetsu; Mori, NaokiLeukemia Research (2006), 30 (3), 313-321CODEN: LEREDD; ISSN:0145-2126. (Elsevier B.V.)Activation of the activator protein 1 (AP-1) plays a crit. role in oncogenesis by human T-cell leukemia virus type 1 (HTLV-1), the etiol. agent of adult T-cell leukemia (ATL), and is required for maintenance of the malignant phenotype. Curcumin (diferuloylmethane), the major pigment of the spice turmeric, has anti-tumor activity; however, the effect of curcumin against ATL has not been elucidated. In this study, we examd. the effects of curcumin on AP-1 activity in HTLV-1-infected T-cell lines. Curcumin suppressed the constitutive AP-1 DNA-binding and transcriptional activity in HTLV-1-infected T-cell line. Curcumin also inhibited HTLV-1 Tax-induced AP-1 transcriptional activity. JunD was detectable as a major component of the AP-1-DNA complex in HTLV-1-infected T-cell lines using the supershift assay. The expression of JunD was suppressed by curcumin treatment. Curcumin inhibited the growth of HTLV-1-infected T-cell lines by inducing cell cycle arrest followed by apoptosis. Our results suggest that suppression of the constitutively active AP-1 by curcumin is due to, at least in-part, reducing the expression of JunD by curcumin. Inhibition of AP-1 activity by curcumin may be one of the mechanisms responsible for the anti-ATL effect of curcumin. We propose that curcumin is a potentially promising compd. for the treatment of ATL.
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111Mishra, A.; Kumar, R.; Tyagi, A.; Kohaar, I.; Hedau, S.; Bharti, A. C.; Sarker, S.; Dey, D.; Saluja, D.; Das, B. Curcumin modulates cellular AP-1, NF-kB, and HPV16 E6 proteins in oral cancer ecancer 2015, 9, 525 DOI: 10.3332/ecancer.2015.525Google ScholarThere is no corresponding record for this reference.
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112Tomita, M. Retraction: Curcumin targets Akt cell survival signaling pathway in HTLV-I-infected T-cell lines Cancer Sci. 2011, 102, 499 DOI: 10.1111/j.1349-7006.2010.01831.xGoogle Scholar112https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXitFSmu70%253D&md5=696d442e2dd7ae4601e65fc3fc72b816Anti-adult T-cell leukemia effects of a novel synthetic retinoid, Am80 (Tamibarotene). [Retraction of document cited in CA149:548495]Nakazato, Tetsuro; Okudaira, Taeko; Ishikawa, Chie; Nakama, Shinji; Sawada, Shigeki; Tomita, Mariko; Uchihara, Jun-nosuke; Taira, Naoya; Masuda, Masato; Tanaka, Yuetsu; Ohshiro, Kazuiku; Takasu, Nobuyuki; Mori, NaokiCancer Science (2011), 102 (2), 499CODEN: CSACCM; ISSN:1347-9032. (Wiley-Blackwell)This article has been retracted by the authors, the journal Editor-in-Chief, Yusuke Nakamura, and Blackwell Publishing Asia Pty Ltd., due to inappropriate image utilization in three of the figures within the article.
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113Balasubramanyam, K.; Varier, R. A.; Altaf, M.; Swaminathan, V.; Siddappa, N. B.; Ranga, U.; Kundu, T. K. Curcumin, a novel p300/CREB-binding protein-specific inhibitor of acetyltransferase, represses the acetylation of histone/nonhistone proteins and histone acetyltransferase-dependent chromatin transcription J. Biol. Chem. 2004, 279, 51163– 51171 DOI: 10.1074/jbc.M409024200Google ScholarThere is no corresponding record for this reference.
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114Simon, R. P.; Robaa, D.; Alhalabi, Z.; Sippl, W.; Jung, M. Katching-up on small molecule modulators of lysine acetyltransferases J. Med. Chem. 2016, 59, 1249– 1270 DOI: 10.1021/acs.jmedchem.5b01502Google Scholar114https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXitVygt7rK&md5=afcf613db1cfa04320b93aed8b25cec1KATching-Up on Small Molecule Modulators of Lysine AcetyltransferasesSimon, Roman P.; Robaa, Dina; Alhalabi, Zayan; Sippl, Wolfgang; Jung, ManfredJournal of Medicinal Chemistry (2016), 59 (4), 1249-1270CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The reversible acetylation of lysines is one of the best characterized epigenetic modifications. Its involvement in many key physiol. and pathol. processes has been documented in numerous studies. Lysine deacetylases (KDACs) and acetyltransferases (KATs) maintain the acetylation equil. at histones but also many other proteins. Besides acetylation, also other acyl groups are reversibly installed at the side chain of lysines in proteins. Because of their involvement in disease, KDACs and KATs were proposed to be promising drug targets, and for KDACs, indeed, five inhibitors are now approved for human use. While there is a similar level of evidence for the potential of KATs as drug targets, no inhibitor is in clin. trials. Here, we review the evidence for the diverse roles of KATs in disease pathol., provide an overview of structural features and the available modulators, including those targeting the bromodomains of KATs, and present an outlook.
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115Lu, X.; Deng, Y.; Yu, D.; Cao, H.; Wang, L.; Liu, L.; Yu, C.; Zhang, Y.; Guo, X.; Yu, G. Histone acetyltransferase p300 mediates histone acetylation of PS1 and BACE1 in a cellular model of Alzheimer’s disease PLoS One 2014, 9, e103067 DOI: 10.1371/journal.pone.0103067Google ScholarThere is no corresponding record for this reference.
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116Cui, L.; Miao, J.; Cui, L. Cytotoxic effect of curcumin on malaria parasite Plasmodium falciparum: Inhibition of histone acetylation and generation of reactive oxygen species Antimicrob. Agents Chemother. 2007, 51, 488– 494 DOI: 10.1128/AAC.01238-06Google Scholar116https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhsVOqurg%253D&md5=580eac24ab97fc225fc588f88091b5aeCytotoxic effect of curcumin on malaria parasite Plasmodium falciparum: inhibition of histone acetylation and generation of reactive oxygen speciesCui, Long; Miao, Jun; Cui, LiwangAntimicrobial Agents and Chemotherapy (2007), 51 (2), 488-494CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)The emergence of multidrug-resistant parasites is a major concern for malaria control, and development of novel drugs is a high priority. Curcumin, a natural polyphenolic compd., possesses diverse pharmacol. properties. Among its antiprotozoan activities, curcumin was potent against both chloroquine-sensitive and -resistant Plasmodium falciparum strains. Consistent with findings in mammalian cell lines, curcumin's prooxidant activity promoted the prodn. in P. falciparum of reactive oxygen species (ROS), whose cytotoxic effect could be antagonized by coincubation with antioxidants and ROS scavengers. Curcumin treatment also resulted in damage of both mitochondrial and nuclear DNA, probably due to the elevation of intracellular ROS. Furthermore, we have demonstrated that curcumin inhibited the histone acetyltransferase (HAT) activity of the recombinant P. falciparum general control nonderepressed 5 (PfGCN5) in vitro and reduced nuclear HAT activity of the parasite in culture. Curcumin-induced hypoacetylation of histone H3 at K9 and K14, but not H4 at K5, K8, K12, and K16, suggested that curcumin caused specific inhibition of the PfGCN5 HAT. Taken together, these results indicated that at least the generation of ROS and down-regulation of PfGCN5 HAT activity accounted for curcumin's cytotoxicity for malaria parasites.
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117Kutluay, S. B.; Doroghazi, J.; Roemer, M. E.; Triezenberg, S. J. Curcumin inhibits herpes simplex virus immediate-early gene expression by a mechanism independent of p300/CBP histone acetyltransferase activity Virology 2008, 373, 239– 247 DOI: 10.1016/j.virol.2007.11.028Google ScholarThere is no corresponding record for this reference.
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118Kang, S.-K.; Cha, S.-H.; Jeon, H.-G. Curcumin-induced histone hypoacetylation enhances caspase-3-dependent glioma cell death and neurogenesis of neural progenitor cells Stem Cells Dev. 2006, 15, 165– 174 DOI: 10.1089/scd.2006.15.165Google ScholarThere is no corresponding record for this reference.
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119Chen, W.; Bacanamwo, M.; Harrison, D. G. Activation of p300 histone acetyltransferase activity is an early endothelial response to laminar shear stress and is essential for stimulation of endothelial nitric-oxide synthase mRNA transcription J. Biol. Chem. 2008, 283, 16293– 16298 DOI: 10.1074/jbc.M801803200Google ScholarThere is no corresponding record for this reference.
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120Chiu, J.; Khan, Z. A.; Farhangkhoee, H.; Chakrabarti, S. Curcumin prevents diabetes-associated abnormalities in the kidneys by inhibiting p300 and nuclear factor-kappaB Nutrition 2009, 25, 964– 972 DOI: 10.1016/j.nut.2008.12.007Google ScholarThere is no corresponding record for this reference.
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121Collins, H. M.; Abdelghany, M. K.; Messmer, M.; Yue, B.; Deeves, S. E.; Kindle, K. B.; Mantelingu, K.; Aslam, A.; Winkler, G. S.; Kundu, T. K.; Heery, D. M. Differential effects of garcinol and curcumin on histone and p53 modifications in tumour cells BMC Cancer 2013, 13, 37 DOI: 10.1186/1471-2407-13-37Google ScholarThere is no corresponding record for this reference.
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122Dahlin, J. L.; Nissink, J. W. M.; Strasser, J. M.; Francis, S.; Higgins, L.; Zhou, H.; Zhang, Z.; Walters, M. A. PAINS in the assay: Chemical mechanisms of assay interference and promiscuous enzymatic inhibition observed during a sulfhydryl-scavenging HTS J. Med. Chem. 2015, 58, 2091– 2113 DOI: 10.1021/jm5019093Google Scholar122https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhvVeisbY%253D&md5=3f77702544cea2ec4c8184b60dd38b8aPAINS in the Assay: Chemical Mechanisms of Assay Interference and Promiscuous Enzymatic Inhibition Observed during a Sulfhydryl-Scavenging HTSDahlin, Jayme L.; Nissink, J. Willem M.; Strasser, Jessica M.; Francis, Subhashree; Higgins, LeeAnn; Zhou, Hui; Zhang, Zhiguo; Walters, Michael A.Journal of Medicinal Chemistry (2015), 58 (5), 2091-2113CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Significant resources in early drug discovery are spent unknowingly pursuing artifacts and promiscuous bioactive compds., while understanding the chem. basis for these adverse behaviors often goes unexplored in pursuit of lead compds. Nearly all the hits from our recent sulfhydryl-scavenging high-throughput screen (HTS) targeting the histone acetyltransferase Rtt109 were such compds. Herein, we characterize the chem. basis for assay interference and promiscuous enzymic inhibition for several prominent chemotypes identified by this HTS, including some pan-assay interference compds. (PAINS). Protein mass spectrometry and ALARM NMR confirmed these compds. react covalently with cysteines on multiple proteins. Unfortunately, compds. contg. these chemotypes have been published as screening actives in reputable journals and even touted as chem. probes or preclin. candidates. Our detailed characterization and identification of such thiol-reactive chemotypes should accelerate triage of nuisance compds., guide screening library design, and prevent follow-up on undesirable chem. matter.
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123Bora-Tatar, G.; Dayangac-Erden, D.; Demir, A. S.; Dalkara, S.; Yelekci, K.; Erdem-Yurter, H. Molecular modifications on carboxylic acid derivatives as potent histone deacetylase inhibitors: Activity and docking studies Bioorg. Med. Chem. 2009, 17, 5219– 5228 DOI: 10.1016/j.bmc.2009.05.042Google Scholar123https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXosVyqsr4%253D&md5=16c0ee960291fadf786fbb4f099ff3beMolecular modifications on carboxylic acid derivatives as potent histone deacetylase inhibitors: Activity and docking studiesBora-Tatar, Gamze; Dayangac-Erden, Didem; Demir, Ayhan S.; Dalkara, Sevim; Yelekci, Kemal; Erdem-Yurter, HayatBioorganic & Medicinal Chemistry (2009), 17 (14), 5219-5228CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)In the light of known HDAC inhibitors, 33 carboxylic acid derivs. were tested to understand the structural requirements for HDAC inhibition activity. Several modifications were applied to develop the structure-activity relationships of carboxylic acid HDAC inhibitors. HDAC inhibition activities were investigated in vitro by using HeLa nuclear ext. in a fluorimetric assay. Mol. docking was also carried out for the human HDAC8 enzyme in order to predict inhibition activity and the 3D poses of inhibitor-enzyme complexes. Of these compds., caffeic acid derivs. such as chlorogenic acid and curcumin were found to be highly potent compared to sodium butyrate, which is a well-known HDAC inhibitor.
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124Wang, S.-H.; Lin, P.-Y.; Chiu, Y.-C.; Huang, J.-S.; Kuo, Y.-T.; Wu, J.-C.; Chen, C.-C. Curcumin-mediated HDAC inhibition suppresses the DNA damage response and contributes to increased DNA damage sensitivity PLoS One 2015, 10, e0134110/0134111– e0134110/0134119 DOI: 10.1371/journal.pone.0134110Google ScholarThere is no corresponding record for this reference.
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125Link, A.; Balaguer, F.; Goel, A. Cancer chemoprevention by dietary polyphenols: Promising role for epigenetics Biochem. Pharmacol. (Amsterdam, Neth.) 2010, 80, 1771– 1792 DOI: 10.1016/j.bcp.2010.06.036Google ScholarThere is no corresponding record for this reference.
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126Rajendran, P.; Ho, E.; Williams, D. E.; Dashwood, R. H. Dietary phytochemicals, HDAC inhibition, and DNA damage/repair defects in cancer cells Clin. Epigenet. 2011, 3, 4 DOI: 10.1186/1868-7083-3-4Google Scholar126https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsFSrur%252FN&md5=51eb4a6b37e6448f267c47ff625fe92bDietary phytochemicals, HDAC inhibition, and DNA damage/repair defects in cancer cellsRajendran, Praveen; Ho, Emily; Williams, David E.; Dashwood, Roderick H.Clinical Epigenetics (2011), 3 (), 4CODEN: CELPCI; ISSN:1868-7083. (BioMed Central Ltd.)A review. Genomic instability is a common feature of cancer etiol. This provides an avenue for therapeutic intervention, since cancer cells are more susceptible than normal cells to DNA damaging agents. However, there is growing evidence that the epigenetic mechanisms that impact DNA methylation and histone status also contribute to genomic instability. The DNA damage response, for example, is modulated by the acetylation status of histone and non-histone proteins, and by the opposing activities of histone acetyltransferase and histone deacetylase (HDAC) enzymes. Many HDACs overexpressed in cancer cells have been implicated in protecting such cells from genotoxic insults. Thus, HDAC inhibitors, in addn. to unsilencing tumor suppressor genes, also can silence DNA repair pathways, inactivate non-histone proteins that are required for DNA stability, and induce reactive oxygen species and DNA double-strand breaks. This review summarizes how dietary phytochems. that affect the epigenome also can trigger DNA damage and repair mechanisms. Where such data is available, examples are cited from studies in vitro and in vivo of polyphenols, organosulfur/organoselenium compds., indoles, sesquiterpene lactones, and misc. agents such as anacardic acid. Finally, by virtue of their genetic and epigenetic mechanisms, cancer chemopreventive agents are being redefined as chemo- or radio-sensitizers. A sustained DNA damage response coupled with insufficient repair may be a pivotal mechanism for apoptosis induction in cancer cells exposed to dietary phytochems. Future research, including appropriate clin. investigation, should clarify these emerging concepts in the context of both genetic and epigenetic mechanisms dysregulated in cancer, and the pros and cons of specific dietary intervention strategies.
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127Bustanji, Y.; Taha, M. O.; Almasri, I. M.; Al-Ghussein, M. A. S.; Mohammad, M. K.; Alkhatib, H. S. Inhibition of glycogen synthase kinase by curcumin: Investigation by simulated molecular docking and subsequent in vitro/in vivo evaluation J. Enzyme Inhib. Med. Chem. 2009, 24, 771– 778 DOI: 10.1080/14756360802364377Google Scholar127https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXmtl2qsrk%253D&md5=fdbbd01680853a24049aa61bc73dd3fdInhibition of glycogen synthase kinase by curcumin: Investigation by simulated molecular docking and subsequent in vitro/in vivo evaluationBustanji, Yasser; Taha, Mutasem O.; Almasri, Ihab M.; Al-Ghussein, Mohamed A. S.; Mohammad, Mohammad K.; Alkhatib, Hatim S.Journal of Enzyme Inhibition and Medicinal Chemistry (2009), 24 (3), 771-778CODEN: JEIMAZ; ISSN:1475-6366. (Informa Healthcare)Curcumin was investigated as an inhibitor of glycogen synthase kinase-3β (GSK-3β) in an attempt to explain some of its interesting multiple pharmacol. effects, such as its anti-diabetic, anti-inflammatory, anti-cancer, anti-malarial and anti-alzheimer's properties. The investigation included simulated docking expts. to fit curcumin within the binding pocket of GSK-3β followed by exptl. in vitro and in vivo validations. Curcumin was found to optimally fit within the binding pocket of GSK-3β via several attractive interactions with key amino acids. Exptl., curcumin was found to potently inhibit GSK-3β (IC50 = 66.3 nM). Furthermore, our in vivo expts. illustrated that curcumin significantly increases liver glycogen in fasting Balb/c mice. Our findings strongly suggest that the diverse pharmacol. activities of curcumin are at least partially mediated by inhibition of GSK-3β.
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128Di Martino, R. M.; De Simone, A.; Andrisano, V.; Bisignano, P.; Bisi, A.; Gobbi, S.; Rampa, A.; Fato, R.; Bergamini, C.; Perez, D. I.; Martinez, A.; Bottegoni, G.; Cavalli, A.; Belluti, F. Versatility of the curcumin scaffold: Discovery of potent and balanced dual BACE-1 and GSK-3beta inhibitors J. Med. Chem. 2016, 59, 531– 544 DOI: 10.1021/acs.jmedchem.5b00894Google Scholar128https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXitVGrsLrJ&md5=349916a940c9cc8d87ca817c689756f1Versatility of the Curcumin Scaffold: Discovery of Potent and Balanced Dual BACE-1 and GSK-3β InhibitorsDi Martino, Rita Maria Concetta; De Simone, Angela; Andrisano, Vincenza; Bisignano, Paola; Bisi, Alessandra; Gobbi, Silvia; Rampa, Angela; Fato, Romana; Bergamini, Christian; Perez, Daniel I.; Martinez, Ana; Bottegoni, Giovanni; Cavalli, Andrea; Belluti, FedericaJournal of Medicinal Chemistry (2016), 59 (2), 531-544CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The multitarget approach has gained increasing acceptance as a useful tool to address complex and multifactorial maladies such as Alzheimer's disease (AD). The concurrent inhibition of the validated AD targets β-secretase (BACE-1) and glycogen synthase kinase-3β (GSK-3β) by attacking both β-amyloid and tau protein cascades has been identified as a promising AD therapeutic strategy. In our study, curcumin was identified as a lead compd. for the simultaneous inhibition of both targets; therefore, synthetic efforts were dedicated to obtaining a small library of novel curcumin-based analogs, and a no. of potent and balanced dual-target inhibitors were obtained. In particular, 2, 6, and 7 emerged as promising drug candidates endowed with neuroprotective potential and brain permeability. Notably, for some new compds. the sym. diketo and the β-keto-enol tautomeric forms were purposely isolated and tested in vitro, allowing us to gain insight into the key requirements for BACE-1 and GSK-3β inhibition.
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129Zhang, X.; Yin, W. K.; Shi, X. D.; Li, Y. Curcumin activates Wnt/beta-catenin signaling pathway through inhibiting the activity of GSK-3beta in APPswe transfected SY5Y cells Eur. J. Pharm. Sci. 2011, 42, 540– 546 DOI: 10.1016/j.ejps.2011.02.009Google Scholar129https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXkvFamu7w%253D&md5=a97d1ccf76a14e414519873d8b34b606Curcumin activates Wnt/β-catenin signaling pathway through inhibiting the activity of GSK-3β in APPswe transfected SY5Y cellsZhang, Xiong; Yin, Wen-ke; Shi, Xiao-dong; Li, YuEuropean Journal of Pharmaceutical Sciences (2011), 42 (5), 540-546CODEN: EPSCED; ISSN:0928-0987. (Elsevier B.V.)Wnt/β-catenin signaling pathway plays an important role in the genesis and development of Alzheimer's disease. The study aims to investigate the effect of Curcumin on the expression of GSK-3β, β-catenin and CyclinD1 in vitro, which are tightly correlated with Wnt/β-catenin signaling pathway, and also to explore the mechanisms, which will provide a novel therapeutic intervention for treatment of Alzheimer's disease. Plasmid APPswe and BACE1-mychis were transiently co-transfected into SHSY5Y cells by Liposfectamin 2000. The cells were treated with Curcumin at 0, 1.25, 5.0, 20.0 μmol/L for 24 h, or with Curcumin at 5.0 μmol/L for 0, and 12, 24 and 48 h for time course assay. Cell lysates were collected for RT-PCR, Western blot assay and immunofluorescent staining were carried out for detecting the effect of Curcumin on the expression of GSK-3β, β-catenin and CyclinD1. RT-PCR and Western blot results showed that the expression of GSK-3β mRNA and protein significantly decreased in the transfected cells treated with Curcumin, and that the changes were in a dose and time-dependent manner (P < 0.05); however, the protein expression of GSK-3β-Ser9 was increased (P < 0.05). Meanwhile, the expressions of β-catenin and transcriptional factors CyclinD1 mRNA and protein increased and the changes were also in a dose and time-dependent manner (P < 0.05). Immunofluorescent staining results not only confirmed the above changes, but also showed that β-catenin had translocated into the nucleus gradually with the increased dosage of Curcumin. Therefore, GSK-3β is a potential target for treatment of AD. Curcumin could activate the Wnt/β-catenin signaling pathway through inhibiting the expression of GSK-3β and inducing the expression of β-catenin and CyclinD1, which will provide a new theory for treatment of neurodegenerative diseases by Curcumin.
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130Yun, J. H.; Park, Y. G.; Lee, K. M.; Kim, J.; Nho, C. W. Curcumin induces apoptotic cell death via Oct4 inhibition and GSK-3beta activation in NCCIT cells Mol. Nutr. Food Res. 2015, 59, 1053– 1062 DOI: 10.1002/mnfr.201400739Google Scholar130https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXnt1Wlsbw%253D&md5=a44051729c7c6e42393b5d1b4db9b325Curcumin induces apoptotic cell death via Oct4 inhibition and GSK-3β activation in NCCIT cellsYun, Ji Ho; Park, Young Gyun; Lee, Kyung-Mi; Kim, Jungho; Nho, Chu WonMolecular Nutrition & Food Research (2015), 59 (6), 1053-1062CODEN: MNFRCV; ISSN:1613-4125. (Wiley-VCH Verlag GmbH & Co. KGaA)Scope : Octamer-binding transcription factor 4 (Oct4) is a key regulator of pluripotent embryonic stem cell maintenance. However, increasing evidence has suggested that Oct4 is also expressed in cancer stem cells (CSCs) and is assocd. with tumor progression and chemoresistance. Curcumin (CUR) is a widely used cancer chemopreventive agent, and it has been used to treat several diseases including cancers. Here, we investigated whether CUR-induced apoptotic cell death by inhibiting Oct4 levels and examg. mol. mechanisms in NCCIT human embryonic carcinoma cells. Methods and results : CUR significantly inhibited Oct4 transcription levels in a dose-dependent manner by dual luciferase expt., also decreased mRNA and protein levels in NCCIT human embryonic carcinoma cells, which express high levels of endogenous Oct4. Interestingly, we found that CUR treatment increased apoptotic cell death including subG0/G1 contents, cleavage caspases, and pro-apoptotic protein, as confirmed with a series of loss-of-function expts. using Oct4 siRNA. Furthermore, CUR induced marked total level of glycogen synthase kinase 3 beta (GSK-3β), resulting in an increase in apoptotic cell death, was evaluated using chem. inhibitor of GSK3-3β. Conclusion : These data suggest that CUR induces apoptotic cell death through Oct4 inhibition and GSK-3β activation. Thus, CUR may be a useful cancer chemopreventive agent to suppress tumor progression or to improve chemoresistance by eliminating CSCs.
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131Xiong, Z.; Hongmei, Z.; Lu, S.; Yu, L. Curcumin mediates presenilin-1 activity to reduce β-amyloid production in a model of Alzheimer’s disease Pharmacol. Rep. 2011, 63, 1101– 1108 DOI: 10.1016/S1734-1140(11)70629-6Google Scholar131https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC38%252FotlKrsw%253D%253D&md5=0c236679133b5c777f1fc92e77feeb84Curcumin mediates presenilin-1 activity to reduce β-amyloid production in a model of Alzheimer's DiseaseXiong Zhang; Hongmei Zhang; Lu Si; Yu LiPharmacological reports : PR (2011), 63 (5), 1101-8 ISSN:1734-1140.Curcumin has been reported to inhibit the generation of Aβ, but the underlying mechanisms by which this occurs remain unknown. Aβ is thought to play an important role in the pathogenesis of Alzheimer's disease (AD). The amyloid hypothesis argues that aggregates of Aβ trigger a complex pathological cascade that leads to neurodegeneration. Aβ is generated by the processing of APP (amyloid precursor protein) by β- and γ-secretases. Presenilin 1 (PS1) is central to γ-secretase activity and is a substrate for GSK-3β, both of which are implicated in the pathogenesis of AD. The present study aimed to investigate the effects of curcumin on the generation of Aβ in cultured neuroblastoma cells and on the in vitro expression of PS1 and GSK-3β. To stimulate Aβ production, a plasmid expressing APP was transfected into human SH-SY5Y neuroblastoma cells. The transfected cells were then treated with curcumin at 0-20 μM for 24 h or with 5 μM curcumin for 0-48 h, and the extracellular levels of Aβ(40/42) were determined by ELISA. The levels of PS1 and GSK-3β mRNA were measured by RT-PCR, and the expression of the PS1 and GSK-3β proteins (including the phosphorylated form of GSK-3β, p-GSK-3β-Ser9) were evaluated by western blotting. Curcumin treatment was found to markedly reduce the production of Aβ(40/42). Treatment with curcumin also decreased both PS1 and GSK-3β mRNA and protein levels in a dose- and time-dependent manner. Furthermore, curcumin increased the inhibitory phosphorylation of GSK-3β protein at Ser9. Therefore, we propose that curcumin decreases Aβ production by inhibiting GSK-3β-mediated PS1 activation.
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132Dahlin, J. L.; Inglese, J.; Walters, M. A. Mitigating risk in academic preclinical drug discovery Nat. Rev. Drug Discovery 2015, 14, 279– 294 DOI: 10.1038/nrd4578Google Scholar132https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXls1artLg%253D&md5=9c7548364bfe54e25e013985436ba876Mitigating risk in academic preclinical drug discoveryDahlin, Jayme L.; Inglese, James; Walters, Michael A.Nature Reviews Drug Discovery (2015), 14 (4), 279-294CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)The no. of academic drug discovery centers has grown considerably in recent years, providing new opportunities to couple the curiosity-driven research culture in academia with rigorous preclin. drug discovery practices used in industry. To fully realize the potential of these opportunities, it is important that academic researchers understand the risks inherent in preclin. drug discovery, and that translational research programs are effectively organized and supported at an institutional level. In this article, we discuss strategies to mitigate risks in several key aspects of preclin. drug discovery at academic drug discovery centers, including organization, target selection, assay design, medicinal chem. and preclin. pharmacol.
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133Yang, F.; Lim, G. P.; Begum, A. N.; Ubeda, O. J.; Simmons, M. R.; Ambegaokar, S. S.; Chen, P. P.; Kayed, R.; Glabe, C. G.; Frautschy, S. A.; Cole, G. M. Curcumin inhibits formation of amyloid beta oligomers and fibrils, binds plaques, and reduces amyloid in vivo J. Biol. Chem. 2005, 280, 5892– 5901 DOI: 10.1074/jbc.M404751200Google Scholar133https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtlClt7w%253D&md5=5f8f6fb0c3529ba9dbeae5f8af096250Curcumin Inhibits Formation of Amyloid β Oligomers and Fibrils, Binds Plaques, and Reduces Amyloid in VivoYang, Fusheng; Lim, Giselle P.; Begum, Aynun N.; Ubeda, Oliver J.; Simmons, Mychica R.; Ambegaokar, Surendra S.; Chen, Pingping P.; Kayed, Rakez; Glabe, Charles G.; Frautschy, Sally A.; Cole, Gregory M.Journal of Biological Chemistry (2005), 280 (7), 5892-5901CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)Alzheimer's disease (AD) involves amyloid β (Aβ) accumulation, oxidative damage, and inflammation, and risk is reduced with increased antioxidant and anti-inflammatory consumption. The phenolic yellow curry pigment curcumin has potent anti-inflammatory and antioxidant activities and can suppress oxidative damage, inflammation, cognitive deficits, and amyloid accumulation. Since the mol. structure of curcumin suggested potential Aβ binding, we investigated whether its efficacy in AD models could be explained by effects on Aβ aggregation. Under aggregating conditions in vitro, curcumin inhibited aggregation (IC50 = 0.8 μM) as well as disaggregated fibrillar Aβ40 (IC50 = 1 μM), indicating favorable stoichiometry for inhibition. Curcumin was a better Aβ40 aggregation inhibitor than ibuprofen and naproxen, and prevented Aβ42 oligomer formation and toxicity between 0.1 and 1.0 μM. Under EM, curcumin decreased dose dependently Aβ fibril formation beginning with 0.125 μM. The effects of curcumin did not depend on Aβ sequence but on fibril-related conformation. AD and Tg2576 mice brain sections incubated with curcumin revealed preferential labeling of amyloid plaques. In vivo studies showed that curcumin injected peripherally into aged Tg mice crossed the blood-brain barrier and bound plaques. When fed to aged Tg2576 mice with advanced amyloid accumulation, curcumin labeled plaques and reduced amyloid levels and plaque burden. Hence, curcumin directly binds small β-amyloid species to block aggregation and fibril formation in vitro and in vivo. These data suggest that low dose curcumin effectively disaggregates Aβ as well as prevents fibril and oligomer formation, supporting the rationale for curcumin use in clin. trials preventing or treating AD.
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134Hudson, S. A.; Ecroyd, H.; Kee, T. W.; Carver, J. A. The thioflavin T fluorescence assay for amyloid fibril detection can be biased by the presence of exogenous compounds FEBS J. 2009, 276, 5960– 5972 DOI: 10.1111/j.1742-4658.2009.07307.xGoogle Scholar134https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXht12qs7rI&md5=2ea6162d19419134f3ff894be6686d78The thioflavin T fluorescence assay for amyloid fibril detection can be biased by the presence of exogenous compoundsHudson, Sean A.; Ecroyd, Heath; Kee, Tak W.; Carver, John A.FEBS Journal (2009), 276 (20), 5960-5972CODEN: FJEOAC; ISSN:1742-464X. (Wiley-Blackwell)Thioflavin T (ThT) dye fluorescence is used regularly to quantify the formation and inhibition of amyloid fibrils in the presence of anti-amyloidogenic compds. such as polyphenols. However, in this study, it was shown, using three polyphenolics (curcumin, quercetin and resveratrol), that ThT fluorescence should be used with caution in the presence of such exogenous compds. The strong absorptive and fluorescent properties of quercetin and curcumin were found to significantly bias the ThT fluorescence readings in both in situ real-time ThT assays and single time-point diln. ThT-type assays. The presence of curcumin at concns. as low as 0.01 and 1 μM was sufficient to interfere with the ThT fluorescence assocd. with fibrillar amyloid-β(1-42) (0.5 μM) and fibrillar reduced and carboxymethylated κ-casein (50 μM), resp. The ThT fluorescence assocd. with fibrillar amyloid-β(1-42) was also biased using higher concns. of resveratrol, a polyphenol that is not spectroscopically active at the wavelengths of ThT fluorescence, implying that there can be direct interactions between ThT and the exogenous compd. and/or competitive binding with ThT for the fibrils. Thus, in all cases where ThT is used in the presence of an exogenous compd., biases for amyloid-assocd. ThT fluorescence should be tested, regardless of whether the additive is spectroscopically active. Simple methods to conduct these tests were described. The Congo red spectral shift assay is demonstrated as a more viable spectrophotometric alternative to ThT, but allied methods, such as TEM, should also be used to assess fibril formation independently of dye-based assays.
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135Thapa, A.; Jett, S. D.; Chi, E. Y. Curcumin attenuates amyloid-β aggregate toxicity and modulates amyloid-β aggregation pathway ACS Chem. Neurosci. 2016, 7, 56– 68 DOI: 10.1021/acschemneuro.5b00214Google Scholar135https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhslGms7bP&md5=8da11a9c15080af82688e26ed5ec639eCurcumin Attenuates Amyloid-β Aggregate Toxicity and Modulates Amyloid-β Aggregation PathwayThapa, Arjun; Jett, Stephen D.; Chi, Eva Y.ACS Chemical Neuroscience (2016), 7 (1), 56-68CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)The abnormal misfolding and aggregation of amyloid-β (Aβ) peptides into β-sheet enriched insol. deposits initiates a cascade of events leading to pathol. processes and culminating in cognitive decline in Alzheimer's disease (AD). In particular, sol. oligomeric/prefibrillar Aβ have been shown to be potent neurotoxins. The naturally occurring polyphenol curcumin has been shown to exert a neuroprotective effect against age-related neurodegenerative diseases such as AD. However, its protective mechanism remains unclear. In this study, we investigated the effects of curcumin on the aggregation of Aβ40 as well as Aβ40 aggregate induced neurotoxicity. Our results show that the curcumin does not inhibit Aβ fibril formation, but rather enriches the population of "off-pathway" sol. oligomers and prefibrillar aggregates that were nontoxic. Curcumin also exerted a nonspecific neuroprotective effect, reducing toxicities induced by a range of Aβ conformers, including monomeric, oligomeric, prefibrillar, and fibrillar Aβ. The neuroprotective effect is possibly membrane-mediated, as curcumin reduced the extent of cell membrane permeabilization induced by Aβ aggregates. Taken together, our study shows that curcumin exerts its neuroprotective effect against Aβ induced toxicity through at least two concerted pathways, modifying the Aβ aggregation pathway toward the formation of nontoxic aggregates and ameliorating Aβ-induced toxicity possibly through a nonspecific pathway.
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136Kayed, R.; Head, E.; Thompson, J. L.; McIntire, T. M.; Milton, S. C.; Cotman, C. W.; Glabe, C. G. Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis Science (Washington, DC, U. S.) 2003, 300, 486– 489 DOI: 10.1126/science.1079469Google Scholar136https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXivFyms7k%253D&md5=028225aa14803cc25c308d6b77679412Common Structure of Soluble Amyloid Oligomers Implies Common Mechanism of PathogenesisKayed, Rakez; Head, Elizabeth; Thompson, Jennifer L.; McIntire, Theresa M.; Milton, Saskia C.; Cotman, Carl W.; Glabe, Charles G.Science (Washington, DC, United States) (2003), 300 (5618), 486-489CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)Sol. oligomers are common to most amyloids and may represent the primary toxic species of amyloids, like the Aβ peptide in Alzheimer's disease (AD). Here the authors show that all of the sol. oligomers tested display a common conformation-dependent structure that is unique to sol. oligomers regardless of sequence. The in vitro toxicity of sol. oligomers is inhibited by oligomer-specific antibody. Sol. oligomers have a unique distribution in human AD brain that is distinct from fibrillar amyloid. These results indicate that different types of sol. amyloid oligomers have a common structure and suggest they share a common mechanism of toxicity.
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137Feng, B. Y.; Shoichet, B. K. A detergent-based assay for the detection of promiscuous inhibitors Nat. Protoc. 2006, 1, 550– 553 DOI: 10.1038/nprot.2006.77Google Scholar137https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhtFOitLjO&md5=8aa7562b5f69c896af7e133ecc35e6deA detergent-based assay for the detection of promiscuous inhibitorsFeng, Brian Y.; Shoichet, Brian K.Nature Protocols (2006), 1 (2), 550-553CODEN: NPARDW; ISSN:1750-2799. (Nature Publishing Group)At micromolar concns., many small mols. self-assoc. into colloidal aggregates that non-specifically inhibit enzymes and other proteins. Here the authors describe a protocol for identifying aggregate-based inhibitors and distinguishing them from small mols. that inhibit via specific mechanisms. As a convenient proxy for promiscuous, aggregate-based inhibition, the authors monitor inhibition of β-lactamase in the absence and presence of detergent. Inhibition that is attenuated in the presence of detergent is characteristic of an aggregate-based mechanism. In the 96-well-format assay described here, about 200 mols. can be tested, in duplicate, per h for detergent-dependent sensitivity. Furthermore, the authors also describe simple expts. that can offer addnl. confirmation of aggregate-based inhibition.
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138Egan, M. E.; Pearson, M.; Weiner, S. A.; Rajendran, V.; Rubin, D.; Gloeckner-Pagel, J.; Canny, S.; Du, K.; Lukacs, G. L.; Caplan, M. J. Curcumin, a major constituent of turmeric, corrects cystic fibrosis defects Science (Washington, DC, U. S.) 2004, 304, 600– 602 DOI: 10.1126/science.1093941Google Scholar138https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXjt1Crsrs%253D&md5=00a8ab6438aee2d6198965e41f1fb379Curcumin, a major constituent of turmeric, corrects cystic fibrosis defectsEgan, Marie E.; Pearson, Marilyn; Weiner, Scott A.; Rajendran, Vanathy; Rubin, Daniel; Gloeckner-Pagel, Judith; Canny, Susan; Du, Kai; Lukacs, Gergely L.; Caplan, Michael J.Science (Washington, DC, United States) (2004), 304 (5670), 600-602CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)Cystic fibrosis is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). The most common mutation, ΔF508, results in the prodn. of a misfolded CFTR protein that is retained in the endoplasmic reticulum and targeted for degrdn. Curcumin is a nontoxic Ca-ATPase pump inhibitor that can be administered to humans safely. Oral administration of curcumin to homozygous ΔF508 CFTR mice in doses comparable, on a wt.-per-wt. basis, to those well tolerated by humans cor. these animals' characteristic nasal p.d. defect. These effects were not obsd. in mice homozygous for a complete knockout of the CFTR gene. Curcumin also induced the functional appearance of ΔF508 CFTR protein in the plasma membranes of transfected baby hamster kidney cells. Thus, curcumin treatment may be able to correct defects assocd. with the homozygous expression of ΔF508 CFTR.
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139Song, Y.; Sonawane, N. D.; Salinas, D.; Qian, L.; Pedemonte, N.; Galietta, L. J. V.; Verkman, A. S. Evidence against the rescue of defective ΔF508-CFTR cellular processing by curcumin in cell culture and mouse models J. Biol. Chem. 2004, 279, 40629– 40633 DOI: 10.1074/jbc.M407308200Google ScholarThere is no corresponding record for this reference.
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140Dey, I.; Shah, K.; Bradbury, N. A. Natural compounds as therapeutic agents in the treatment cystic fibrosis J. Genet. Syndr. Gene Ther. 2016, 7, 284 DOI: 10.4172/2157-7412.1000284Google ScholarThere is no corresponding record for this reference.
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141Seely, K. A.; Levi, M. S.; Prather, P. L. The dietary polyphenols trans-resveratrol and curcumin selectively bind human CB1 cannabinoid receptors with nanomolar affinities and function as antagonists/inverse agonists J. Pharmacol. Exp. Ther. 2009, 330, 31– 39 DOI: 10.1124/jpet.109.151654Google Scholar141https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXosFGhsbk%253D&md5=fdee663c3bd88a2f808e31e6a118d1c3The dietary polyphenols trans-resveratrol and curcumin selectively bind human CB1 cannabinoid receptors with nanomolar affinities and function as antagonists/inverse agonistsSeely, Kathryn A.; Levi, Mark S.; Prather, Paul L.Journal of Pharmacology and Experimental Therapeutics (2009), 330 (1), 31-39CODEN: JPETAB; ISSN:0022-3565. (American Society for Pharmacology and Experimental Therapeutics)The dietary polyphenols trans-resveratrol [5-[(1E)-2-(4-hydroxyphenyl)ethenyl]-1,3-benzenediol; found in red wine] and curcumin [1,7-bis(4-hydroxy-3-methoxyphenyl)-1E,6E-heptadiene-3,5-dione] (found in curry powders) exert anti-inflammatory and antioxidant effects via poorly defined mechanisms. It is interesting that cannabinoids, derived from the marijuana plant (Cannabis sativa), produce similar protective effects via CB1 and CB2 receptors. We examd. whether trans-resveratrol, curcumin, and ASC-J9 [1,7-bis(3,4-dimethoxyphenyl)-5-hydroxy-1E,4E,6E-heptatriene-3-one] (a curcumin analog) act at ligands at cannabinoid receptors. All three bind to human (h) CB1 and mouse CB1 receptors with nanomolar affinities, displaying only micromolar affinities for hCB2 receptors. Characteristic of inverse agonists, the polyphenols inhibit basal G-protein activity in membranes prepd. from Chinese hamster ovary (CHO)-hCB1 cells or mouse brain that is reversed by a neutral CB1 antagonist. Furthermore, they competitively antagonize G-protein activation produced by a CB1 agonist. In intact CHO-hCB1 cells, the polyphenols act as neutral antagonists, producing no effect when tested alone, whereas competitively antagonizing CB1 agonist mediated inhibition of adenylyl cyclase activity. Confirming their neutral antagonist profile in cells, the polyphenols similarly attenuate stimulation of adenylyl cyclase activity produced by a CB1 inverse agonist. In mice, the polyphenols dose-dependently reverse acute hypothermia produced by a CB1 agonist. Upon repeated administration, the polyphenols also reduce body wt. in mice similar to that produced by a CB1 antagonist/inverse agonist. Finally, transresveratrol and curcumin share common structural motifs with other known cannabinoid receptor ligands. Collectively, we suggest that trans-resveratrol and curcumin act as antagonists/inverse agonists at CB1 receptors at dietary relevant concns. Therefore, these polyphenols and their derivs. might be developed as novel, nontoxic CB1 therapeutics for obesity and/or drug dependence.
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142Prather, P. L.; Seely, K. A.; Levi, M. S. Notice of retraction J. Pharmacol. Exp. Ther. 2009, 331, 1147Google Scholar142https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhsFaqsLjL&md5=843e2d615d3727f76083e4e0fe5b7caePolyphenols and cannabinoid receptor functional agonismPrather, Paul L.; Seely, Kathryn A.; Levi, Mark S.Journal of Pharmacology and Experimental Therapeutics (2009), 331 (3), 1147CODEN: JPETAB; ISSN:0022-3565. (American Society for Pharmacology and Experimental Therapeutics)There is no expanded citation for this reference.
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143Sharma, C.; Sadek, B.; Goyal, S. N.; Sinha, S.; Kamal, M. A.; Ojha, S. Small molecules from nature targeting G-protein coupled cannabinoid receptors: Potential leads for drug discovery and development Evidence-Based Complementary Altern. Med. 2015, 2015, 238482 DOI: 10.1155/2015/238482Google Scholar143https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28rhvVClsA%253D%253D&md5=e59ce0b82e5722e4de576e51f037076cSmall Molecules from Nature Targeting G-Protein Coupled Cannabinoid Receptors: Potential Leads for Drug Discovery and DevelopmentSharma Charu; Sadek Bassem; Ojha Shreesh; Goyal Sameer N; Sinha Satyesh; Kamal Mohammad AmjadEvidence-based complementary and alternative medicine : eCAM (2015), 2015 (), 238482 ISSN:1741-427X.The cannabinoid molecules are derived from Cannabis sativa plant which acts on the cannabinoid receptors types 1 and 2 (CB1 and CB2) which have been explored as potential therapeutic targets for drug discovery and development. Currently, there are numerous cannabinoid based synthetic drugs used in clinical practice like the popular ones such as nabilone, dronabinol, and Δ(9)-tetrahydrocannabinol mediates its action through CB1/CB2 receptors. However, these synthetic based Cannabis derived compounds are known to exert adverse psychiatric effect and have also been exploited for drug abuse. This encourages us to find out an alternative and safe drug with the least psychiatric adverse effects. In recent years, many phytocannabinoids have been isolated from plants other than Cannabis. Several studies have shown that these phytocannabinoids show affinity, potency, selectivity, and efficacy towards cannabinoid receptors and inhibit endocannabinoid metabolizing enzymes, thus reducing hyperactivity of endocannabinoid systems. Also, these naturally derived molecules possess the least adverse effects opposed to the synthetically derived cannabinoids. Therefore, the plant based cannabinoid molecules proved to be promising and emerging therapeutic alternative. The present review provides an overview of therapeutic potential of ligands and plants modulating cannabinoid receptors that may be of interest to pharmaceutical industry in search of new and safer drug discovery and development for future therapeutics.
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144Code of Federal Regulations Title 21. Part 182: Substances Generally Recognized as Safe. Section 182.20 Essential oils, oleoresins (solvent-free), and natural extractives (including distillates). U.S. Food and Drug Administration, 2016.Google ScholarThere is no corresponding record for this reference.
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145Ringman, J. M.; Bardens, J.; Apostolova, L. G.; Frautschy, S. A.; Teng, E.; Cole, G. M.; Begum, A. N.; Beigi, M.; Gylys, K. H.; Badmaev, V.; Heath, D. D.; Porter, V.; Vanek, Z.; Marshall, G. A.; Hellemann, G.; Sugar, C.; Masterman, D. L.; Montine, T. J.; Cummings, J. L. Oral curcumin for Alzheimer’s disease: Tolerability and efficacy in a 24-week randomized, double blind, placebo-controlled study Alzheimer's Res. Ther. 2012, 4, 43 DOI: 10.1186/alzrt146Google Scholar145https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXit1CntLw%253D&md5=a2478f2b60ca63a95de1da293fe2b2deOral curcumin for Alzheimer's disease: tolerability and efficacy in a 24-week randomized, double blind, placebo-controlled studyRingman, John M.; Frautschy, Sally A.; Teng, Edmond; Begum, Aynun N.; Bardens, Jenny; Beigi, Maryam; Gylys, Karen H.; Badmaev, Vladimir; Heath, Dennis D.; Apostolova, Liana G.; Porter, Verna; Vanek, Zeba; Marshall, Gad A.; Hellemann, Gerhard; Sugar, Catherine; Masterman, Donna L.; Montine, Thomas J.; Cummings, Jeffrey L.; Cole, Greg M.Alzheimer's Research & Therapy (2012), 4 (5), 43CODEN: ARTLCD; ISSN:1758-9193. (BioMed Central Ltd.)Introduction: Curcumin is a polyphenolic compd. derived from the plant Curcuma Long Lin that has been demonstrated to have antioxidant and anti-inflammatory effects as well as effects on reducing beta-amyloid aggregation. It reduces pathol. in transgenic models of Alzheimer's disease (AD) and is a promising candidate for treating human AD. The purpose of the current study is to generate tolerability and preliminary clin. and biomarker efficacy data on curcumin in persons with AD. Methods: We performed a 24-wk randomized, double blind, placebo-controlled study of Curcumin C3 Complex with an open-label extension to 48 wk. Thirty-six persons with mild-to-moderate AD were randomized to receive placebo, 2 g/day, or 4 g/day of oral curcumin for 24 wk. For weeks 24 through 48, subjects that were receiving curcumin continued with the same dose, while subjects previously receiving placebo were randomized in a 1:1 ratio to 2 g/day or 4 g/day. The primary outcome measures were incidence of adverse events, changes in clin. lab. tests and the Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) at 24 wk in those completing the study. Secondary outcome measures included the Neuropsychiatric Inventory (NPI), the Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) scale, levels of Aβ1-40 and Aβ1-42 in plasma and levels of Aβ1-42, t-tau, p-tau181 and F2-isoprostanes in cerebrospinal fluid. Plasma levels of curcumin and its metabolites up to four hours after drug administration were also measured. Results: Mean age of completers (n = 30) was 73.5 years and mean Mini-Mental Status Examn. (MMSE) score was 22.5. One subject withdrew in the placebo (8%, worsened memory) and 5/24 subjects withdrew in the curcumin group (21%, 3 due to gastrointestinal symptoms). Curcumin C3 Complex was assocd. with lowered hematocrit and increased glucose levels that were clin. insignificant. There were no differences between treatment groups in clin. or biomarker efficacy measures. The levels of native curcumin measured in plasma were low (7.32 ng/mL). Conclusions: Curcumin was generally well-tolerated although three subjects on curcumin withdrew due to gastrointestinal symptoms. We were unable to demonstrate clin. or biochem. evidence of efficacy of Curcumin C3 Complex in AD in this 24-wk placebo-controlled trial although preliminary data suggest limited bioavailability of this compd.
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146Pfizer. Bioequivalence study comparing a new 10 mg atorvastatin tablet to a 10 mg atorvastatin commercial tablet. https://clinicaltrials.gov/ct2/show/NCT00917579, 2009Google ScholarThere is no corresponding record for this reference.
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147Sharma, R. A.; Euden, S. A.; Platton, S. L.; Cooke, D. N.; Shafayat, A.; Hewitt, H. R.; Marczylo, T. H.; Morgan, B.; Hemingway, D.; Plummer, S. M.; Pirmohamed, M.; Gescher, A. J.; Steward, W. P. Phase I clinical trial of oral curcumin: Biomarkers of systemic activity and compliance Clin. Cancer Res. 2004, 10, 6847– 6854 DOI: 10.1158/1078-0432.CCR-04-0744Google Scholar147https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXpslGltLg%253D&md5=9fde9f88cfcfca6a6e10a339d8596029Phase I Clinical Trial of Oral Curcumin: Biomarkers of Systemic Activity and ComplianceSharma, Ricky A.; Euden, Stephanie A.; Platton, Sharon L.; Cooke, Darren N.; Shafayat, Aisha; Hewitt, Heather R.; Marczylo, Timothy H.; Morgan, Bruno; Hemingway, David; Plummer, Simon M.; Pirmohamed, Munir; Gescher, Andreas J.; Steward, William P.Clinical Cancer Research (2004), 10 (20), 6847-6854CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)Curcumin, a polyphenolic antioxidant derived from a dietary spice, exhibits anticancer activity in rodents and in humans. Its efficacy appears to be related to induction of glutathione S-transferase enzymes, inhibition of prostaglandin E2 (PGE2) prodn., or suppression of oxidative DNA adduct (M1G) formation. We designed a dose-escalation study to explore the pharmacol. of curcumin in humans. Fifteen patients with advanced colorectal cancer refractory to std. chemotherapies consumed capsules compatible with curcumin doses between 0.45 and 3.6 g daily for up to 4 mo. Levels of curcumin and its metabolites in plasma, urine, and feces were analyzed by high-pressure liq. chromatog. and mass spectrometry. Three biomarkers of the potential activity of curcumin were translated from preclin. models and measured in patient blood leukocytes: glutathione S-transferase activity, levels of M1G, and PGE2 prodn. induced ex vivo. Dose-limiting toxicity was not obsd. Curcumin and its glucuronide and sulfate metabolites were detected in plasma in the 10 nmol/L range and in urine. A daily dose of 3.6 g curcumin engendered 62% and 57% decreases in inducible PGE2 prodn. in blood samples taken 1 h after dose on days 1 and 29, resp., of treatment compared with levels obsd. immediately predose (P < 0.05). A daily oral dose of 3.6 g of curcumin is advocated for Phase II evaluation in the prevention or treatment of cancers outside the gastrointestinal tract. PGE2 prodn. in blood and target tissue may indicate biol. activity. Levels of curcumin and its metabolites in the urine can be used to assess general compliance.
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148Dhillon, N.; Aggarwal, B. B.; Newman, R. A.; Wolff, R. A.; Kunnumakkara, A. B.; Abbruzzese, J. L.; Ng, C. S.; Badmaev, V.; Kurzrock, R. Phase II trial of curcumin in patients with advanced pancreatic cancer Clin. Cancer Res. 2008, 14, 4491– 4499 DOI: 10.1158/1078-0432.CCR-08-0024Google Scholar148https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXosFGitLw%253D&md5=9e2760727409ab572fb37a21fc2f619fPhase II Trial of Curcumin in Patients with Advanced Pancreatic CancerDhillon, Navneet; Aggarwal, Bharat B.; Newman, Robert A.; Wolff, Robert A.; Kunnumakkara, Ajaikumar B.; Abbruzzese, James L.; Ng, Chaan S.; Badmaev, Vladimir; Kurzrock, RazelleClinical Cancer Research (2008), 14 (14), 4491-4499CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)Pancreatic cancer is almost always lethal, and the only U.S. Food and Drug Administration-approved therapies for it, gemcitabine and erlotinib, produce objective responses in <10% of patients. We evaluated the clin. biol. effects of curcumin (diferuloylmethane), a plant-derived dietary ingredient with potent nuclear factor-κB (NF-κB) and tumor inhibitory properties, against advanced pancreatic cancer. Patients received 8 g curcumin by mouth daily until disease progression, with restaging every 2 mo. Serum cytokine levels for interleukin (IL)-6, IL-8, IL-10, and IL-1 receptor antagonists and peripheral blood mononuclear cell expression of NF-κB and cyclooxygenase-2 were monitored. Twenty-five patients were enrolled, with 21 evaluable for response. Circulating curcumin was detectable as drug in glucuronide and sulfate conjugate forms, albeit at low steady-state levels, suggesting poor oral bioavailability. Two patients showed clin. biol. activity. One had ongoing stable disease for >18 mo; interestingly, one addnl. patient had a brief, but marked, tumor regression (73%) accompanied by significant increases (4- to 35-fold) in serum cytokine levels (IL-6, IL-8, IL-10, and IL-1 receptor antagonists). No toxicities were obsd. Curcumin down-regulated expression of NF-κB, cyclooxygenase-2, and phosphorylated signal transducer and activator of transcription 3 in peripheral blood mononuclear cells from patients (most of whom had baseline levels considerably higher than those found in healthy volunteers). Whereas there was considerable interpatient variation in plasma curcumin levels, drug levels peaked at 22 to 41 ng/mL and remained relatively const. over the first 4 wk. Oral curcumin is well tolerated and, despite its limited absorption, has biol. activity in some patients with pancreatic cancer.
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149Asher, G. N.; Spelman, K. Clinical utility of curcumin extract Altern. Ther. Health Med. 2013, 19, 20– 22Google Scholar149https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3srmtFynsg%253D%253D&md5=6d8271d065a5272093b7d7f50850ae81Clinical utility of curcumin extractAsher Gary N; Spelman KevinAlternative therapies in health and medicine (2013), 19 (2), 20-2 ISSN:1078-6791.Turmeric root has been used medicinally in China and India for thousands of years. The active components are thought to be the curcuminoids, primarily curcumin, which is commonly available worldwide as a standardized extract. This article reviews the pharmacology of curcuminoids, their use and efficacy, potential adverse effects, and dosage and standardization. Preclinical studies point to mechanisms of action that are predominantly anti-inflammatory and antineoplastic, while early human clinical trials suggest beneficial effects for dyspepsia, peptic ulcer, inflammatory bowel disease, rheumatoid arthritis, osteoarthritis, uveitis, orbital pseudotumor, and pancreatic cancer. Curcumin is well-tolerated; the most common side effects are nausea and diarrhea. Theoretical interactions exist due to purported effects on metabolic enzymes and transport proteins, but clinical reports do not support any meaningful interactions. Nonetheless, caution, especially with chemotherapy agents, is advised. Late-phase clinical trials are still needed to confirm most beneficial effects.
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150Gupta, S. C.; Patchva, S.; Aggarwal, B. B. Therapeutic roles of curcumin: Lessons learned from clinical trials AAPS J. 2013, 15, 195– 218 DOI: 10.1208/s12248-012-9432-8Google Scholar150https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXktFWmsA%253D%253D&md5=c4da4ca00682052f5a273b89c0a7404aTherapeutic Roles of Curcumin: Lessons Learned from Clinical TrialsGupta, Subash C.; Patchva, Sridevi; Aggarwal, Bharat B.AAPS Journal (2013), 15 (1), 195-218CODEN: AJAOB6; ISSN:1550-7416. (Springer)A review. Extensive research over the past half century has shown that curcumin (diferuloylmethane), a component of the golden spice turmeric (Curcuma longa), can modulate multiple cell signaling pathways. Extensive clin. trials over the past quarter century have addressed the pharmacokinetics, safety, and efficacy of this nutraceutical against numerous diseases in humans. Some promising effects have been obsd. in patients with various pro-inflammatory diseases including cancer, cardiovascular disease, arthritis, uveitis, ulcerative proctitis, Crohn's disease, ulcerative colitis, irritable bowel disease, tropical pancreatitis, peptic ulcer, gastric ulcer, idiopathic orbital inflammatory pseudotumor, oral lichen planus, gastric inflammation, vitiligo, psoriasis, acute coronary syndrome, atherosclerosis, diabetes, diabetic nephropathy, diabetic microangiopathy, lupus nephritis, renal conditions, acquired immunodeficiency syndrome, β-thalassemia, biliary dyskinesia, Dejerine-Sottas disease, cholecystitis, and chronic bacterial prostatitis. Curcumin has also shown protection against hepatic conditions, chronic arsenic exposure, and alc. intoxication. Dose-escalating studies have indicated the safety of curcumin at doses as high as 12 g/day over 3 mo. Curcumin's pleiotropic activities emanate from its ability to modulate numerous signaling mols. such as pro-inflammatory cytokines, apoptotic proteins, NF-κB, cyclooxygenase-2, 5-LOX, STAT3, C-reactive protein, prostaglandin E2, prostate-specific antigen, adhesion mols., phosphorylase kinase, transforming growth factor-β, triglyceride, ET-1, creatinine, HO-1, AST, and ALT in human participants. In clin. trials, curcumin has been used either alone or in combination with other agents. Various formulations of curcumin, including nanoparticles, liposomal encapsulation, emulsions, capsules, tablets, and powder, have been examd. In this review, we discuss in detail the various human diseases in which the effect of curcumin has been investigated.
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151Hsu, C.-H.; Cheng, A.-L. Clinical studies with curcumin Adv. Exp. Med. Biol. 2007, 595, 471– 480 DOI: 10.1007/978-0-387-46401-5_21Google Scholar151https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2szlslGmsg%253D%253D&md5=d4df9c648b604f1401e1c72e96e7ebedClinical studies with curcuminHsu Chih-Hung; Cheng Ann-LiiAdvances in experimental medicine and biology (2007), 595 (), 471-80 ISSN:0065-2598.Curcumin has long been expected to be a therapeutic or preventive agent for several major human diseases because of its antioxidative, anti-inflammatory, and anticancerous effects. In phase I clinical studies, curcumin with doses up to 3600-8000 mg daily for 4 months did not result in discernible toxicities except mild nausea and diarrhea. The pharmacokinetic studies of curcumin indicated in general a low bioavailability of curcumin following oral application. Nevertheless, the pharmacologically active concentration of curcumin could be achieved in colorectal tissue in patients taking curcumin orally and might also be achievable in tissues such as skin and oral mucosa, which are directly exposed to the drugs applied locally or topically. The effect of curcumin was studied in patients with rheumatoid arthritis, inflammatory eye diseases, inflammatory bowel disease, chronic pancreatitis, psoriasis, hyperlipidemia, and cancers. Although the preliminary results did support the efficacy of curcumin in these diseases, the data to date are all preliminary and not conclusive. It is imperative that well-designed clinical trials, supported by better formulations of curcumin or novel routes of administration, be conducted in the near future.
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152Oppenheimer, A. Turmeric (curcumin) in biliary diseases Lancet 1937, 229, 619– 621 DOI: 10.1016/S0140-6736(00)98193-5Google ScholarThere is no corresponding record for this reference.
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153National Institutes of Health. "ClinicalTrials.gov." Registry and results database of clinical studies of human participants. http://clinicaltrials.gov (accessed October 6, 2016) .Google ScholarThere is no corresponding record for this reference.
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154Hurlstone, D. P.; Karajeh, M.; Sanders, D. S.; Drew, S. K.; Cross, S. S. Rectal aberrant crypt foci identified using high-magnification-chromoscopic colonoscopy: Biomarkers for flat and depressed neoplasia Am. J. Gastroenterol. 2005, 100, 1283– 1289 DOI: 10.1111/j.1572-0241.2005.40891.xGoogle Scholar154https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2M3osVOrsw%253D%253D&md5=6734217544f4bb9e1067c1b7f6595346Rectal aberrant crypt foci identified using high-magnification-chromoscopic colonoscopy: biomarkers for flat and depressed neoplasiaHurlstone David P; Karajeh Mohammed; Sanders David S; Drew Sister K; Cross Simon SThe American journal of gastroenterology (2005), 100 (6), 1283-9 ISSN:0002-9270.BACKGROUND: Aberrant crypt foci may represent preneoplastic lesions in the human colon. The prevalence of aberrant crypt foci detected using magnification chromoscopic colonoscopy is known to follow a stepwise progression from normal subjects to those with exophytic adenomas and colon cancer. No studies have addressed the prevalence of rectal aberrant crypt foci in patients with flat and depressed colonic lesions that cluster within the right hemi-colon and may undergo de novo neoplastic transformation. METHODS: All patients underwent total colonoscopy by a single endoscopist using the Olympus CF240Z magnifying colonoscope. Flat and depressed lesions were diagnosed using targeted indigo carmine chromoscopy. Prior to extubation, pan high-magnification-chromoscopy using indigo carmine was applied to the rectum and the distal 10 cm of mucosa examined using forward and retroflexed views. Aberrant crypt foci were defined as two or more crypts with dilated or slit-like openings that were raised above the adjacent mucosa. Using high-magnification chromoscopic colonoscopy we assessed the prevalence and dysplastic features of aberrant crypt foci in three groups: endoscopically "normal" subjects, patients with flat/depressed adenoma, and flat/depressed cancer. RESULTS: Two thousand five hundred and fifty-nine patients underwent colonoscopy of which 1,000 were eligible for inclusion. The median number of aberrant crypt foci per patient in the endoscopically normal, adenoma, and cancer group was 1 (range: 0-5), 9 (range: 0-22), and 38 (range: 14-64), respectively. The estimated relative risk of dysplastic aberrant crypt foci when comparing the flat adenoma group with the endoscopically "normal" group was 4.68 (95% CI: 2.23-9.91) with the relative risk for flat cancer versus endoscopically normal group being 21.8 (95% CI: 10.9-23.8). Patients with >5 flat adenomas had higher crypt foci densities than those with <5 adenomas (r=0.53; p<0.001). CONCLUSIONS: The number of aberrant crypt foci in normal patients, patients with flat adenoma, and flat cancer follow a stepwise incremental change as previously observed for exophytic adenomas and cancer. Detection of aberrant crypt foci in the rectum may be a useful biomarker for proximal colonic flat neoplasia and could be used at index flexible sigmoidoscopic screening to stratify risk of proximal colonic neoplasia. Patients with dysplastic aberrant crypt foci of high density should receive total colonoscopy.
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155Mattson, M. P.; Cheng, A. Neurohormetic phytochemicals: Low-dose toxins that induce adaptive neuronal stress responses Trends Neurosci. 2006, 29, 632– 639 DOI: 10.1016/j.tins.2006.09.001Google ScholarThere is no corresponding record for this reference.
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156Brondino, N.; Re, S.; Boldrini, A.; Cuccomarino, A.; Lanati, N.; Barale, F.; Politi, P. Curcumin as a therapeutic agent in dementia: A mini systematic review of human studies Sci. World J. 2014, 2014, 174282 DOI: 10.1155/2014/174282Google ScholarThere is no corresponding record for this reference.
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157Chandra, V.; Pandav, R.; Dodge, H. H.; Johnston, J. M.; Belle, S. H.; DeKosky, S. T.; Ganguli, M. Incidence of Alzheimer’s disease in a rural community in India: The Indo-US study Neurology 2001, 57, 985– 989 DOI: 10.1212/WNL.57.6.985Google Scholar157https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3MrisVemsQ%253D%253D&md5=42734f49b011dc09f7c1c6c5ca9e690dIncidence of Alzheimer's disease in a rural community in India: the Indo-US studyChandra V; Pandav R; Dodge H H; Johnston J M; Belle S H; DeKosky S T; Ganguli MNeurology (2001), 57 (6), 985-9 ISSN:0028-3878.OBJECTIVE: To determine overall and age-specific incidence rates of AD in a rural, population-based cohort in Ballabgarh, India, and to compare them with those of a reference US population in the Monongahela Valley of Pennsylvania. METHODS: A 2-year, prospective, epidemiologic study of subjects aged > or =55 years utilizing repeated cognitive and functional ability screening, followed by standardized clinical evaluation using the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, and the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria for the diagnosis, and the Clinical Dementia Rating scale for the staging, of dementia and AD. RESULTS: Incidence rates per 1000 person-years for AD with CDR > or =0.5 were 3.24 (95% CI: 1.48-6.14) for those aged > or =65 years and 1.74 (95% CI: 0.84-3.20) for those aged > or =55 years. Standardized against the age distribution of the 1990 US Census, the overall incidence rate in those aged > or =65 years was 4.7 per 1000 person-years, substantially lower than the corresponding rate of 17.5 per 1000 person-years in the Monongahela Valley. CONCLUSION: These are the first AD incidence rates to be reported from the Indian subcontinent, and they appear to be among the lowest ever reported. However, the relatively short duration of follow-up, cultural factors, and other potential confounders suggest caution in interpreting this finding.
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158Ng, T.-P.; Chiam, P.-C.; Lee, T.; Chua, H.-C.; Lim, L.; Kua, E.-H. Curry consumption and cognitive function in the elderly Am. J. Epidemiol. 2006, 164, 898– 906 DOI: 10.1093/aje/kwj267Google Scholar158https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD28nhvVKqsw%253D%253D&md5=bfca5b72527ef9b1d78a3bb8da672c1bCurry consumption and cognitive function in the elderlyNg Tze-Pin; Chiam Peak-Chiang; Lee Theresa; Chua Hong-Choon; Lim Leslie; Kua Ee-HeokAmerican journal of epidemiology (2006), 164 (9), 898-906 ISSN:0002-9262.Curcumin, from the curry spice turmeric, has been shown to possess potent antioxidant and antiinflammatory properties and to reduce beta-amyloid and plaque burden in experimental studies, but epidemiologic evidence is lacking. The authors investigated the association between usual curry consumption level and cognitive function in elderly Asians. In a population-based cohort (n = 1,010) of nondemented elderly Asian subjects aged 60-93 years in 2003, the authors compared Mini-Mental State Examination (MMSE) scores for three categories of regular curry consumption, taking into account known sociodemographic, health, and behavioral correlates of MMSE performance. Those who consumed curry "occasionally" and "often or very often" had significantly better MMSE scores than did subjects who "never or rarely" consumed curry. The authors reported tentative evidence of better cognitive performance from curry consumption in nondemented elderly Asians, which should be confirmed in future studies.
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159Li, S.; Yuan, W.; Deng, G.; Wang, P.; Yang, P.; Aggarwal, B. B. Chemical composition and product quality control of turmeric (Curcuma longa l.) Pharm. Crops 2011, 2, 28– 54 DOI: 10.2174/2210290601102010028Google Scholar159https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXht1GjtbfO&md5=c80633c79db31449ddb1511f394084faChemical composition and product quality control of turmeric (Curcuma longa L.)Li, Shiyou; Yuan, Wei; Deng, Guangrui; Wang, Ping; Yang, Peiying; Aggarwal, Bharat B.Pharmaceutical Crops (2011), 2 (), 28-54CODEN: PCHRBU; ISSN:2210-2906. (Bentham Science Publishers Ltd.)A review. Chem. constituents of various tissues of turmeric (Curcuma longa L.) have been extensively investigated. To date, at least 235 compds., primarily phenolic compds. and terpenoids have been identified from the species, including 22 diarylheptanoids and diarylpentanoids, eight phenylpropene and other phenolic compds., 68 monoterpenes, 109 sesquiterpenes, five diterpenes, three triterpenoids, four sterols, two alkaloids, and 14 other compds. Curcuminoids (diarylheptanoids) and essential oils are major bioactive ingredients showing various bioactivities in in vitro and in vivo bioassays. Curcuminoids in turmeric are primarily accumulated in rhizomes. The essential oils from leaves and flowers are usually dominated by monoterpenes while those from roots and rhizomes primarily contained sesquiterpenes. The contents of curcuminoids in turmeric rhizomes vary often with varieties, locations, sources, and cultivation conditions, while there are significant variations in compn. of essential oils of turmeric rhizomes with varieties and geog. locations. Further, both curcuminoids and essential oils vary in contents with different extn. methods and are unstable with extn. and storage processes. As a result, the quality of com. turmeric products can be markedly varied. While curcumin (1), demethoxycurcumin (2), and bisdemethoxycurcumin (5) have been used as marker compds. for the quality control of rhizomes, powders, and ext. ("curcumin") products, Ar-turmerone (99), α-turmerone (100), and β-turmerone (101) may be used to control the product quality of turmeric oil and oleoresin products. Authentication of turmeric products can be achieved by chromatog. and NMR techniques, DNA markers, with morphol. and anat. data as well as GAP and other information available.
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160Clark, C. M.; Sheppard, L.; Fillinbaum, G. G.; Galasko, D.; Morris, J. C.; Koss, E.; Mohs, R.; Heyman, A. Variability in annual mini-mental state examination score in patients with probable Alzheimer’s disease Arch. Neurol. (Chicago) 1999, 56, 857– 862 DOI: 10.1001/archneur.56.7.857Google ScholarThere is no corresponding record for this reference.
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161Dahlin, J. L.; Walters, M. A. The essential roles of chemistry in high-throughput screening triage Future Med. Chem. 2014, 6, 1265– 1290 DOI: 10.4155/fmc.14.60Google Scholar161https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsVeisbjF&md5=4ca8e43d7a85a1f67be930d40bfefad4The essential roles of chemistry in high-throughput screening triageDahlin, Jayme L.; Walters, Michael A.Future Medicinal Chemistry (2014), 6 (11), 1265-1290CODEN: FMCUA7; ISSN:1756-8919. (Future Science Ltd.)It is increasingly clear that academic high-throughput screening (HTS) and virtual HTS triage suffers from a lack of scientists trained in the art and science of early drug discovery chem. Many recent publications report the discovery of compds. by screening that are most likely artifacts or promiscuous bioactive compds., and these results are not placed into the context of previous studies. For HTS to be most successful, it is our contention that there must exist an early partnership between biologists and medicinal chemists. Their combined skill sets are necessary to design robust assays and efficient workflows that will weed out assay artifacts, false positives, promiscuous bioactive compds. and intractable screening hits, efforts that ultimately give projects a better chance at identifying truly useful chem. matter. Expertise in medicinal chem., chemoinformatics and purifn. sciences (anal. chem.) can enhance the post-HTS triage process by quickly removing these problematic chemotypes from consideration, while simultaneously prioritizing the more promising chem. matter for follow-up testing. It is only when biologists and chemists collaborate effectively that HTS can manifest its full promise.
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162Atanasov, A. G.; Waltenberger, B.; Pferschy-Wenzig, E. M.; Linder, T.; Wawrosch, C.; Uhrin, P.; Temml, V.; Wang, L.; Schwaiger, S.; Heiss, E. H.; Rollinger, J. M.; Schuster, D.; Breuss, J. M.; Bochkov, V.; Mihovilovic, M. D.; Kopp, B.; Bauer, R.; Dirsch, V. M.; Stuppner, H. Discovery and resupply of pharmacologically active plant-derived natural products: A review Biotechnol. Adv. 2015, 33, 1582– 1614 DOI: 10.1016/j.biotechadv.2015.08.001Google Scholar162https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhvFGjsbjJ&md5=e1f2296576f1f80b984d99adbf83a20dDiscovery and resupply of pharmacologically active plant-derived natural products: A reviewAtanasov, Atanas G.; Waltenberger, Birgit; Pferschy-Wenzig, Eva-Maria; Linder, Thomas; Wawrosch, Christoph; Uhrin, Pavel; Temml, Veronika; Wang, Limei; Schwaiger, Stefan; Heiss, Elke H.; Rollinger, Judith M.; Schuster, Daniela; Breuss, Johannes M.; Bochkov, Valery; Mihovilovic, Marko D.; Kopp, Brigitte; Bauer, Rudolf; Dirsch, Verena M.; Stuppner, HermannBiotechnology Advances (2015), 33 (8), 1582-1614CODEN: BIADDD; ISSN:0734-9750. (Elsevier)A review. Medicinal plants have historically proven their value as a source of mols. with therapeutic potential, and nowadays still represent an important pool for the identification of novel drug leads. In the past decades, pharmaceutical industry focused mainly on libraries of synthetic compds. as drug discovery source. They are comparably easy to produce and resupply, and demonstrate good compatibility with established high throughput screening (HTS) platforms. However, at the same time there has been a declining trend in the no. of new drugs reaching the market, raising renewed scientific interest in drug discovery from natural sources, despite of its known challenges. In this survey, a brief outline of historical development is provided together with a comprehensive overview of used approaches and recent developments relevant to plant-derived natural product drug discovery. Assocd. challenges and major strengths of natural product-based drug discovery are critically discussed. A snapshot of the advanced plant-derived natural products that are currently in actively recruiting clin. trials is also presented. Importantly, the transition of a natural compd. from a "screening hit" through a "drug lead" to a "marketed drug" is assocd. with increasingly challenging demands for compd. amt., which often cannot be met by re-isolation from the resp. plant sources. In this regard, existing alternatives for resupply are also discussed, including different biotechnol. approaches and total org. synthesis. While the intrinsic complexity of natural product-based drug discovery necessitates highly integrated interdisciplinary approaches, the reviewed scientific developments, recent technol. advances, and research trends clearly indicate that natural products will be among the most important sources of new drugs also in the future.
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163Wagner, H. Synergy research: Approaching a new generation of phytopharmaceuticals Fitoterapia 2011, 82, 34– 37 DOI: 10.1016/j.fitote.2010.11.016Google ScholarThere is no corresponding record for this reference.
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164Gertsch, J. The metabolic plant feedback hypothesis: How plant secondary metabolites nonspecifically impact human health Planta Med. 2016, 82, 920– 929 DOI: 10.1055/s-0042-108340Google Scholar164https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XpslyltLo%253D&md5=2df35d563676ad519af5828c5a0f3dbcThe Metabolic Plant Feedback Hypothesis: How Plant Secondary Metabolites Nonspecifically Impact Human Health*Gertsch, JurgPlanta Medica (2016), 82 (11/12), 920-929CODEN: PLMEAA; ISSN:0032-0943. (Georg Thieme Verlag)A review. Humans can ingest gram amts. of plant secondary metabolites daily through diet. Many of these phytochems. are bioactive beyond our current understanding because they act through weak neg. biol. feedback mechanisms, undetectable in vitro. Homeostatic-type assessments shed light on the evolutionary implications of the human diet from plants, giving rise to the metabolic plant feedback hypothesis. The hypothesis states that ancient diets rich in carbohydrates coincide with bulk dietary phytochems. that act as nonspecific inhibitors of metabolic and inflammatory processes. Consequently, food-derived phytochems. are likely to be equally effective as herbal medicines for these indications. In addn. to the ubiquitous flavonoids, terpenoids, and fatty acids in the diet, the likely impact of chronic chlorophyll ingestion on human health is discussed, and data on its modulation of blood glucose levels are presented. A major deduction of this hypothesis is that starchy diets lacking plant secondary metabolites are assocd. with multimorbidity (lifestyle diseases) including obesity, type 2 diabetes, and cardiovascular disease. It is proposed that the intake of leafy vegetables, spices, and herbal remedies rich in phytochems. matches the transition and genetic adaptation to early agriculture, playing a compensatory role in the mismatch of old genes and new diets.
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Abstract
Figure 1
Figure 1. Structural comparison of curcumin and artemisinin. Curcumin has been the focus of heavy research for new drug development. Artemisinin is an FDA approved antimalarial.
Figure 2
Figure 2. Comparison of publication frequency for biological studies of curcumin and artemisinin. The numbers of manuscripts per year were retrieved from SciFinder by searching for the substances curcumin (CAS no. 458-37-7) or artemisinin (CAS no. 63968-64-9) and then filtering by “biological study” and “document type” = journal. (Data accessed May 3, 2016.)
Figure 3
Figure 3. Major phytoconstituents of extracts of Curcuma longa. Compounds 1, 3, and 4, often grouped together as “curcuminoids”, generally make up approximately 1–6% of turmeric by weight. (33) Of a curcuminoid extract, 1 makes up 60–70% by weight, while 3 (20–27%) and 4 (10–15%) are more minor components. The major constituent of a curcuminoid extract, 1, and the properties important for its consideration as a lead compound for therapeutic development are the focus of this review.
Figure 4
Figure 4. Tautomerization of compound 1. NMR studies show that compound 1 is not present in solution as the diketone (1a) but only as a mixture of the equally present (due to symmetry) enol structures (1b). (63)
Figure 5
Figure 5. Major chemical degradation pathways of compound 1. (A) Solvolysis under alkaline pH in buffered aqueous solution rapidly leads to multiple fragmentation byproducts. (27) (B) Autoxidation in buffered medium creates a bicyclopentadione (8) that is the major degradation product in aqueous conditions. (66) (C) Photodegradation of 1 can occur when in crystalline form and dissolved in organic solvent. (68) (D) When dissolved in certain organic solvents (like isopropanol), photodegradation can include reaction with the solvent as a substrate. (69)
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References
ARTICLE SECTIONS
This article references 164 other publications.
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1Yuan, D.; Yang, X.; Guo, J. C. A great honor and a huge challenge for China: You-you tu getting the nobel prize in physiology or medicine J. Zhejiang Univ., Sci., B 2016, 17, 405– 408 DOI: 10.1631/jzus.B1600094There is no corresponding record for this reference.
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2Hanson, M. Is the 2015 Nobel Prize a turning point for traditional Chinese medicine? https://theconversation.com/is-the-2015-nobel-prize-a-turning-point-for-traditional-chinese-medicine-48643 (accessed June 6, 2016) .There is no corresponding record for this reference.
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3Baell, J.; Walters, M. A. Chemistry: Chemical con artists foil drug discovery Nature (London, U. K.) 2014, 513, 481– 483 DOI: 10.1038/513481a3https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhs1WjsL7M&md5=f5788d81d006460c688e4b78e6200503Chemistry: Chemical con artists foil drug discoveryBaell, Jonathan; Walters, Michael A.Nature (London, United Kingdom) (2014), 513 (7519), 481-483CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)A review. Naivety about promiscuous, assay-duping mols. is polluting the literature and wasting resources, warn Jonathan Baell and Michael A. Walters. Academic drug discoverers must be more vigilant. Mols. that show the strongest activity in screening might not be the best starting points for drugs. PAINS hits should almost always be ignored. Even trained medicinal chemists have to be careful until they become experienced in screening.
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4Bisson, J.; McAlpine, J. B.; Friesen, J. B.; Chen, S.-N.; Graham, J.; Pauli, G. F. Can invalid bioactives undermine natural product-based drug discovery? J. Med. Chem. 2016, 59, 1671– 1690 DOI: 10.1021/acs.jmedchem.5b010094https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtVChsro%253D&md5=cc3256ccc9a96d61cb9b81bf2a9be9f2Can Invalid Bioactives Undermine Natural Product-Based Drug Discovery?Bisson, Jonathan; McAlpine, James B.; Friesen, J. Brent; Chen, Shao-Nong; Graham, James; Pauli, Guido F.Journal of Medicinal Chemistry (2016), 59 (5), 1671-1690CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)High-throughput biol. has contributed a wealth of data on chems., including natural products (NPs). Recently, attention was drawn to certain, predominantly synthetic, compds. that are responsible for disproportionate percentages of hits but are false actives. Spurious bioassay interference led to their designation as pan-assay interference compds. (PAINS). NPs lack comparable scrutiny, which this study aims to rectify. Systematic mining of 80+ years of the phytochem. and biol. literature, using the NAPRALERT database, revealed that only 39 compds. represent the NPs most reported by occurrence, activity, and distinct activity. Over 50% are not explained by phenomena known for synthetic libraries, and all had manifold ascribed bioactivities, designating them as invalid metabolic panaceas (IMPs). Cumulative distributions of ∼200,000 NPs uncovered that NP research follows power-law characteristics typical for behavioral phenomena. Projection into occurrence-bioactivity-effort space produces the hyperbolic black hole of NPs, where IMPs populate the high-effort base.
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5Burgos-Moron, E.; Calderon-Montano, J. M.; Salvador, J.; Robles, A.; Lopez-Lazaro, M. The dark side of curcumin Int. J. Cancer 2010, 126, 1771– 1775 DOI: 10.1002/ijc.249675https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtl2itbw%253D&md5=dba8c958325cf5b0b45e888e051c9c04The dark side of curcuminBurgos-Moron, Estefania; Calderon-Montano, Jose Manuel; Salvador, Javier; Robles, Antonio; Lopez-Lazaro, MiguelInternational Journal of Cancer (2010), 126 (7), 1771-1775CODEN: IJCNAW; ISSN:0020-7136. (Wiley-Liss, Inc.)A review, on the therapeutic use and safety of curcumin.
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6Baell, J. B. Feeling nature’s PAINS: Natural products, natural product drugs, and pan assay interference compounds (PAINS) J. Nat. Prod. 2016, 79, 616– 628 DOI: 10.1021/acs.jnatprod.5b009476https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XivVWktrc%253D&md5=199b040b1f6f3d636521879acae0114dFeeling Nature's PAINS: Natural Products, Natural Product Drugs, and Pan Assay Interference Compounds (PAINS)Baell, Jonathan B.Journal of Natural Products (2016), 79 (3), 616-628CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)We have previously reported on classes of compds. that can interfere with bioassays via a no. of different mechanisms and termed such compds. Pan Assay INterference compds., or PAINS. These compds. were defined on the basis of high-throughput data derived from vendor-supplied synthetics. The question therefore arises whether the concept of PAINS is relevant to compds. of natural origin. Here, it is shown that this is indeed the case, but that the context of the biol. readout is an important factor that must be brought into consideration.
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7Chin, D.; Huebbe, P.; Pallauf, K.; Rimbach, G. Neuroprotective properties of curcumin in Alzheimer’s disease - merits and limitations Curr. Med. Chem. 2013, 20, 3955– 3985 DOI: 10.2174/092986731132099902107https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsFyms7fP&md5=beaff04bd5c682c35627cb4749ecf389Neuroprotective Properties of Curcumin in Alzheimer's Disease - Merits and LimitationsChin, Dawn; Huebbe, Patricia; Pallauf, Kathrin; Rimbach, GeraldCurrent Medicinal Chemistry (2013), 20 (32), 3955-3985CODEN: CMCHE7; ISSN:0929-8673. (Bentham Science Publishers Ltd.)A review. As demographics in developed nations shift towards an aging population, neurodegenerative pathologies, esp. dementias such as Alzheimer's disease, pose one of the largest challenges to the modern health care system. Since there is yet no cure for dementia, there is great pressure to discover potential therapeutics for these diseases. One popular candidate is curcumin or diferuloylmethane, a polyphenolic compd. that is the main curcuminoid found in Curcuma longa (family Zingiberaceae). In recent years, curcumin has been reported to possess anti-amyloidogenic, antiinflammatory, anti-oxidative, and metal chelating properties that may result in potential neuroprotective effects. Particularly, the hydrophobicity of the curcumin mol. hints at the possibility of blood-brain barrier penetration and accumulation in the brain. However, curcumin exhibits extremely low bioavailability, mainly due to its poor aq. soly., poor stability in soln., and rapid intestinal first-pass and hepatic metab. Despite the many efforts that are currently being made to improve the bioavailability of curcumin, brain concn. of curcumin remains low. Furthermore, although many have reported that curcumin possesses a relatively low toxicity profile, curcumin applied at high doses, which is not uncommon practice in many in vivo and clin. studies, may present certain dangers that in our opinion have not been addressed sufficiently. Herein, the neuroprotective potential of curcumin, with emphasis on Alzheimer's disease, as well as its limitations will be discussed in detail.
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8Glaser, J.; Holzgrabe, U. Focus on PAINS: False friends in the quest for selective anti-protozoal lead structures from nature? MedChemComm 2016, 7, 214– 223 DOI: 10.1039/C5MD00481K8https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhvFCrsQ%253D%253D&md5=449fb431ba2964ca31fc19d7b9cbed93Focus on PAINS: false friends in the quest for selective anti-protozoal lead structures from Nature?Glaser, J.; Holzgrabe, U.MedChemComm (2016), 7 (2), 214-223CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)Pan-assay interference compds. (PAINS) are mols. showing promising but deceptive activities in various biochem. screenings mainly due to unselective interactions with the target. Overall awareness of this problem has been raised recently. Many natural products inherently have PAINS characteristics but are nevertheless uncritically acclaimed as new antiprotozoal lead structures. However, a non-selective mode of action may be the cause of obsd. activity. This review describes the most common assay-interfering characteristics of antiprotozoal natural products, discusses significant examples from the recent literature and strategies to deal with these promiscuous structures.
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9Heger, M.; van Golen, R. F.; Broekgaarden, M.; Michel, M. C. The molecular basis for the pharmacokinetics and pharmacodynamics of curcumin and its metabolites in relation to cancers Pharmacol. Rev. 2014, 66, 222– 307 DOI: 10.1124/pr.110.0040449https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsVGnu7fM&md5=519c5283d1a5d0c96421e7a3364cf44eThe molecular basis for the pharmacokinetics and pharmacodynamics of curcumin and its metabolites in relation to cancersHeger, Michal; van Golen, Rowan F.; Broekgaarden, Mans; Michel, Martin C.Pharmacological Reviews (2014), 66 (1), 222-307, 338 pp.CODEN: PAREAQ; ISSN:1521-0081. (American Society for Pharmacology and Experimental Therapeutics)This review addresses the oncopharmacol. properties of curcumin at the mol. level. First, the interactions between curcumin and its mol. targets are addressed on the basis of curcumin's distinct chem. properties, which include H-bond donating and accepting capacity of the β-dicarbonyl moiety and the phenylic hydroxyl groups, H-bond accepting capacity of the methoxy ethers, multivalent metal and nonmetal cation binding properties, high partition coeff., rotamerization around multiple C-C bonds, and the ability to act as a Michael acceptor. Next, the in vitro chem. stability of curcumin is elaborated in the context of its susceptibility to photochem. and chem. modification and degrdn. (e.g., alk. hydrolysis). Specific modification and degradatory pathways are provided, which mainly entail radical-based intermediates, and the in vitro catabolites are identified. The implications of curcumin's (photo) chem. instability are addressed in light of pharmaceutical curcumin prepns., the use of curcumin analogs, and implementation of nanoparticulate drug delivery systems. Furthermore, the pharmacokinetics of curcumin and its most important degrdn. products are detailed in light of curcumin's poor bioavailability. Particular emphasis is placed on xenobiotic phase I and II metab. as well as excretion of curcumin in the intestines (first pass), the liver (second pass), and other organs in addn. to the pharmacokinetics of curcumin metabolites and their systemic clearance. Lastly, a summary is provided of the clin. pharmacodynamics of curcumin followed by a detailed account of curcumin's direct mol. targets, whereby the phenotypical/biol. changes induced in cancer cells upon completion of the curcumin-triggered signaling cascade(s) are addressed in the framework of the hallmarks of cancer. The direct mol. targets include the ErbB family of receptors, protein kinase C, enzymes involved in prostaglandin synthesis, vitamin D receptor, and DNA.
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10Elias, G.; Jacob, P. J.; Hareeshbabu, E.; Mathew, V. B.; Krishnan, B.; Krishnakumar, K. Curcumin: Transforming the spice to a wonder drug Int. J. Pharm. Sci. Res. 2015, 6, 2671– 2680 DOI: 10.13040/IJPSR.0975-8232.6(7).2671-8010https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhs1GnsL3O&md5=0756b8875f65de2e35c1178150c51039Curcumin: transforming the spice to a wonder drugElias, Geetha; Jacob, P. Jaismy; Hareeshbabu, E.; Mathew, V. Baldwin; Krishnan, Bibitha; Krishnakumar, K.International Journal of Pharmaceutical Sciences and Research (2015), 6 (7), 2671-2680CODEN: IJPSTT; ISSN:0975-8232. (International Journal of Pharmaceutical Sciences and Research)A review. Turmeric is a spice obtained from the dried rhizomes of Curcuma longa, family Zingiberaceae. It has been extensively used in traditional Indian (Ayurveda) and Chinese medicine for various ailments such as anti-inflammatory, blood purifier and even as a cosmetic. Curcumin, the chief constituent in turmeric has been isolated centuries ago, has been found to have a wide range of pharmacol. actions such as antioxidant, anti-inflammatory, anticancer, antimicrobial and much more. Thus curcumin and its analogs have immense therapeutic potential for use in rheumatoid arthritis, Crohn's disease, cancer, diabetes, cardiovascular disease, HIV-I and Alzheimer's disease. Phase I clin. studies have shown that high doses of curcumin is well tolerated in man. Despite its safety, curcumin still evades clin. use due to poor bioavailability. Novel formulations of curcumin with piperine, sol. fibers of fenugreek, liposomes, micelles, nanoparticles, cyclodextrin and turmerone have shown enhanced bioavailability to some extent, each one having its own limitations. Recent formulation of curcuminoid with 45% turmerone seems to be promising. Further research in this direction is imperative to realize the clin. use of this promising mol.
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11Neckers, L.; Trepel, J.; Lee, S.; Chung, E.-J.; Lee, M.-J.; Jung, Y.-J.; Marcu, M. G. Curcumin is an inhibitor of p300 histone acetyltransferase Med. Chem. (Sharjah, United Arab Emirates) 2006, 2, 169– 174 DOI: 10.2174/15734060677605613311https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xislyht7w%253D&md5=123a01f4dccf8849f30bd68bbab80024Curcumin is an inhibitor of p300 histone acetyltransferaseMarcu, Monica G.; Jung, Yun-Jin; Lee, Sunmin; Chung, Eun-Joo; Lee, Min-Jung; Trepel, Jane; Neckers, LenMedicinal Chemistry (2006), 2 (2), 169-174CODEN: MCEHAJ; ISSN:1573-4064. (Bentham Science Publishers Ltd.)Histone acetyltransferases (HATs), and p300/CBP in particular, have been implicated in cancer cell growth and survival, and as such, HATs represent novel, therapeutically relevant mol. targets for drug development. In this study, we demonstrate that the small mol. natural product curcumin, whose medicinal properties have long been recognized in India and Southeast Asia, is a selective HAT inhibitor. Furthermore the data indicate that α, β unsatd. carbonyl groups in the curcumin side chain function as Michael reaction sites and that the Michael reaction acceptor functionality of curcumin is required for its HAT-inhibitory activity. In cells, curcumin promoted proteasome-dependent degrdn. of p300 and the closely related CBP protein without affecting the HATs PCAF or GCN5. In addn. to inducing p300 degrdn. curcumin inhibited the acetyltransferase activity of purified p300 as assessed using either histone H3 or p53 as substrate. Radiolabeled curcumin formed a covalent assocn. with p300, and tetrahydrocurcumin displayed no p300 inhibitory activity, consistent with a Michael reaction-dependent mechanism. Finally, curcumin was able to effectively block histone hyperacetylation in both PC3-M prostate cancer cells and peripheral blood lymphocytes induced by the histone deacetylase inhibitor MS-275. These data thus identify the medicinal natural product curcumin as a novel lead compd. for development of possibly therapeutic, p300/CBP-specific HAT inhibitors.
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12Rainey-Smith, S. R.; Brown, B. M.; Sohrabi, H. R.; Shah, T.; Goozee, K. G.; Gupta, V. B.; Martins, R. N. Curcumin and cognition: A randomised, placebo-controlled, double-blind study of community-dwelling older adults Br. J. Nutr. 2016, 115, 2106– 2113 DOI: 10.1017/S000711451600120312https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtVyiur3J&md5=2b8737b23ff7737c43605c246303f203Curcumin and cognition: a randomised, placebo-controlled, double-blind study of community-dwelling older adultsRainey-Smith, Stephanie R.; Brown, Belinda M.; Sohrabi, Hamid R.; Shah, Tejal; Goozee, Kathryn G.; Gupta, Veer B.; Martins, Ralph N.British Journal of Nutrition (2016), 115 (12), 2106-2113CODEN: BJNUAV; ISSN:0007-1145. (Cambridge University Press)Curcumin therapy in animals has produced pos. cognitive and behavioral outcomes; results of human trials, however, have been inconsistent. In this study, we report the results of a 12-mo, randomized, placebo-controlled, double-blind study that investigated the ability of a curcumin formulation to prevent cognitive decline in a population of community-dwelling older adults. Individuals (n 96) ingested either placebo or 1500 mg/d BiocurcumaxTM for 12 mo. A battery of clin. and cognitive measures was administered at baseline and at the 6-mo and 12-mo follow-up assessments. A significant time×treatment group interaction was obsd. for the Montreal Cognitive Assessment (repeated-measures anal.; time×treatment; F=3·85, P<0·05). Subsequent anal. revealed that this assocn. was driven by a decline in function of the placebo group at 6 mo that was not obsd. in the curcumin treatment group. No differences were obsd. between the groups for all other clin. and cognitive measures. Our findings suggest that further longitudinal assessment is required to investigate changes in cognitive outcome measures, ideally in conjunction with biol. markers of neurodegeneration.
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13Okamura, T.; Kubo, K. Turmeric pigment-containing chocolate with excellent flavor, texture, and hangover prevention/treatment properties. JP2009183206A, 2009.There is no corresponding record for this reference.
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14Kwon, H. N. Functional noodles for relieving hangover and its manufacturing method. KR1314917B1, 2013.There is no corresponding record for this reference.
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15Rezq, E.-S. A. M.; Mansour, M. T. A.-A.; Kumosani, T. A. Long acting conserved natural functional groups curcumin. WO2010057503A2, 2010.There is no corresponding record for this reference.
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16Wang, A.; An, X.; Zhou, Y. Application of curcumin to medicinal preparations for treating erectile dysfunction. CN101822656A, 2010.There is no corresponding record for this reference.
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17Isaacs, E.; Cobbledick, T. Complete supplement formulae for maintenance of hair growth and condition. GB2484812A, 2012.There is no corresponding record for this reference.
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18Huh, S.; Lee, J.; Jung, E.; Kim, S.-C.; Kang, J.-I.; Lee, J.; Kim, Y.-W.; Sung, Y. K.; Kang, H.-K.; Park, D. A cell-based system for screening hair growth-promoting agents Arch. Dermatol. Res. 2009, 301, 381– 385 DOI: 10.1007/s00403-009-0931-018https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXmsVOru7w%253D&md5=0ae619cd8cb9f111d91863b722fbef6bA cell-based system for screening hair growth-promoting agentsHuh, Sungran; Lee, Jongsung; Jung, Eunsun; Kim, Sang-Cheol; Kang, Jung-Il; Lee, Jienny; Kim, Yong-Woo; Sung, Young Kwan; Kang, Hee-Kyoung; Park, DeokhoonArchives of Dermatological Research (2009), 301 (5), 381-385CODEN: ADREDL; ISSN:0340-3696. (Springer)Androgen-inducible transforming growth factor β (TGF-β1) derived from dermal papilla cells (DPCs) is a catagen inducer that mediates hair growth suppression in androgenetic alopecia (AGA). In this study, a cell-based assay system was developed to monitor TGF-β1 promoter activity and then used to evaluate the effects of activated TGF-β1 promoter in human epidermal keratinocytes (HaCaT). To accomplish this, a pMetLuc-TGF-β1 promoter plasmid that expresses the luciferase reporter gene in response to TGF-β1 promoter activity was constructed. Treatment of HaCaT with dihydrotestosterone, which is known to be a primary factor of AGA, resulted in a concn.-dependent increase in TGF-β1 promoter activity. However, treatment of HaCaT with the TGF-β1 inhibitor, curcumin, resulted in a concn.-dependant decrease in TGF-β1 expression. Subsequent use of this assay system to screen TGF-β1 revealed that HaCaT that were treated with apigenin showed decreased levels of TGF-β1 expression. In addn., treatment with apigenin also significantly increased the proliferation of both SV40T-DPCs (human DPCs) and HaCaT cells. Furthermore, apigenin stimulated the elongation of hair follicles in a rat vibrissa hair follicle organ culture. Taken together, these findings suggest that apigenin, which is known to have antioxidant, anti-inflammatory, and anti-tumor properties, stimulates hair growth through downregulation of the TGF-β1 gene. In addn., these results suggest that this assay system could be used to quant. measure TGF-β1 promoter activity in HaCaT, thereby facilitating the screening of agents promoting hair growth.
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19Ahluwalia, G. S.; Shander, D.; Styczynski, P. Inhibition of hair growth with protein kinase C inhibitors. WO9609806A2, 1996.There is no corresponding record for this reference.
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20Jana, S.; Paul, S.; Swarnakar, S. Curcumin as anti-endometriotic agent: Implication of MMP-3 and intrinsic apoptotic pathway Biochem. Pharmacol. (Amsterdam, Neth.) 2012, 83, 797– 804 DOI: 10.1016/j.bcp.2011.12.030There is no corresponding record for this reference.
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21Naz, R. K.; Lough, M. L. Curcumin as a potential non-steroidal contraceptive with spermicidal and microbicidal properties Eur. J. Obstet. Gynecol. Reprod. Biol. 2014, 176, 142– 148 DOI: 10.1016/j.ejogrb.2014.01.02421https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXltl2ms7k%253D&md5=be6b73ddbb9d17c3b3aba2b213034fa9Curcumin as a potential non-steroidal contraceptive with spermicidal and microbicidal propertiesNaz, R. K.; Lough, M. L.European Journal of Obstetrics & Gynecology and Reproductive Biology (2014), 176 (), 142-148CODEN: EOGRAL; ISSN:0301-2115. (Elsevier Ireland Ltd.)Curcumin, a component of the curry powder turmeric, has immense biol. properties, including anticancer effects. The objective of this study was to det. if curcumin can provide a novel non-steroidal contraceptive having both spermicidal and microbicidal properties. The effect of curcumin, with and without photosensitization, was examd. on human sperm forward motility and growth of several aerobic (n = 8) and anaerobic bacteria (n = 4) and yeast (n = 7) strains implicated in vaginosis, vaginitis, and vaginal infections in women. The effect of various concns. of curcumin on human sperm and microbes (aerobic and anaerobic bacteria and yeast) was tested. The effect on sperm was examd. by counting the sperm forward motility, and on microbes by agar and broth dilns. and colony counting. Each expt. was repeated using different semen specimens, and bacteria and yeast stocks. Curcumin caused a concn.-dependent inhibition of sperm forward motility with a total block at ≥250 μM concn. After photosensitization, the effective concn. to completely block sperm forward motility decreased 25-fold, now requiring only 10 μM concn. for total inhibition. Curcumin concns. between 100 and 500 μM completely blocked the growth of all the bacteria and yeast strains tested. After photosensitization, the effective concn. to completely inhibit microbial growth decreased 10-fold for aerobic bacteria and yeast, and 5-fold for anaerobic bacteria. These findings suggest that curcumin can block sperm function and bacteria/yeast growth. It can potentially provide an ideal non-steroidal contraceptive having both spermicidal and microbicidal properties against vaginal infections.
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22Data pertaining to these claims are easily accessible by any Internet search engine, e.g., https://www.google.com/#q=curcumin+AND+health+benefitsThere is no corresponding record for this reference.
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23Goel, A.; Kunnumakkara, A. B.; Aggarwal, B. B. Curcumin as "curecumin": From kitchen to clinic Biochem. Pharmacol. (Amsterdam, Neth.) 2008, 75, 787– 809 DOI: 10.1016/j.bcp.2007.08.016There is no corresponding record for this reference.
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24Kumar, A.; Chetia, H.; Sharma, S.; Kabiraj, D.; Talukdar, N. C.; Bora, U. Curcumin resource database Database 2015, 2015, bav070 DOI: 10.1093/database/bav070There is no corresponding record for this reference.
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25Wang, J.; Zhang, C.-J.; Chia, W. N.; Loh, C. C. Y.; Li, Z.; Lee, Y. M.; He, Y.; Yuan, L.-X.; Lim, T. K.; Liu, M.; Liew, C. X.; Lee, Y. Q.; Zhang, J.; Lu, N.; Lim, C. T.; Hua, Z.-C.; Liu, B.; Shen, H.-M.; Tan, K. S. W.; Lin, Q. Haem-activated promiscuous targeting of artemisinin in Plasmodium falciparum Nat. Commun. 2015, 6, 10111 DOI: 10.1038/ncomms1011125https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXitVynsLjO&md5=a532a76cdd2f33b0ca23e733e6247a0cHaem-activated promiscuous targeting of artemisinin in Plasmodium falciparumWang, Jigang; Zhang, Chong-Jing; Chia, Wan Ni; Loh, Cheryl C. Y.; Li, Zhengjun; Lee, Yew Mun; He, Yingke; Yuan, Li-Xia; Lim, Teck Kwang; Liu, Min; Liew, Chin Xia; Lee, Yan Quan; Zhang, Jianbin; Lu, Nianci; Lim, Chwee Teck; Hua, Zi-Chun; Liu, Bin; Shen, Han-Ming; Tan, Kevin S. W.; Lin, QingsongNature Communications (2015), 6 (), 10111CODEN: NCAOBW; ISSN:2041-1723. (Nature Publishing Group)The mechanism of action of artemisinin and its derivs., the most potent of the anti-malarial drugs, is not completely understood. Here we present an unbiased chem. proteomics anal. to directly explore this mechanism in Plasmodium falciparum. We use an alkyne-tagged artemisinin analog coupled with biotin to identify 124 artemisinin covalent binding protein targets, many of which are involved in the essential biol. processes of the parasite. Such a broad targeting spectrum disrupts the biochem. landscape of the parasite and causes its death. Furthermore, using alkyne-tagged artemisinin coupled with a fluorescent dye to monitor protein binding, we show that haem, rather than free ferrous iron, is predominantly responsible for artemisinin activation. The haem derives primarily from the parasite's haem biosynthesis pathway at the early ring stage and from Hb digestion at the latter stages. Our results support a unifying model to explain the action and specificity of artemisinin in parasite killing.
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26Medhi, B.; Patyar, S.; Rao, R. S.; Byrav, D. S. P.; Prakash, A. Pharmacokinetic and toxicological profile of artemisinin compounds: An update Pharmacology 2009, 84, 323– 332 DOI: 10.1159/00025265826https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhsFaqt7nO&md5=005201fe4409b98be94d9c8615ec6859Pharmacokinetic and Toxicological Profile of Artemisinin Compounds: An UpdateMedhi, Bikash; Patyar, Sazal; Rao, Ramya S.; Byrav DS, Prasad; Prakash, AjayPharmacology (2009), 84 (6), 323-332CODEN: PHMGBN; ISSN:0031-7012. (S. Karger AG)A review. Artemisinin has been used effectively in malaria treatment. With the emerging resistance to malaria, the optimum and judicial use of the drug has become important. The drug metab. and toxicol. can have an impact on the therapeutic profile and clin. use of this antimalarial agent. In this review, we discuss the pharmacokinetics and toxicol. aspects of artemisinin and its therapeutic implications. Artemisinins have several dosing routes including oral, i.m., i.v. and rectal. With repeated dosing, artemisinin has propensity for autoinduction, leading to decreased plasma levels on repeated dosing. Combination with other antimalarials in most cases did not influence the pharmacokinetics of artemisinins. Interactions with cytochrome P450 inhibitors are known but these neither affect the efficacy nor the toxicity of the resp. deriv. Artemisinins are generally regarded to be of low toxicity. Two major problems assocd. with them are neurotoxicity and reproductive toxicity. But the extent of this neurotoxicity is dependent on the nature of the compd., on the route of administration, and on the nature of the formulation. Moreover, it occurs in humans at very high doses. However, as a matter of precaution, the use of artemisinins in the first trimester of pregnancy has been contraindicated.
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27Wang, Y.-J.; Pan, M.-H.; Cheng, A.-L.; Lin, L.-I.; Ho, Y.-S.; Hsieh, C.-Y.; Lin, J.-K. Stability of curcumin in buffer solutions and characterization of its degradation products J. Pharm. Biomed. Anal. 1997, 15, 1867– 1876 DOI: 10.1016/S0731-7085(96)02024-927https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXlvVejtbo%253D&md5=15cd834a8238d9d1f71e5ea74e3d40d5Stability of curcumin in buffer solutions and characterization of its degradation productsWang, Ying-Jan; Pan, Min-Hsiung; Cheng, Ann-Lii; Lin, Liang-In; Ho, Yuan-Soon; Hsieh, Chang-Yao; Lin, Jen-KunJournal of Pharmaceutical and Biomedical Analysis (1997), 15 (12), 1867-1876CODEN: JPBADA; ISSN:0731-7085. (Elsevier)The degrdn. kinetics of curcumin under various pH conditions and the stability of curcumin in physiol. matrixes were investigated. When curcumin was incubated in 0.1 M phosphate buffer and serum-free medium, pH 7.2 at 37°C, about 90% decompd. within 30 min. A series of pH conditions ranging from 3 to 10 were tested and the result showed that decompn. was pH-dependent and occurred faster at neutral-basic conditions. It is more stable in cell culture medium contg. 10% fetal calf serum and in human blood; less than 20% of curcumin decompd. within 1 h, and after incubation for 8 h, about 50% of curcumin is still remained. Trans-6-(4'-hydroxy-3'-methoxyphenyl)-2,4-dioxo-5-hexenal was predicted as major degrdn. product and vanillin, ferulic acid, feruloyl methane were identified as minor degrdn. products. The amt. of vanillin increased with incubation time.
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28Yang, K. Y.; Lin, L. C.; Tseng, T. Y.; Wang, S. C.; Tsai, T. H. Oral bioavailability of curcumin in rat and the herbal analysis from Curcuma longa by LC-MS/MS J. Chromatogr. B: Anal. Technol. Biomed. Life Sci. 2007, 853, 183– 189 DOI: 10.1016/j.jchromb.2007.03.01028https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXmsFKkt74%253D&md5=91dea0673d30e9917a903ba8c984c2e0Oral bioavailability of curcumin in rat and the herbal analysis from Curcuma longa by LC-MS/MSYang, Kuo-Yi; Lin, Lei-Chwen; Tseng, Ting-Yu; Wang, Shau-Chun; Tsai, Tung-HuJournal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences (2007), 853 (1-2), 183-189CODEN: JCBAAI; ISSN:1570-0232. (Elsevier B.V.)This study presents a validated liq. chromatog. technique coupled with tandem mass spectrometry (LC-MS/MS) to measure curcumin in rat plasma and provide curcuminoids anal. from the ext. of Curcumin longa L. This method was applied to investigate the pharmacokinetics of curcumin in a freely moving rat. The analytes were sepd. by a reversed phase C18 column (150 × 4.6 mm I.D., particle size 5 μm) and eluted with acetonitrile-1 mM HCOOH mobile phase (70:30, vol./vol.) with a flow rate of 0.8 mL/min in rat plasma and herbal exts. Multiple reaction monitoring (MRM) was used to monitor the transition of the deprotonated mol. m/z of 367 [M - H]- to the product ion 217 for curcumin, a m/z of 337-217 for demethoxycurcumin and a m/z of 265-224 for honokiol (internal std.) anal. The limit of detection (LOD) and quantification (LOQ) of curcumin in the rat plasma were 1 and 5 ng/mL, resp. The method was linear in the range of 5-1000 ng/mL with a coeff. of correlation greater than 0.996 in the rat plasma. After curcumin (500 mg/kg, p.o.) administration, the max. concn. (C max) and the time to reach max. concn. (T max) were 0.06 ± 0.01 μg/mL and 41.7 ± 5.4 min, resp. The elimination half-life (t 1/2,β) were 28.1 ± 5.6 and 44.5 ± 7.5 min for curcumin (500 mg/kg, p.o.) and curcumin (10 mg/kg, i.v.), resp. The oral bioavailability was about 1%.
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29Chow, S.-C.; Chiu, S.-T. A note on design and analysis of clinical trials Drug Des.: Open Access 2013, 2, 102 DOI: 10.4172/2169-0138.1000102There is no corresponding record for this reference.
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30National Institutes of Health. NIH RePORTER. Research portfolio online reporting tools. Reports, data, and analysis of NIH research activities. http://projectreporter.nih.gov/reporter.cfm (accessed October 6, 2016) .There is no corresponding record for this reference.
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31Kuttan, R.; Bhanumathy, P.; Nirmala, K.; George, M. C. Potential anticancer activity of turmeric (Curcuma longa) Cancer Lett. (N. Y., NY, U. S.) 1985, 29, 197– 202 DOI: 10.1016/0304-3835(85)90159-431https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL28XmtFKmtg%253D%253D&md5=8bcbde767c97604f0d99e296064f718bPotential anticancer activity of turmeric (Curcuma longa)Kuttan, Ramadasan; Bhanumathy, P.; Nirmala, K.; George, M. C.Cancer Letters (Shannon, Ireland) (1985), 29 (2), 197-202CODEN: CALEDQ; ISSN:0304-3835.Anticancer activity of the rhizomes of turmeric was evaluated in vitro using tissue culture methods and in vivo in mice using Dalton's lymphoma cells grown as ascites form. Turmeric ext. inhibited the cell growth in Chinese Hamster Ovary (CHO) cell culture at a concn. of 0.4 mg/mL and was cytotoxic to lymphocytes and Dalton's lymphoma cells at the same concn. Cytotoxic effect was found within 30 min at room temp. The active constituent was found to be curcumin [458-37-7] which showed cytotoxicity to lymphocytes and Dalton's lymphoma cells at a concn. of 4 μg/mL. Initial expts. indicated that turmeric ext. and curcumin reduced the development of animal tumors.
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32Niranjan, A.; Singh, S.; Dhiman, M.; Tewari, S. K. Biochemical composition of Curcuma longa l. Accessions Anal. Lett. 2013, 46, 1069– 1083 DOI: 10.1080/00032719.2012.75154132https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhvVeku7vL&md5=074030903fba86cfb0c939073d2a9dd4Biochemical Composition of Curcuma longa L. AccessionsNiranjan, Abhishek; Singh, Shweta; Dhiman, Manjul; Tewari, S. K.Analytical Letters (2013), 46 (7), 1069-1083CODEN: ANALBP; ISSN:0003-2719. (Taylor & Francis, Inc.)The essential oil compn. and total phenolic content (TPC) of curcuminoids were studied in rhizomes of nine Curcuma longa L. accessions. Curcuminoids, present in com. available turmeric rhizomes, play vital roles in various pharmacol. activities. A simple, rapid, and sensitive high performance liq. chromatog. photodiode array (HPLC-PDA) method was optimized for simultaneous detn. of curcuminoids, namely, a mixt. of curcumin, demethoxy curcumin (DMC), and bisdemethoxy curcumin (BDMC) in rhizomes of C. longa. Chromatog. sepn. was performed on an RP C18 column within 13 min (11.4 to 12.95 min). Elution was accomplished by the application of acetonitrile and 1.5% acetic acid in water in a gradient system with flow rate of 2.0 mL min-1. PDA was employed for qual. and quant. anal. The calibration curves were found linear (0.99) for all cucuminoids; the limit of detection and quantification ranged between 1.01 μ g mL-1 to 1.16 μ g mL-1 and 2.30 μ g mL-1 to 3.05 μ g mL-1, resp., while recovery values ranged between 97.97% to 98.32%. The amt. of curcumin varied from 0.46% to 2.17%, DMC from 0.13% to 0.92% and BDMC from 0.06% to 0.52%. The validated method was successively used to det. the above compds. in C. longa rhizomes. The TPC in rhizomes ranged from 14.12 mg g-1 to 27.72 mg g-1. The chem. compn. of rhizome essential oil, analyzed by gas chromatog. mass spectrometry (GCMS) showed large variations in major compds. like ar-tumerone (7.31-38.66%), β-curcumene (1.58-24.53%), and curlone (1.55-15.97%).
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33Priyadarsini, K. I. The chemistry of curcumin: From extraction to therapeutic agent Molecules 2014, 19, 20091– 20112 DOI: 10.3390/molecules19122009133https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitFOksLzE&md5=905dd120d7b649acf106858f980af304The chemistry of curcumin: from extraction to therapeutic agentPriyadarsini, Kavirayani IndiraMolecules (2014), 19 (12), 20091-20112, 22 pp.CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)A review. Curcumin, a pigment from turmeric, is one of the very few promising natural products that has been extensively investigated by researchers from both the biol. and chem. point of view. While there are several reviews on the biol. and pharmacol. effects of curcumin, chem. reviews are comparatively scarcer. In this article, an overview of different aspects of the unique chem. research on curcumin will be discussed. These include methods for the extn. from turmeric, lab. synthesis methods, chem. and photochem. degrdn. and the chem. behind its metab. Addnl. other chem. reactions that have biol. relevance like nucleophilic addn. reactions, and metal chelation will be discussed. Recent advances in the prepn. of new curcumin nanoconjugates with metal and metal oxide nanoparticles will also be mentioned. Directions for future investigations to be undertaken in the chem. of curcumin have also been suggested.
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34Food and Drug Administration Office of Food Additive Safety. Agency Response Letter GRAS Notice No. Grn 000460. U.S. Food and Drug Administration, 2013.There is no corresponding record for this reference.
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35Majeed, S. The state of the curcumin market. Natural Products Insider; Informa Exhibitions, 2015; http://www.naturalproductsinsider.com/articles/2015/12/the-state-of-the-curcumin-market.aspx.There is no corresponding record for this reference.
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36Niranjan, A.; Prakash, D. Chemical constituents and biological activities of turmeric (Curcuma longa l.) - a review J. Food Sci. Technol. (New Delhi, India) 2008, 45, 109– 116There is no corresponding record for this reference.
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37Panahi, Y.; Hosseini, M. S.; Khalili, N.; Naimi, E.; Majeed, M.; Sahebkar, A. Antioxidant and anti-inflammatory effects of curcuminoid-piperine combination in subjects with metabolic syndrome: A randomized controlled trial and an updated meta-analysis Clin. Nutr. 2015, 34, 1101– 1108 DOI: 10.1016/j.clnu.2014.12.01937https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXosFGqsA%253D%253D&md5=ab3ebfedd8e61e8516196e53653f0522Antioxidant and anti-inflammatory effects of curcuminoid-piperine combination in subjects with metabolic syndrome: A randomized controlled trial and an updated meta-analysisPanahi, Yunes; Hosseini, Mahboobeh Sadat; Khalili, Nahid; Naimi, Effat; Majeed, Muhammed; Sahebkar, AmirhosseinClinical Nutrition (2015), 34 (6), 1101-1108CODEN: CLNUDP; ISSN:0261-5614. (Elsevier Ltd.)Oxidative stress and inflammation have been proposed as emerging components of metabolic syndrome (MetS). Curcuminoids are natural polyphenols with strong antioxidant and anti-inflammatory properties. To study the effectiveness of supplementation with a bioavailable curcuminoid prepn. on measures of oxidative stress and inflammation in patients with MetS. Our secondary aim was to perform a meta-anal. of data from all randomized controlled trials in order to est. the effect size of curcuminoids on plasma C-reactive protein (CRP) concns. In this randomized double-blind placebo-controlled trial, 117 subjects with MetS (according to the NCEP-ATPIII diagnostic criteria) were randomly assigned to curcuminoids (n = 59; drop-outs = 9) or placebo (n = 58; drop-outs = 8) for eight weeks. Curcuminoids were administered at a daily dose of 1 g, and were co-supplemented with piperine (10 mg/day) in order to boost oral bioavailability. Serum activities of superoxide dismutase (SOD) and concns. of malondialdehyde (MDA) and CRP were measured at baseline and at study end. Regarding the importance of CRP as a risk marker and risk factor of cardiovascular disease, a random-effects meta-anal. of clin. trials was performed to est. the overall impact of curcuminoid therapy on circulating concns. of CRP. The robustness of estd. effect size was evaluated using leave-one-out sensitivity anal. Supplementation with curcuminoid-piperine combination significantly improved serum SOD activities (p < 0.001) and reduced MDA (p < 0.001) and CRP (p < 0.001) concns. compared with placebo. Quant. data synthesis revealed a significant effect of curcuminoids vs. placebo in reducing circulating CRP concns. (weighed mean difference: -2.20 mg/L; 95% confidence interval [CI]: -3.96, -0.44; p = 0.01). This effect was robust in sensitivity anal. Short-term supplementation with curcuminoid-piperine combination significantly improves oxidative and inflammatory status in patients with MetS. Curcuminoids could be regarded as natural, safe and effective CRP-lowering agents.
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38Yue, G. G.; Chan, B. C.; Hon, P. M.; Lee, M. Y.; Fung, K. P.; Leung, P. C.; Lau, C. B. Evaluation of in vitro anti-proliferative and immunomodulatory activities of compounds isolated from Curcuma longa Food Chem. Toxicol. 2010, 48, 2011– 2020 DOI: 10.1016/j.fct.2010.04.03938https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXptlGiurs%253D&md5=cdbd6f10972ac4a0067941309fc758aeEvaluation of in vitro anti-proliferative and immunomodulatory activities of compounds isolated from Curcuma longaYue, Grace G. L.; Chan, Ben C. L.; Hon, Po-Ming; Lee, Mavis Y. H.; Fung, Kwok-Pui; Leung, Ping-Chung; Lau, Clara B. S.Food and Chemical Toxicology (2010), 48 (8-9), 2011-2020CODEN: FCTOD7; ISSN:0278-6915. (Elsevier Ltd.)The rhizome of Curcuma longa (CL) has been commonly used in Asia as a potential candidate for the treatment of different diseases, including inflammatory disorders and cancers. The present study evaluated the anti-proliferative activities of the isolated compds. (three curcuminoids and two turmerones) from CL, using human cancer cell lines HepG2, MCF-7 and MDA-MB-231. The immunomodulatory activities of turmerones (α and arom.) isolated from CL were also examd. using human peripheral blood mononuclear cells (PBMC). Our results showed that the curcuminoids (curcumin, demethoxycurcumin and bisdemethoxycurcumin) and α-turmerone significantly inhibited proliferation of cancer cells in dose-dependent manner. The IC50 values of these compds. in cancer cells ranged from 11.0 to 41.8 μg/mL. α-Turmerone induced MDA-MB-231 cells to undergo apoptosis, which was confirmed by annexin-V and propidium iodide staining, and DNA fragmentation assay. The caspase cascade was activated as shown by a significant decrease of procaspases-3, -8 and -9 in α-turmerone treated cells. Both α-turmerone and arom.-turmerone showed stimulatory effects on PBMC proliferation and cytokine prodn. The anti-proliferative effect of α-turmerone and immunomodulatory activities of ar-turmerone was shown for the first time. The findings revealed the potential use of CL crude ext. (contg. curcuminoids and volatile oil including turmerones) as chemopreventive agent.
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39Hu, S.; Maiti, P.; Ma, Q.; Zuo, X.; Jones, M. R.; Cole, G. M.; Frautschy, S. A. Clinical development of curcumin in neurodegenerative disease Expert Rev. Neurother. 2015, 15, 629– 637 DOI: 10.1586/14737175.2015.104498139https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXpt1Kmsbw%253D&md5=463b61b79a9c1f33b39cb7a066ec4dd5Clinical development of curcumin in neurodegenerative diseaseHu, Shuxin; Maiti, Panchanan; Ma, Qiulan; Zuo, Xiaohong; Jones, Mychica R.; Cole, Greg M.; Frautschy, Sally A.Expert Review of Neurotherapeutics (2015), 15 (6), 629-637CODEN: ERNXAR; ISSN:1473-7175. (Informa Healthcare)A review. Curcumin, a polyphenolic antioxidant derived from the turmeric root has undergone extensive preclin. development, showing remarkable efficacy in wound repair, cancer and inflammatory disorders. This review addresses the rationale for its use in neurodegenerative disease, particularly Alzheimer's disease. Curcumin is a pleiotropic mol., which not only directly binds to and limits aggregation of the β-sheet conformations of amyloid characteristic of many neurodegenerative diseases but also restores homeostasis of the inflammatory system, boosts the heat shock system to enhance clearance of toxic aggregates, scavenges free radicals, chelates iron and induces anti-oxidant response elements. Although curcumin corrects dysregulation of multiple pathways, it may exert many effects via a few mol. targets. Pharmaceutical development of natural compds. like curcumin and synthetic derivs. have strong scientific rationale, but will require overcoming various hurdles including; high cost of trials, concern about profitability and misconceptions about drug specificity, stability, and bioavailability.
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40Baell, J. B.; Holloway, G. A. New substructure filters for removal of pan assay interference compounds (PAINS) from screening libraries and for their exclusion in bioassays J. Med. Chem. 2010, 53, 2719– 2740 DOI: 10.1021/jm901137j40https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhsF2qsLw%253D&md5=fbf397aa4910753c550425708c866fd2New Substructure Filters for Removal of Pan Assay Interference Compounds (PAINS) from Screening Libraries and for Their Exclusion in BioassaysBaell, Jonathan B.; Holloway, Georgina A.Journal of Medicinal Chemistry (2010), 53 (7), 2719-2740CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)This report describes a no. of substructural features which can help to identify compds. that appear as frequent hitters (promiscuous compds.) in many biochem. high throughput screens. The compds. identified by such substructural features are not recognized by filters commonly used to identify reactive compds. Even though these substructural features were identified using only one assay detection technol., such compds. have been reported to be active from many different assays. In fact, these compds. are increasingly prevalent in the literature as potential starting points for further exploration, whereas they may not be.
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41Fang, J.; Lu, J.; Holmgren, A. Thioredoxin reductase is irreversibly modified by curcumin: A novel molecular mechanism for its anticancer activity J. Biol. Chem. 2005, 280, 25284– 25290 DOI: 10.1074/jbc.M41464520041https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXlsFyqtbw%253D&md5=373d0ddf866fdab1c60f811c75a200d7Thioredoxin Reductase Is Irreversibly Modified by Curcumin: a novel molecular mechanism for its anticancer activityFang, Jianguo; Lu, Jun; Holmgren, ArneJournal of Biological Chemistry (2005), 280 (26), 25284-25290CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)The thioredoxin reductase (TrxR) isoenzymes, TrxR1 in cytosol or nucleus and TrxR2 in mitochondria, are essential mammalian selenocysteine (Sec)-contg. flavoenzymes with a -Gly-Cys-Sec-Gly active site. TrxRs are the only enzymes catalyzing the NADPH-dependent redn. of the active site disulfide in thioredoxins (Trxs), which play essential roles in substrate redns., defense against oxidative stress, and redox regulation by thiol redox control. TrxRs have been found to be overexpressed by a no. of human tumors. Curcumin, which is consumed daily by millions of people, is a polyphenol derived from the plant Curcuma longa. This phytochem. has well known anticancer and antiangiogenic properties. In this study we report that rat TrxR1 activity in Trx-dependent disulfide redn. was inhibited by curcumin. The IC50 value for the enzyme was 3.6 μM after incubation at room temp. for 2 h in vitro. The inhibition occurred with enzyme only in the presence of NADPH and persisted after removal of curcumin. By using mass spectrometry and blotting anal., we proved that this irreversible inhibition by curcumin was caused by alkylation of both residues in the catalytically active site (Cys496/Sec497) of the enzyme. However, the curcumin-modified enzyme showed a strongly induced NADPH oxidase activity to produce reactive oxygen species. Inhibition of TrxR by curcumin added to cultured HeLa cells was also obsd. with an IC50 of around 15 μM. Modification of TrxR by curcumin provides a possible mechanistic explanation for its cancer preventive activity, shifting the enzyme from an antioxidant to a prooxidant.
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42Jurrmann, N.; Birgelius-Flohe, R.; Boel, G.-F. Curcumin blocks interleukin-1 (IL-1) signaling by inhibiting the recruitment of the IL-1 receptor-associated kinase IRAK in murine thymoma EL-4 cells J. Nutr. 2005, 135, 1859– 186442https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXnvVSmtbw%253D&md5=4f1d09035024b3143e88516145eed14eCurcumin blocks interleukin-1 (IL-1) signaling by inhibiting the recruitment of the IL-1 receptor-associated kinase IRAK in murine thymoma EL-4 cellsJurrmann, Nadine; Birgelius-Flohe, Regina; Boel, Gaby-FleurJournal of Nutrition (2005), 135 (8), 1859-1864CODEN: JONUAI; ISSN:0022-3166. (American Society for Nutritional Sciences)Curcumin is a dietary compd. with diverse anti-inflammatory and anticarcinogenic effects in several exptl. models. A mechanism by which curcumin exerts these actions might be the direct modification of protein thiols, thereby altering the activity of the affected proteins. An early event in inflammatory signaling cascades is the recruitment of the interleukin-1 (IL-1) receptor-assocd. kinase (IRAK) to the IL-1 receptor (IL-1RI) upon stimulation with IL-1. IRAK recruitment was shown recently to be inhibited by agents that modify thiols of IRAK. We asked, therefore, whether IRAK is also a target for curcumin. Curcumin indeed blocked IRAK thiols in a murine T-cell line stably overexpressing IRAK (EL-4IRAK), which resulted in the inhibition of IRAK recruitment to the IL-1RI and phosphorylation of IRAK and IL-1RI-assocd. proteins. Inhibitory effects were not reversible by thiol-reducing agents. Thus, modification by curcumin did not occur by oxidn. but rather by alkylation, as is typical for electrophilic compds. reacting as Michael addn. acceptors. The block in one of the earliest events in the IL-1 signaling cascade can explain the often obsd. inhibition of IL-1-mediated signaling steps by curcumin further downstream. Hence, thiol modification might be a crucial step in the anti-inflammatory functions of curcumin.
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43Jung, Y.; Xu, W.; Kim, H.; Ha, N.; Neckers, L. Curcumin-induced degradation of ErbB2: A role for the E3 ubiquitin ligase CHIP and the Michael reaction acceptor activity of curcumin Biochim. Biophys. Acta, Mol. Cell Res. 2007, 1773, 383– 390 DOI: 10.1016/j.bbamcr.2006.11.00443https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXitFOhs7g%253D&md5=f683d493b87afaad168bc86c7d90c319Curcumin-induced degradation of ErbB2: A role for the E3 ubiquitin ligase CHIP and the Michael reaction acceptor activity of curcuminJung, Yunjin; Xu, Wanping; Kim, Heejung; Ha, Namchul; Neckers, LenBiochimica et Biophysica Acta, Molecular Cell Research (2007), 1773 (3), 383-390CODEN: BBAMCO; ISSN:0167-4889. (Elsevier Ltd.)We investigated the mol. mechanism underlying curcumin depletion of ErbB2 protein. Curcumin induced ErbB2 ubiquitination but pretreatment with proteasome inhibitors neither prevented curcumin depletion of ErbB2 protein nor further accumulated ubiquitinated ErbB2. Curcumin increased assocn. of endogenous and ectopically expressed CHIP, a chaperone-dependent ubiquitin ligase, with ErbB2. In COS7 cells cotransfected with ErbB2 and various CHIP plasmids followed by curcumin treatment, CHIP-H260Q (a mutant lacking ubiquitin ligase activity) promoted less curcumin-induced ErbB2 ubiquitination than did wild type CHIP, and CHIP-K30A (a mutant incapable of binding Hsp90 and Hsp70) neither assocd. with ErbB2 nor promoted its ubiquitination. ErbB2 mutants lacking the kinase domain failed to assoc. with CHIP and were completely resistant to ubiquitination and depletion induced by curcumin. Finally, curcumin's Michael reaction acceptor functionality was required for both covalent assocn. of curcumin with ErbB2 and curcumin-mediated ErbB2 depletion. These data suggest (1) that CHIP-dependent ErbB2 ubiquitination is implicated in curcumin-stimulated ErbB2 depletion, and (2) that covalent modification of ErbB2 by curcumin is the proximal signal which initiates this process.
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44Chin, D.; Huebbe, P.; Frank, J.; Rimbach, G.; Pallauf, K. Curcumin may impair iron status when fed to mice for six months Redox Biol. 2014, 2, 563– 569 DOI: 10.1016/j.redox.2014.01.01844https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXht1Kqt7nL&md5=341aef7f9099bc467e28d37266d50f97Curcumin may impair iron status when fed to mice for six monthsChin, Dawn; Huebbe, Patricia; Frank, Jan; Rimbach, Gerald; Pallauf, KathrinRedox Biology (2014), 2 (), 563-569CODEN: RBEIB3; ISSN:2213-2317. (Elsevier B.V.)Curcumin has been shown to have many potentially health beneficial properties in vitro and in animal models with clin. studies on the toxicity of curcumin reporting no major side effects. However, curcumin may chelate dietary trace elements and could thus potentially exert adverse effects. Here, we investigated the effects of a 6 mo dietary supplementation with 0.2% curcumin on iron, zinc, and copper status in C57BL/6J mice. Compared to non-supplemented control mice, we obsd. a significant redn. in iron, but not zinc and copper stores, in the liver and the spleen, as well as strongly suppressed liver hepcidin and ferritin expression in the curcumin-supplemented mice. The expression of the iron-importing transport proteins divalent metal transporter 1 and transferrin receptor 1 was induced, while hepatic and splenic inflammatory markers were not affected in the curcumin-fed mice. The mRNA expression of other putative target genes of curcumin, including the nuclear factor (erythroid-derived 2)-like 2 and haem oxygenase 1 did not differ between the groups. Most of the published animal trials with curcumin-feeding have not reported adverse effects on iron status or the spleen. However, it is possible that long-term curcumin supplementation and a Western-type diet may aggravate iron deficiency. Therefore, our findings show that further studies are needed to evaluate the effect of curcumin supplementation on iron status.
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45Schneider, C.; Gordon, O. N.; Edwards, R. L.; Luis, P. B. Degradation of curcumin: From mechanism to biological implications J. Agric. Food Chem. 2015, 63, 7606– 7614 DOI: 10.1021/acs.jafc.5b0024445https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXlsVShtbk%253D&md5=aa5e9f46a4065b3ec8d86b19cb95538dDegradation of Curcumin: From Mechanism to Biological ImplicationsSchneider, Claus; Gordon, Odaine N.; Edwards, Rebecca L.; Luis, Paula B.Journal of Agricultural and Food Chemistry (2015), 63 (35), 7606-7614CODEN: JAFCAU; ISSN:0021-8561. (American Chemical Society)Curcumin is the main bioactive ingredient in turmeric ext. and widely consumed as part of the spice mix curry or as a dietary supplement. Turmeric has a long history of therapeutic application in traditional Asian medicine. Biomedical studies conducted in the past two decades have identified a large no. of cellular targets and effects of curcumin. In vitro curcumin rapidly degrades in an autoxidative transformation to diverse chem. species, the formation of which has only recently been appreciated. This paper discusses how the degrdn. and metab. of curcumin, through products and their mechanism of formation, provide a basis for the interpretation of preclin. data and clin. studies. It is suggested that the previously unrecognized diversity of its degrdn. products could be an important factor in explaining the polypharmacol. of curcumin.
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46Duan, D.; Doak, A. K.; Nedyalkova, L.; Shoichet, B. K. Colloidal aggregation and the in vitro activity of traditional Chinese medicines ACS Chem. Biol. 2015, 10, 978– 988 DOI: 10.1021/cb500948746https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtFCntLg%253D&md5=04d107e8f0350ca38afd0131c4322fe6Colloidal Aggregation and the in Vitro Activity of Traditional Chinese MedicinesDuan, Da; Doak, Allison K.; Nedyalkova, Lyudmila; Shoichet, Brian K.ACS Chemical Biology (2015), 10 (4), 978-988CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)Traditional Chinese Medicines (TCMs) have been the sole source of therapeutics in China for two millennia. In recent drug discovery efforts, purified components of TCM formulations have shown activity in many in vitro assays, raising concerns of promiscuity. Here, we investigated 14 bioactive small mols. isolated from TCMs for colloidal aggregation. At concns. commonly used in cell-based or biochem. assay conditions, eight of these compds. formed particles detectable by dynamic light scattering and showed detergent-reversible inhibition against β-lactamase and malate dehydrogenase, two counter-screening enzymes. When three of these compds. were tested against their literature-reported mol. targets, they showed similar reversal of their inhibitory activity in the presence of detergent. For three of the most potent aggregators, contributions to promiscuity via oxidative cycling were investigated; addn. of 1 mM DTT had no effect on their activity, which is inconsistent with an oxidative mechanism. TCMs are often active at micromolar concns.; this study suggests that care must be taken to control for artifactual activity when seeking their primary targets. Implications for the formulation of these mols. are considered.
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47Ingolfsson, H. I.; Thakur, P.; Herold, K. F.; Hobart, E. A.; Ramsey, N. B.; Periole, X.; de Jong, D. H.; Zwama, M.; Yilmaz, D.; Hall, K.; Maretzky, T.; Hemmings, H. C., Jr.; Blobel, C.; Marrink, S. J.; Kocer, A.; Sack, J. T.; Andersen, O. S. Phytochemicals perturb membranes and promiscuously alter protein function ACS Chem. Biol. 2014, 9, 1788– 1798 DOI: 10.1021/cb500086e47https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXptlyqt7s%253D&md5=b61876239e926b652adea2e130627bc3Phytochemicals Perturb Membranes and Promiscuously Alter Protein FunctionIngolfsson, Helgi I.; Thakur, Pratima; Herold, Karl F.; Hobart, E. Ashley; Ramsey, Nicole B.; Periole, Xavier; de Jong, Djurre H.; Zwama, Martijn; Yilmaz, Duygu; Hall, Katherine; Maretzky, Thorsten; Hemmings, Hugh C.; Blobel, Carl; Marrink, Siewert J.; Kocer, Armagan; Sack, Jon T.; Andersen, Olaf S.ACS Chemical Biology (2014), 9 (8), 1788-1798CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)A wide variety of phytochems. are consumed for their perceived health benefits. Many of these phytochems. have been found to alter numerous cell functions, but the mechanisms underlying their biol. activity tend to be poorly understood. Phenolic phytochems. are particularly promiscuous modifiers of membrane protein function, suggesting that some of their actions may be due to a common, membrane bilayer-mediated mechanism. To test whether bilayer perturbation may underlie this diversity of actions, we examd. five bioactive phenols reported to have medicinal value: capsaicin from chili peppers, curcumin from turmeric, EGCG from green tea, genistein from soybeans, and resveratrol from grapes. We find that each of these widely consumed phytochems. alters lipid bilayer properties and the function of diverse membrane proteins. Mol. dynamics simulations show that these phytochems. modify bilayer properties by localizing to the bilayer/soln. interface. Bilayer-modifying propensity was verified using a gramicidin-based assay, and indiscriminate modulation of membrane protein function was demonstrated using four proteins: membrane-anchored metalloproteases, mechanosensitive ion channels, and voltage-dependent potassium and sodium channels. Each protein exhibited similar responses to multiple phytochems., consistent with a common, bilayer-mediated mechanism. Our results suggest that many effects of amphiphilic phytochems. are due to cell membrane perturbations, rather than specific protein binding.
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48Priyadarsini, K. I. Photophysics, photochemistry and photobiology of curcumin: Studies from organic solutions, bio-mimetics and living cells J. Photochem. Photobiol., C 2009, 10, 81– 95 DOI: 10.1016/j.jphotochemrev.2009.05.00148https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXptlektL8%253D&md5=1356fe80bacb33742766c7fad061a991Photophysics, photochemistry and photobiology of curcumin: Studies from organic solutions, bio-mimetics and living cellsPriyadarsini, K. IndiraJournal of Photochemistry and Photobiology, C: Photochemistry Reviews (2009), 10 (2), 81-95CODEN: JPPCAF; ISSN:1389-5567. (Elsevier B.V.)A review. Curcumin, with its recent success as an antitumor agent, has been attracting researchers from wide ranging fields of physics, chem., biol. and medicine. The chem. structure of curcumin has two o-methoxy phenols attached sym. through α,β-unsatd. β-diketone linker, which also induces keto-enol tautomerism. Due to this, curcumin exhibits many interesting photophys. and photochem. properties. The absorption max. of curcumin is ∼408-430 nm in most of the org. solvents, while the emission max. is very sensitive to the surrounding solvent medium (460-560 nm) and the Stokes' shift varied from 2000 to 6000 cm-1. The fluorescence quantum yield in most of the solvents is low and reduced significantly in presence of water. The fluorescence lifetime is short (<1 ns) and displayed multi-exponential decay profile. The singlet excited states of curcumin decay by non-radiative processes contributed mainly by intra- and intermol. proton transfer with very low intersystem crossing efficiency. Polarity, π-bonding nature, hydrogen bond donating and accepting properties of the solvent influence the excited state photophysics of curcumin in a complex manner. The triplet excited states of curcumin absorb at 720 nm and react with oxygen to produce singlet mol. oxygen. The photodegrdn. of curcumin produces smaller phenols and the photobiol. activity of curcumin is due to the generation of reactive oxygen species. Being lipophilic in nature, the water soly. of curcumin could be enhanced upon the addn. of surfactants, polymers, cyclodextrins, lipids and proteins. Changes in the absorption and fluorescence properties of curcumin have been found useful to follow its interaction and site of binding in these systems. Curcumin fluorescence could be employed to follow the unfolding pattern and structural changes in proteins. The intracellular curcumin showed more fluorescence in tumor cells than in normal cells and fluorescence spectroscopy could be used to monitor its preferential localization in the membrane of tumor cells. This review, presents the current status of research on the photophys., photochem. and photobiol. processes of curcumin in homogeneous solns., bio-mimetics and living cells. Based on these studies, the possibility of developing curcumin, as a bimol. sensitive fluorescent probe is also discussed.
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49Esatbeyoglu, T.; Ulbrich, K.; Rehberg, C.; Rohn, S.; Rimbach, G. Thermal stability, antioxidant, and anti-inflammatory activity of curcumin and its degradation product 4-vinyl guaiacol Food Funct. 2015, 6, 887– 893 DOI: 10.1039/C4FO00790E49https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXotVKhsA%253D%253D&md5=1a16da1ec4ac5e7b7a5e351ad8f274dbThermal stability, antioxidant, and anti-inflammatory activity of curcumin and its degradation product 4-vinyl guaiacolEsatbeyoglu, Tuba; Ulbrich, Katrin; Rehberg, Clemens; Rohn, Sascha; Rimbach, GeraldFood & Function (2015), 6 (3), 887-893CODEN: FFOUAI; ISSN:2042-6496. (Royal Society of Chemistry)Curcumin is a secondary plant metabolite present in Curcuma longa L. Since curcumin is widely used as a food colorant in thermally processed food it may undergo substantial chem. changes which in turn could affect its biol. activity. In the current study, curcumin was roasted at 180 °C up to 70 min and its kinetic of degrdn. was analyzed by means of HPLC-PDA and LC-MS, resp. Roasting of curcumin resulted in the formation of the degrdn. products vanillin, ferulic acid, and 4-vinyl guaiacol. In cultured hepatocytes roasted curcumin as well as 4-vinyl guaiacol enhanced the transactivation of the redox-regulated transcription factor Nrf2, known to be centrally involved in cellular stress response and antioxidant defense mechanisms. The antioxidant enzyme paraoxonase 1 was induced by roasted curcumin and 4-vinyl guaiacol. Furthermore, roasted curcumin and 4-vinyl guaiacol decreased interleukin-6 gene expression in lipopolysaccharide stimulated murine macrophages. Current data suggest that curcumin undergoes degrdn. due to roasting and its degrdn. product exhibit significant biol. activity in cultured cells.
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50Avonto, C.; Taglialatela-Scafati, O.; Pollastro, F.; Minassi, A.; Di Marzo, V.; De Petrocellis, L.; Appendino, G. An NMR spectroscopic method to identify and classify thiol-trapping agents: Revival of Michael acceptors for drug discovery? Angew. Chem., Int. Ed. 2011, 50, 467– 471 DOI: 10.1002/anie.20100595950https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXitlGiuw%253D%253D&md5=8fd61bce5e0dfeb9209a6572516fd583An NMR Spectroscopic Method to Identify and Classify Thiol-Trapping Agents: Revival of Michael Acceptors for Drug Discovery?Avonto, Cristina; Taglialatela-Scafati, Orazio; Pollastro, Federica; Minassi, Alberto; Di Marzo, Vincenzo; De Petrocellis, Luciano; Appendino, GiovanniAngewandte Chemie, International Edition (2011), 50 (2), 467-471, S467/1-S467/30CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)We have developed a simple and quick NMR spectroscopic method to identify Michael acceptor sites in complex multifunctional compds. The method sorts them out in reversible and irreversible thiol sinks, and predicts their potential to modify proteins, as validated by the identification of several new chemotypes of TRPA1 activators. These include well-known anti-inflammatory agents, such as curcumin and parthenolide, which had been overlooked as ligands for this druggable end point of inflammation.
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51Pauli, G. F.; Chen, S. N.; Friesen, J. B.; McAlpine, J. B.; Jaki, B. U. Analysis and purification of bioactive natural products: The AnaPurNa study J. Nat. Prod. 2012, 75, 1243– 1255 DOI: 10.1021/np300066q51https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XnsVeru70%253D&md5=15d145c2988692d26558d6d4361337d9Analysis and Purification of Bioactive Natural Products: The AnaPurNa StudyPauli, Guido F.; Chen, Shao-Nong; Friesen, J. Brent; McAlpine, James B.; Jaki, Birgit U.Journal of Natural Products (2012), 75 (6), 1243-1255CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)A review on the survey of anal. methodol. such as chromatog. and spectroscopy used for isolation and purity assessment of bioactive natural products (NPs), which have been employed in the almost 2000 publications in the recent years.
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52Simmler, C.; Hajirahimkhan, A.; Lankin, D. C.; Bolton, J. L.; Jones, T.; Soejarto, D. D.; Chen, S. N.; Pauli, G. F. Dynamic residual complexity of the isoliquiritigenin-liquiritigenin interconversion during bioassay J. Agric. Food Chem. 2013, 61, 2146– 2157 DOI: 10.1021/jf304445p52https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXivFCgtrk%253D&md5=3e1d3de79750615a80d04164d8f6c429Dynamic Residual Complexity of the Isoliquiritigenin-Liquiritigenin Interconversion During BioassaySimmler, Charlotte; Hajirahimkhan, Atieh; Lankin, David C.; Bolton, Judy L.; Jones, Tristesse; Soejarto, Djaja D.; Chen, Shao-Nong; Pauli, Guido F.Journal of Agricultural and Food Chemistry (2013), 61 (9), 2146-2157CODEN: JAFCAU; ISSN:0021-8561. (American Chemical Society)Bioactive components in food plants can undergo dynamic processes that involve multiple chem. species. For example, 2'-hydroxychalcones can readily isomerize into flavanones. Although chem. well documented, this reaction has barely been explored in the context of cell-based assays. The present time-resolved study fills this gap by investigating the isomerization of isoliquiritigenin (a 2'-hydroxychalcone) and liquiritigenin (a flavanone) in two culture media (Dulbecco's modified eagle medium and Roswell Park Memorial Institute medium) with and without MCF-7 cells, using high-performance liq. chromatog.-diode array detector-electrospray ionization/atm. pressure chem. ionization-mass spectrometry for anal. Both compds. were isomerized and epimerized under all investigated biol. conditions, leading to mixts. of isoliquiritigenin and R/S-liquiritigenin, with 19.6% R enantiomeric excess. Consequently, all three species can potentially modulate the biol. responses. This exemplifies dynamic residual complexity and demonstrates how both nonchiral reactions and enantiomeric discrimination can occur in bioassay media, with or without cells. The findings highlight the importance of controlling in situ chem. reactivity, influenced by biol. systems when evaluating the mode of action of bioactives.
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53Gordon, O. N.; Luis, P. B.; Sintim, H. O.; Schneider, C. Unraveling curcumin degradation: Autoxidation proceeds through spiroepoxide and vinylether intermediates en route to the main bicyclopentadione J. Biol. Chem. 2015, 290, 4817– 4828 DOI: 10.1074/jbc.M114.61878553https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXjtlGju74%253D&md5=55623efe8a52f2763ea949a89b82063cUnraveling Curcumin DegradationGordon, Odaine N.; Luis, Paula B.; Sintim, Herman O.; Schneider, ClausJournal of Biological Chemistry (2015), 290 (8), 4817-4828CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)Curcumin is a dietary anti-inflammatory and chemopreventive agent consisting of two methoxyphenol rings connected by a conjugated heptadienedione chain. Curcumin is unstable at physiol. pH and rapidly degrades in an autoxidn. reaction to a major bicyclopentadione product in which the 7-carbon chain has undergone oxygenation and double cyclization. Early degrdn. products (but not the final bicyclopentadione) mediate topoisomerase poisoning and possibly many other activities of curcumin, but it is not known how many and what autoxidn. products are formed, nor their mechanism of formation. Here, using [14C2]curcumin as a tracer, seven novel autoxidn. products, including two reaction intermediates, were isolated and identified using one- and two-dimensional NMR and mass spectrometry. The unusual spiroepoxide and vinylether reaction intermediates are precursors to the final bicyclopentadione product. A mechanism for the autoxidn. of curcumin is proposed that accounts for the addn. and exchange of oxygen that have been detd. using 18O2 and H218O. Several of the byproducts are formed from an endoperoxide intermediate via reactions that are well precedented in lipid peroxidn. The electrophilic spiroepoxide intermediate formed a stable adduct with N-acetylcysteine, suggesting that oxidative transformation is required for biol. effects mediated by covalent adduction to protein thiols. The spontaneous autoxidn. distinguishes curcumin among natural polyphenolic compds. of therapeutic interest; the formation of chem. diverse reactive and electrophilic products provides a novel paradigm for understanding the polypharmacol. effects of curcumin.
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54Workman, P.; Collins, I. Probing the probes: Fitness factors for small molecule tools Chem. Biol. (Oxford, U. K.) 2010, 17, 561– 577 DOI: 10.1016/j.chembiol.2010.05.01354https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXotVWqs78%253D&md5=16be01da2339173aae8207030bf83c12Probing the Probes: Fitness Factors For Small Molecule ToolsWorkman, Paul; Collins, IanChemistry & Biology (Cambridge, MA, United States) (2010), 17 (6), 561-577CODEN: CBOLE2; ISSN:1074-5521. (Cell Press)A review. Chem. probes for interrogating biol. processes are of considerable current interest. Cell permeable small mol. tools have a major role in facilitating the functional annotation of the human genome, understanding both physiol. and pathol. processes, and validating new mol. targets. To be valuable, chem. tools must satisfy necessary criteria and recent publications have suggested objective guidelines for what makes a useful chem. probe. Although recognizing that such guidelines may be valuable, we caution against overly restrictive rules that may stifle innovation in favor of a "fit-for-purpose" approach. Reviewing the literature and providing examples from the cancer field, we recommend a series of "fitness factors" to be considered when assessing chem. probes. We hope this will encourage innovative chem. biol. research while minimizing the generation of poor quality and misleading biol. data, thus increasing understanding of the particular biol. area, to the benefit of basic research and drug discovery.
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55Singh, J.; Petter, R. C.; Baillie, T. A.; Whitty, A. The resurgence of covalent drugs Nat. Rev. Drug Discovery 2011, 10, 307– 317 DOI: 10.1038/nrd341055https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXktVGmu7g%253D&md5=2190289081e151416c097be4a5b04460The resurgence of covalent drugsSingh, Juswinder; Petter, Russell C.; Baillie, Thomas A.; Whitty, AdrianNature Reviews Drug Discovery (2011), 10 (4), 307-317CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)A review. Covalent drugs haveproved to be successful therapies for various indications, but largely owing to safety concerns, they are rarely considered when initiating a target-directed drug discovery project. There is a need to reassess this important class of drugs, and to reconcile the discordance between the historic success of covalent drugs and the reluctance of most drug discovery teams to include them in their armamentarium. This Review surveys the prevalence and pharmacol. advantages of covalent drugs, discusses how potential risks and challenges may be addressed through innovative design, and presents the broad opportunities provided by targeted covalent inhibitors.
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56Kalgutkar, A. S.; Dalvie, D. K. Drug discovery for a new generation of covalent drugs Expert Opin. Drug Discovery 2012, 7, 561– 581 DOI: 10.1517/17460441.2012.68874456https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XptFWmt7k%253D&md5=b7fc8e60b263dda5765dd8380f52df17Drug discovery for a new generation of covalent drugsKalgutkar, Amit S.; Dalvie, Deepak K.Expert Opinion on Drug Discovery (2012), 7 (7), 561-581CODEN: EODDBX; ISSN:1746-0441. (Informa Healthcare)A review. Introduction: The design of target-specific covalent inhibitors is conceptually attractive because of increased biochem. efficiency through covalency and increased duration of action that outlasts the pharmacokinetics of the agent. Although many covalent inhibitors have been approved or are in advanced clin. trials to treat indications such as cancer and hepatitis C, there is a general tendency to avoid them as drug candidates because of concerns regarding immune-mediated toxicity that can arise from indiscriminate reactivity with off-target proteins.Areas covered: The review examines potential reason(s) for the excellent safety record of marketed covalent agents and advanced clin. candidates for emerging therapeutic targets. A significant emphasis is placed on proteomic techniques and chem./biochem. reactivity assays that aim to provide a systematic rank ordering of pharmacol. selectivity relative to off-target protein reactivity of covalent inhibitors.Expert opinion: While tactics to examine selective covalent modification of the pharmacol. target are broadly applicable in drug discovery, it is unclear whether the output from such studies can prospectively predict idiosyncratic immune-mediated drug toxicity. Opinions regarding an acceptable threshold of protein reactivity/body burden for a toxic electrophile and a non-toxic electrophilic covalent drug have not been defined. Increasing confidence in proteomic and chem./biochem. reactivity screens will require a retrospective side-by-side profiling of marketed covalent drugs and electrophiles known to cause deleterious toxic effects via non-selective covalent binding.
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57Schröder, J.; Klinger, A.; Oellien, F.; Marhoefer, R. J.; Duszenko, M.; Selzer, P. M. Docking-based virtual screening of covalently binding ligands: An orthogonal lead discovery approach J. Med. Chem. 2013, 56, 1478– 1490 DOI: 10.1021/jm301393257https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3szisFyhtA%253D%253D&md5=a5186da21cd91e5bbe05c3cd96701258Docking-based virtual screening of covalently binding ligands: an orthogonal lead discovery approachSchroder Jorg; Klinger Anette; Oellien Frank; Marhofer Richard J; Duszenko Michael; Selzer Paul MJournal of medicinal chemistry (2013), 56 (4), 1478-90 ISSN:.In pharmaceutical industry, lead discovery strategies and screening collections have been predominantly tailored to discover compounds that modulate target proteins through noncovalent interactions. Conversely, covalent linkage formation is an important mechanism for a quantity of successful drugs in the market, which are discovered in most cases by hindsight instead of systematical design. In this article, the implementation of a docking-based virtual screening workflow for the retrieval of covalent binders is presented considering human cathepsin K as a test case. By use of the docking conditions that led to the best enrichment of known actives, 44 candidate compounds with unknown activity on cathepsin K were finally selected for experimental evaluation. The most potent inhibitor, 4-(N-phenylanilino)-6-pyrrolidin-1-yl-1,3,5-triazine-2-carbonitrile (CP243522), showed a K(i) of 21 nM and was confirmed to have a covalent reversible mechanism of inhibition. The presented approach will have great potential in cases where covalent inhibition is the desired drug discovery strategy.
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58Davids, M. S.; Brown, J. R. Ibrutinib: A first in class covalent inhibitor of Bruton’s tyrosine kinase Future Oncol. 2014, 10, 957– 967 DOI: 10.2217/fon.14.5158https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXpvFCrtbc%253D&md5=345b4e839a830be822d474f62755a022Ibrutinib: a first in class covalent inhibitor of Bruton's tyrosine kinaseDavids, Matthew S.; Brown, Jennifer R.Future Oncology (2014), 10 (6), 957-967CODEN: FOUNBN; ISSN:1479-6694. (Future Medicine Ltd.)A review. Ibrutinib (formerly PCI-32765) is a potent, covalent inhibitor of Bruton's tyrosine kinase, a kinase downstream of the B-cell receptor that is crit. for B-cell survival and proliferation. In preclin. studies, ibrutinib bound to Bruton's tyrosine kinase with high affinity, leading to inhibition of B-cell receptor signaling, decreased B-cell activation and induction of apoptosis. In clin. studies, ibrutinib has been well-tolerated and has demonstrated profound anti-tumor activity in a variety of hematol. malignancies, most notably chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), leading to US FDA approval for relapsed CLL and MCL. Ongoing studies are evaluating ibrutinib in other types of non-Hodgkin's lymphoma, such as diffuse large B-cell lymphoma and Waldenstroem's macrogobulinemia, in larger Phase III studies in CLL and MCL, and in combination studies with monoclonal antibodies and chemotherapy. Future studies will combine ibrutinib with other promising novel agents currently in development in hematol. malignancies.
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59Flanagan, M. E.; Abramite, J. A.; Anderson, D. P.; Aulabaugh, A.; Dahal, U. P.; Gilbert, A. M.; Li, C.; Montgomery, J.; Oppenheimer, S. R.; Ryder, T.; Schuff, B. P.; Uccello, D. P.; Walker, G. S.; Wu, Y.; Brown, M. F.; Chen, J. M.; Hayward, M. M.; Noe, M. C.; Obach, R. S.; Philippe, L.; Shanmugasundaram, V.; Shapiro, M. J.; Starr, J.; Stroh, J.; Che, Y. Chemical and computational methods for the characterization of covalent reactive groups for the prospective design of irreversible inhibitors J. Med. Chem. 2014, 57, 10072– 10079 DOI: 10.1021/jm501412a59https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvVyjtLbM&md5=3ccf59ab7a494655185e5eb5becf8c48Chemical and Computational Methods for the Characterization of Covalent Reactive Groups for the Prospective Design of Irreversible InhibitorsFlanagan, Mark E.; Abramite, Joseph A.; Anderson, Dennis P.; Aulabaugh, Ann; Dahal, Upendra P.; Gilbert, Adam M.; Li, Chao; Montgomery, Justin; Oppenheimer, Stacey R.; Ryder, Tim; Schuff, Brandon P.; Uccello, Daniel P.; Walker, Gregory S.; Wu, Yan; Brown, Matthew F.; Chen, Jinshan M.; Hayward, Matthew M.; Noe, Mark C.; Obach, R. Scott; Philippe, Laurence; Shanmugasundaram, Veerabahu; Shapiro, Michael J.; Starr, Jeremy; Stroh, Justin; Che, YeJournal of Medicinal Chemistry (2014), 57 (23), 10072-10079CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Interest in drugs that covalently modify their target is driven by the desire for enhanced efficacy that can result from the silencing of enzymic activity until protein resynthesis can occur, along with the potential for increased selectivity by targeting uniquely positioned nucleophilic residues in the protein. However, covalent approaches carry addnl. risk for toxicities or hypersensitivity reactions that can result from covalent modification of unintended targets. Here we describe methods for measuring the reactivity of covalent reactive groups (CRGs) with a biol. relevant nucleophile, glutathione (GSH), along with kinetic data for a broad array of electrophiles. We also describe a computational method for predicting electrophilic reactivity, which taken together can be applied to the prospective design of thiol-reactive covalent inhibitors.
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60Jost, C.; Nitsche, C.; Scholz, T.; Roux, L.; Klein, C. D. Promiscuity and selectivity in covalent enzyme inhibition: A systematic study of electrophilic fragments J. Med. Chem. 2014, 57, 7590– 7599 DOI: 10.1021/jm5006918There is no corresponding record for this reference.
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61Mah, R.; Thomas, J. R.; Shafer, C. M. Drug discovery considerations in the development of covalent inhibitors Bioorg. Med. Chem. Lett. 2014, 24, 33– 39 DOI: 10.1016/j.bmcl.2013.10.00361https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvFOlsr3O&md5=9407bcb76e83065f5a56a97b63547edeDrug discovery considerations in the development of covalent inhibitorsMah, Robert; Thomas, Jason R.; Shafer, Cynthia M.Bioorganic & Medicinal Chemistry Letters (2014), 24 (1), 33-39CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)A review. In recent years, the no. of drug candidates with a covalent mechanism of action progressing through clin. trials or being approved by the FDA has increased significantly. And as interest in covalent inhibitors has increased, the tech. challenges for characterizing and optimizing these inhibitors have become evident. A no. of new tools have been developed to aid this process, but these have not gained wide-spread use. This review will highlight a no. of methods and tools useful for prosecuting covalent inhibitor drug discovery programs.
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62Moghaddam, M. F.; Tang, Y.; O’Brien, Z.; Richardson, S. J.; Bacolod, M.; Chaturedi, P.; Apuy, J.; Kulkarni, A. A proposed screening paradigm for discovery of covalent inhibitor drugs Drug Metab. Lett. 2014, 8, 19– 30 DOI: 10.2174/187231280866614031715173562https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhslGqur%252FF&md5=97ff5ba47e9547cbae3e5d10ec35112eA Proposed Screening Paradigm for Discovery of Covalent Inhibitor DrugsMoghaddam, Mehran F.; Tang, Yang; O'Brien, Zhihong; Richardson, Samantha J.; Bacolod, Maria; Chaturedi, Prasoon; Apuy, Julius; Kulkarni, AshutoshDrug Metabolism Letters (2014), 8 (1), 19-30CODEN: DMLRBM; ISSN:1872-3128. (Bentham Science Publishers Ltd.)The in vitro and in vivo preclin. ADME properties of 10 clin. late stage or marketed covalent inhibitors were evaluated in order to define advancement criteria for discovery of future drugs in this arena. Our studies revealed the following: After incubating with S9 fractions for 30 min, the rat and human in vitro stability for these compds. ranged from 1% to 100%. The blood stability ranged from 30% to 100%. There was a broad range of CYP inhibition with prevalence for time-dependent inhibition of at least one enzyme. The Caco-2 permeability (A→B) ranged from negligible (0.6 x 10-6 cm/s) to highly permeable (31 x 10-6 cm/s) and the efflux ratio also varied widely (0.2-30). Most of the compds. were highly protein bound in both rat and human with binding ≥ 90%. Rat plasma clearance for the 10 compds. ranged from slow (11 mL/min/kg) to very rapid (350 mL/min/kg). The Vss ranged from low (0.67 L/kg) to very high (115 L/kg). MRT's also ranged from short (0.5 h) to long (7.4 h). The oral exposures also showed a very broad range with Cmax's ranging from 0.01-77 μM and exposure levels ranging from 0.03-106 μM.hr. In conclusion, the wide range in in vitro and in vivo ADME data makes these particular ADME assays non-discriminatory in the selection of promising compds. In our opinion, non-traditional assays such as target mass modification, target confirmation by amino acid sequencing, cellular target occupancy, and target turnover rate data in combination with the pharmacokinetic profiles are the crit. considerations for progression of irreversible compds. in early discovery. ; <b>Biog.</b>: Mehran Moghaddam, PhD, is.
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63Payton, F.; Sandusky, P.; Alworth, W. L. NMR study of the solution structure of curcumin J. Nat. Prod. 2007, 70, 143– 146 DOI: 10.1021/np060263s63https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXmsVylsg%253D%253D&md5=256dfb68d48c05c70b191b1ad4c9f5e7NMR Study of the Solution Structure of CurcuminPayton, Florastina; Sandusky, Peter; Alworth, William L.Journal of Natural Products (2007), 70 (2), 143-146CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)Curcumin [1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione (I)] is derived from the rhizomes of Curcuma longa. Although early studies concluded that curcumin exists predominantly as a keto-enol tautomer, II, in several recent articles the soln. structure of curcumin has been represented as a β-diketone tautomer, I. We have investigated the structure of curcumin in solvents ranging in polarity from CDCl3 to mixts. of DMSO-d6 in water, and in buffered aq. DMSO-d6 solns. with pH values varying from 3 to 9. The soln. structure of curcumin was detd. on the basis of NMR techniques, including DEPT, HMQC, HMBC, and COSY. The results of the NMR studies show definitely that curcumin exists in soln. as keto-enol tautomers, II.
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64Jagannathan, R.; Abraham, P. M.; Poddar, P. Temperature-dependent spectroscopic evidences of curcumin in aqueous medium: A mechanistic study of its solubility and stability J. Phys. Chem. B 2012, 116, 14533– 14540 DOI: 10.1021/jp305051664https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhslKhsrrO&md5=63b9c38eaf6b4ff167901c50441b5c5aTemperature-Dependent Spectroscopic Evidences of Curcumin in Aqueous Medium: A Mechanistic Study of Its Solubility and StabilityJagannathan, Ramya; Abraham, Priya Mary; Poddar, PankajJournal of Physical Chemistry B (2012), 116 (50), 14533-14540CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)In curcumin, keto-enol-enolate equil. of the heptadiene-dione moiety dets. its physiochem. and antioxidant properties. However, its poor soly. in water at neutral pH and room temp. decreases its bioavailability. Potential therapeutic applications have triggered an interest in manipulating the soly. of curcumin in water as its stability and soly. in water remains poorly understood. Here, the mechanism behind its soly. at various temps. and the influence of interplay of temp., intramol. H-bonding, and intermol. forces is reported, which leads to aggregation-disaggregation at various temps. Remarkable change is obsd. in temp.-dependent electronic transition behavior of curcumin, however, the absorption spectra after cooling and heating cycles remain unchanged, hinting much better thermal stability of curcumin in water than previously thought. This study indicates that it is perhaps the breaking of intramol. hydrogen bonding which leads to exposure of polar groups and hence responsible for the dissoln. of curcumin at higher temp. The formation of intermol. aggregates might be responsible behind a better room temp. stability of the mols. after cooling its aq. suspension from 90 to 25 °C. These curcumin soly. studies have great application in biol. research with ref. to bioavailability and to understand target oriented mode of action of curcumin.
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65Takagi, T.; Ramachandran, C.; Bermejo, M.; Yamashita, S.; Yu, L. X.; Amidon, G. L. A provisional biopharmaceutical classification of the top 200 oral drug products in the United States, Great Britain, Spain, and Japan Mol. Pharmaceutics 2006, 3, 631– 643 DOI: 10.1021/mp060018265https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhtVagsr%252FN&md5=fab640e0a7885c72de8022ef1cdf0e72A Provisional Biopharmaceutical Classification of the Top 200 Oral Drug Products in the United States, Great Britain, Spain, and JapanTakagi, Toshihide; Ramachandran, Chandrasekharan; Bermejo, Marival; Yamashita, Shinji; Yu, Lawrence X.; Amidon, Gordon L.Molecular Pharmaceutics (2006), 3 (6), 631-643CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)Orally administered, immediate-release (IR) drug products in the top 200 drug product lists from the United States (US), Great Britain (GB), Spain (ES), and Japan (JP) were provisionally classified based on the Biopharmaceutics Classification System (BCS). The provisional classification is based on the aq. soly. of the drugs reported in readily available ref. literature and a correlation of human intestinal membrane permeability for a set of 29 ref. drugs with their calcd. partition coeffs. Oral IR drug products constituted more that 50% of the top 200 drug products on all four lists, and ranged from 102 to 113 in no. Drugs with dose nos. less than or equal to unity are defined as high-soly. drugs. More than 50% of the oral IR drug products on each list were detd. to be high-soly. drugs (55-59%). The provisional classification of permeability is based on correlations of the human intestinal permeabilities of 29 ref. drugs with the calcd. Log P or CLogP lipophilicity values for the uncharged chem. form. The Log P and CLogP ests. were linearly correlated (r2 = 0.79) for 187 drugs. Metoprolol was chosen as the ref. compd. for permeability and Log P or CLogP. A total of 62-69.0% and 56-60% of the drugs on the four lists exhibited CLogP and Log P ests., resp., greater than or equal to the corresponding metoprolol value and are provisionally classified as high-permeability drugs. We have compared the BCS classification in this study with the recently proposed BDDCS classification based on fraction dose metab. Although the two approaches are based on different in vivo processes, fraction dose metabolized and fraction dose absorbed are highly correlated and, while depending on the choice of ref. drug for permeability classification, e.g., metoprolol vs. cimetidine or atenolol, show excellent agreement in drug classification. In summary, more than 55% of the drug products were classified as high-soly. (Class 1 and Class 3) drugs in the four lists, suggesting that in vivo bioequivalence (BE) may be assured with a less expensive and more easily implemented in vitro dissoln. test.
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66Griesser, M.; Pistis, V.; Suzuki, T.; Tejera, N.; Pratt, D. A.; Schneider, C. Autoxidative and cyclooxygenase-2 catalyzed transformation of the dietary chemopreventive agent curcumin J. Biol. Chem. 2011, 286, 1114– 1124 DOI: 10.1074/jbc.M110.17880666https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXjtFaqtw%253D%253D&md5=297d642ba6a73eac6ff4028a30486048Autoxidative and Cyclooxygenase-2 Catalyzed Transformation of the Dietary Chemopreventive Agent CurcuminGriesser, Markus; Pistis, Valentina; Suzuki, Takashi; Tejera, Noemi; Pratt, Derek A.; Schneider, ClausJournal of Biological Chemistry (2011), 286 (2), 1114-1124CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)The efficacy of the diphenol curcumin as a cancer chemopreventive agent is limited by its chem. and metabolic instability. Non-enzymic degrdn. has been described to yield vanillin, ferulic acid, and feruloylmethane through cleavage of the heptadienone chain connecting the phenolic rings. Here we provide evidence for an alternative mechanism, resulting in autoxidative cyclization of the heptadienone moiety as a major pathway of degrdn. Autoxidative transformation of curcumin was pH-dependent with the highest rate at pH 8 (2.2 μM/min) and assocd. with stoichiometric uptake of O2. Oxidn. was also catalyzed by recombinant cyclooxygenase-2 (COX-2) (50 nM; 7.5 μM/min), and the rate was increased ≈10-fold by the addn. of 300 μM H2O2. The COX-2 catalyzed transformation was inhibited by acetaminophen but not indomethacin, suggesting catalysis occurred by the peroxidase activity. We propose a mechanism of enzymic or autoxidative hydrogen abstraction from a phenolic hydroxyl to give a quinone methide and a delocalized radical in the heptadienone chain that undergoes 5-exo cyclization and oxygenation. Hydration of the quinone methide (measured by the incorporation of O-18 from H[Formula: see text]O) and rearrangement under loss of water gives the final dioxygenated bicyclopentadione product. When curcumin was added to RAW264.7 cells, the bicyclopentadione was increased 1.8-fold in cells activated by LPS; vanillin and other putative cleavage products were negligible. Oxidn. to a reactive quinone methide is the mechanistic basis of many phenolic anti-cancer drugs. It is possible, therefore, that oxidative transformation of curcumin, a prominent but previously unrecognized reaction, contributes to its cancer chemopreventive activity.
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67Gordon, O. N.; Schneider, C. Vanillin and ferulic acid: Not the major degradation products of curcumin Trends Mol. Med. 2012, 18, 361– 363DOI: 10.1016/j.molmed.2012.04.011
(author reply, pp 363–364)
67https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtVShsb7K&md5=c47a9a41885123b2c24a6876164b88b5Vanillin and ferulic acid: not the major degradation products of curcuminGordon, Odaine N.; Schneider, ClausTrends in Molecular Medicine (2012), 18 (7), 361-363CODEN: TMMRCY; ISSN:1471-4914. (Elsevier Ltd.)A polemic in response to Shen and Ji (Trends Mol. Med. 2012, 18, 138-144) is given. In their study, Shen and Ji described the hypothesis that metabolites of curcumin, specifically vanillin and ferulic acid, could account for its striking polypharmacol. as well as for the enigmatically low levels of curcumin in animal and human plasma upon dietary administration. The authors believed that testing of this hypothesis requires that the degrdn. products are pos. identified, such that the correct products are considered for activity. They also contested the widely held notion that vanillin, ferulic acid, and feruloylmethane are abundant products of the nonenzymic degrdn. of curcumin. -
68Khurana, A.; Ho, C. T. High-performance liquid-chromatographic analysis of curcuminoids and their photo-oxidative decomposition compounds in Curcuma longa l J. Liq. Chromatogr. 1988, 11, 2295– 2304 DOI: 10.1080/0148391880806720068https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL1MXhtlWntb8%253D&md5=f4d2b7c5ba26ff53372351af286c9098High performance liquid chromatographic analysis of curcuminoids and their photo-oxidative decomposition compounds in Curcuma longa LKhurana, Amrik; Ho, Chi TangJournal of Liquid Chromatography (1988), 11 (11), 2295-304CODEN: JLCHD8; ISSN:0148-3919.Photochem. oxidn. of curcuminoids such as curcumin, bisdemethoxycurcumin, and demethoxycurcumin in dry powder of Curcuma longa (zingiberaceae) root and in EtOH and MeOH exts. has been studied following sunlight exposure for 120 h. Whatman PartiSphere-5 NH2 and Whatman PartiSphere-5 WCX columns were used to analyze curcuminoids and their degrdn. products. The curcuminoids were found to be more stable in the dry powder of C. longa root than in EtOH and MeOH exts. Vanillin, p-hydroxybenzaldehyde, ferulic aldehyde, p-hydroxybenzoic acid, vanillic acid, and ferulic acid were identified as the oxidn. products.
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69Tønnesen, H. H.; Karlsen, J.; van Henegouwen, G. B. Studies on curcumin and curcuminoids. VIII. Photochemical stability of curcumin Z. Lebensm.-Unters. Forsch. 1986, 183, 116– 122 DOI: 10.1007/BF0104192869https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaL2s%252FitFGisw%253D%253D&md5=df5990866da489cef1a76a237c02659bStudies on curcumin and curcuminoids. VIII. Photochemical stability of curcuminTonnesen H H; Karlsen J; van Henegouwen G BZeitschrift fur Lebensmittel-Untersuchung und -Forschung (1986), 183 (2), 116-22 ISSN:0044-3026.The photodecomposition of curcumin when exposed to UV/visible radiation is studied. The main degradation products are identified. The reaction mechanisms are investigated and the order of the over-all degradation reactions and the half-lives of curcumin in different solvents and in the solid state are determined.
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70Ghosh, M.; Singh, A. T.; Xu, W.; Sulchek, T.; Gordon, L. I.; Ryan, R. O. Curcumin nanodisks: Formulation and characterization Nanomedicine 2011, 7, 162– 167 DOI: 10.1016/j.nano.2010.08.00270https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXltFGjsL4%253D&md5=34d7bc2edf1aa1cbd50482aabe80a2d1Curcumin nanodisks: formulation and characterizationGhosh, Mistuni; Singh, Amareshwar T. K.; Xu, Wenwei; Sulchek, Todd; Gordon, Leo I.; Ryan, Robert O.Nanomedicine (Philadelphia, PA, United States) (2011), 7 (2), 162-167CODEN: NANOBF; ISSN:1549-9634. (Elsevier Inc.)Nanodisks (NDs) are nanoscale, disk-shaped phospholipid bilayers whose edge is stabilized by apolipoproteins. In the present study, NDs were formulated with the bioactive polyphenol curcumin at a 6:1 phospholipid-to-curcumin molar ratio. At. force microscopy revealed that curcumin-NDs are particles with diams. <50 nm and the thickness of a phospholipid bilayer. When formulated in NDs, curcumin is water sol. and gives rise to a characteristic absorbance spectrum with a peak centered at 420 nm. Fluorescence spectroscopy of curcumin-NDs provided evidence of self-quenching. Incubation of curcumin-NDs with empty NDs relieved the self-quenching, indicating redistribution of curcumin between curcumin-loaded and empty NDs. In HepG2 cells, curcumin-NDs mediated enhanced cell growth inhibition as compared with free curcumin. In a cell culture model of mantle cell lymphoma, curcumin-NDs were a more potent inducer of apoptosis than free curcumin. The nanoscale size of the complexes, combined with their ability to solubilize curcumin, indicates NDs may have in vivo therapeutic applications.
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71Sun, M.; Su, X.; Ding, B.; He, X.; Liu, X.; Yu, A.; Lou, H.; Zhai, G. Advances in nantoechnology-based delivery systems for curcumin Nanomedicine (London, U. K.) 2012, 7, 1085– 1100 DOI: 10.2217/nnm.12.8071https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtFWjsrrN&md5=40a117c92bc233432ec7fe287272195bAdvances in nanotechnology-based delivery systems for curcuminSun, Min; Su, Xun; Ding, Buyun; He, Xiuli; Liu, Xiuju; Yu, Aihua; Lou, Hongxiang; Zhai, GuangxiNanomedicine (London, United Kingdom) (2012), 7 (7), 1085-1100CODEN: NLUKAC; ISSN:1743-5889. (Future Medicine Ltd.)A review. Curcumin (CUR), a bioactive component of turmeric, which is a commonly used spice and nutritional supplement, is isolated from the rhizomes of Curcuma longa Linn. (Zingiberaceae). In recent years, the potential pharmacol. actions of CUR in inflammatory disorders, cardiovascular disease, cancer, Alzheimer's disease and neurol. disorders were shown. However, the clin. application of CUR is severely limited by its main drawbacks such as instability, low soly., poor bioavailability and rapid metab. Multifarious nanotechnol.-based delivery approaches were used to enhance the oral bioavailability, biol. activity or tissue-targeting ability of CUR. This article reviews potential novel drug delivery systems for CUR including liposomes, polymeric nanoparticles, solid lipid nanoparticles, micelles, nanogels, nanosuspensions, nanoemulsions, complexes and dendrimer/dimer, which provide promising results for CUR to improve its biol. activities.
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72Tamvakopoulos, C.; Dimas, K.; Sofianos, Z. D.; Hatziantoniou, S.; Han, Z.; Liu, Z. L.; Wyche, J. H.; Pantazis, P. Metabolism and anticancer activity of the curcumin analogue, dimethoxycurcumin Clin. Cancer Res. 2007, 13, 1269– 1277 DOI: 10.1158/1078-0432.CCR-06-183972https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhvF2htr0%253D&md5=1df697514606695d2121e226e413fbbcMetabolism and Anticancer Activity of the Curcumin Analogue, DimethoxycurcuminTamvakopoulos, Constantin; Dimas, Konstantinos; Sofianos, Zacharias D.; Hatziantoniou, Sophia; Han, Zhiyong; Liu, Zhong-Li; Wyche, James H.; Pantazis, PanayotisClinical Cancer Research (2007), 13 (4), 1269-1277CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)Purpose: The plant-derived compd. curcumin has shown promising abilities as a cancer chemoprevention and chemotherapy agent in vitro and in vivo but exhibits poor bioavailability. Therefore, there is a need to investigate modified curcumin congeners for improved anticancer activity and pharmacokinetic properties. Exptl. Design: The synthetic curcumin analog dimethoxycurcumin was compared with curcumin for ability to inhibit proliferation and apoptosis of human HCT116 colon cancer cells in vitro by estg. the GI50 and LC50 values and detecting the extent of apoptosis by flow cytometry anal. of the cell cycle. Metabolic stability and/or identification of metabolites were evaluated by recently developed mass spectrometric approaches after incubation with mouse and human liver microsomes and cancer cells in vitro. Addnl., circulating levels of dimethoxycurcumin and curcumin were detd. in mice following i.p. administration. Results: Dimethoxycurcumin is significantly more potent than curcumin in inhibiting proliferation and inducing apoptosis in HCT116 cells treated for 48 h. Nearly 100% of curcumin but <30% of dimethoxycurcumin was degraded in cells treated for 48 h, and incubation with liver microsomes confirmed the limited metab. of dimethoxycurcumin. Both compds. were rapidly degraded in vivo but dimethoxycurcumin was more stable. Conclusions: Compared with curcumin, dimethoxycurcumin is (a) more stable in cultured cells, (b) more potent in the ability to kill cancer cells by apoptosis, (c) less extensively metabolized in microsomal systems, and (d) more stable in vivo. It is likely that the differential extent of apoptosis induced by curcumin and dimethoxycurcumin in vitro is assocd. with the metabolite profiling and/or the extent of stability.
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73Robinson, T. P.; Hubbard, R. B. t.; Ehlers, T. J.; Arbiser, J. L.; Goldsmith, D. J.; Bowen, J. P. Synthesis and biological evaluation of aromatic enones related to curcumin Bioorg. Med. Chem. 2005, 13, 4007– 4013 DOI: 10.1016/j.bmc.2005.03.054There is no corresponding record for this reference.
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74Liang, G.; Shao, L.; Wang, Y.; Zhao, C.; Chu, Y.; Xiao, J.; Zhao, Y.; Li, X.; Yang, S. Exploration and synthesis of curcumin analogues with improved structural stability both in vitro and in vivo as cytotoxic agents Bioorg. Med. Chem. 2009, 17, 2623– 2631 DOI: 10.1016/j.bmc.2008.10.04474https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXjsFajsrk%253D&md5=c723d921647ac6ad129e2935e22f8260Exploration and synthesis of curcumin analogues with improved structural stability both in vitro and in vivo as cytotoxic agentsLiang, Guang; Shao, Lili; Wang, Yi; Zhao, Chengguang; Chu, Yanhui; Xiao, Jian; Zhao, Yu; Li, Xiaokun; Yang, ShulinBioorganic & Medicinal Chemistry (2009), 17 (6), 2623-2631CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)Curcumin has a surprisingly wide range of chemo-preventive and chemo-therapeutic activities and is under investigation for the treatment of various human cancers. However, the clin. application of curcumin has been significantly limited by its instability and poor metabolic property. Although a no. of synthetic modifications of curcumin have been studied intensively in order to develop a mol. with enhanced bioactivities, few synthetic studies were done for the improvement of pharmacokinetic profiles. In the present study, a series of mono-carbonyl analogs of curcumin were designed and synthesized by deleting the reactive β-diketone moiety, which was considered to be responsible for the pharmacokinetic limitation of curcumin. The results of the in vitro stability studies and in vivo pharmacokinetic studies indicated that the stability of these mono-carbonyl analogs was greatly enhanced in vitro and their pharmacokinetic profiles were also significantly improved in vivo. Furthermore, the cytotoxic activities of mono-carbonyl analogs were evaluated in seven different tumor cell lines by MTT assay and the structure-activity relation (SAR) was discussed and concluded. The results suggest that the five-carbon linker-contg. analogs of curcumin may be favorable for the curcumin-based drug development both pharmacokinetically and pharmacol.
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75Lim, T.-G.; Lee, S.-Y.; Huang, Z.; Lim, D. Y.; Chen, H.; Jung, S. K.; Bode, A. M.; Lee, K. W.; Dong, Z. Curcumin suppresses proliferation of colon cancer cells by targeting CDK2 Cancer Prev. Res. 2014, 7, 466– 474 DOI: 10.1158/1940-6207.CAPR-13-038775https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXlslSmt70%253D&md5=a609b37581ee658cbbfed899768c9cb1Curcumin Suppresses Proliferation of Colon Cancer Cells by Targeting CDK2Lim, Tae-Gyu; Lee, Sung-Young; Huang, Zunnan; Lim, Do Young; Chen, Hanyong; Jung, Sung Keun; Bode, Ann M.; Lee, Ki Won; Dong, ZigangCancer Prevention Research (2014), 7 (4), 466-474CODEN: CPRACC; ISSN:1940-6207. (American Association for Cancer Research)Curcumin, the yellow pigment of turmeric found in Southeast Indian food, is one of the most popular phytochems. for cancer prevention. Numerous reports have demonstrated modulation of multiple cellular signaling pathways by curcumin and its mol. targets in various cancer cell lines. To identify a new mol. target of curcumin, we used shape screening and reverse docking to screen the Protein Data Bank against curcumin. Cyclin-dependent kinase 2 (CDK2), a major cell-cycle protein, was identified as a potential mol. target of curcumin. Indeed, in vitro and ex vivo kinase assay data revealed a dramatic suppressive effect of curcumin on CDK2 kinase activity. Furthermore, curcumin induced G1 cell-cycle arrest, which is regulated by CDK2 in HCT116 cells. Although the expression levels of CDK2 and its regulatory subunit, cyclin E, were not changed, the phosphorylation of retinoblastoma (Rb), a well-known CDK2 substrate, was reduced by curcumin. Because curcumin induced cell-cycle arrest, we investigated the antiproliferative effect of curcumin on HCT116 colon cancer cells. In this expt., curcumin suppressed HCT116 cell proliferation effectively. To det. whether CDK2 is a direct target of curcumin, CDK2 expression was knocked down in HCT116 cells. As expected, HCT116 sh-CDK2 cells exhibited G1 arrest and reduced proliferation. Because of the low levels of CDK2 in HCT116 sh-CDK2 cells, the effects of curcumin on G1 arrest and cell proliferation were not substantially relative to HCT116 sh-control cells. From these results, we identified CDK2 as a direct target of curcumin in colon cancer cells. Cancer Prev Res; 7(4); 466-74. ©2014 AACR.
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76Balasubramanian, K. Molecular orbital basis for yellow curry spice curcumin’s prevention of Alzheimer’s disease J. Agric. Food Chem. 2006, 54, 3512– 3520 DOI: 10.1021/jf060353376https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XjsFOitrk%253D&md5=c8bdb36531df9ab157271d6eebdf2169Molecular Orbital Basis for Yellow Curry Spice Curcumin's Prevention of Alzheimer's DiseaseBalasubramanian, KrishnanJournal of Agricultural and Food Chemistry (2006), 54 (10), 3512-3520CODEN: JAFCAU; ISSN:0021-8561. (American Chemical Society)It is demonstrated by using high-level ab initio computations that the yellow curcumin pigment, bis(4-hydroxy-3-methoxyphenyl)-1,6-diene-3,5-dione, in the east Indian root plant turmeric (Curcuma longa) exhibits unique charge and bonding characteristics that facilitate penetration into the blood-brain barrier and binding to amyloid β (Aβ). Alzheimer's disease is caused by Aβ accumulation in the brain cells combined with oxidative stress and inflammation. Consistent with the recent exptl. work by Cole and co-workers (Yang, F., et al. J. Biol. Chem. 2004, 280, 5892-5901) that demonstrates curcumin pigment's binding ability to Aβ both in vivo and in vitro, it is shown here that curcumin possesses suitable charge and bonding features to facilitate the binding to Aβ. In addn., curcumin's anti-inflammatory and antioxidant properties are also attributed to electronic and structural features. It is shown that the presence of an enolic center and two phenolic polar groups sepd. by an essentially hydrophobic bridge of a conjugated network provides both hydrophobic and hydrophilic features to the curcumin pigment, thereby facilitating penetration into the blood-brain barrier through the former property and then binding to Aβ oligomer through the latter property. Both d. functional and Moller-Plesset perturbation (MP2) computations have been carried out on the curcumin pigment to obtain fully optimized geometries in the gas phase and aq. soln. and also the at. charges. Different isomers (keto and enol forms) have been considered to show that the enol form is the most favored and has all of the properties for an ideal antioxidant with also features to penetrate the blood-brain barrier and to bind to Aβ. This is demonstrated with natural bond charges, highest occupied and lowest unoccupied MOs, dipole moments, and Laplacian plots. The computed ionization potential and electron affinity show that curcumin has a low mol. hardness and thus has a propensity to dissoc. its phenolic -OH, and the resulting charge undergoes delocalization throughout the structure, resulting in excitonic features. This feature seems to be also important for its binding capability to human proteins such as human serum albumin and Aβ.
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77Ciccone, L.; Tepshi, L.; Nencetti, S.; Stura, E. A. Transthyretin complexes with curcumin and bromo-estradiol: Evaluation of solubilizing multicomponent mixtures New Biotechnol. 2015, 32, 54– 64 DOI: 10.1016/j.nbt.2014.09.00277https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsFyltLfM&md5=66f2e8289d2c9135727f307f523325ebTransthyretin complexes with curcumin and bromo-estradiol: evaluation of solubilizing multicomponent mixturesCiccone, Lidia; Tepshi, Livia; Nencetti, Susanna; Stura, Enrico A.New Biotechnology (2015), 32 (1), 54-64CODEN: NBEIBR; ISSN:1871-6784. (Elsevier B.V.)Crystallog. structure detn. of protein-ligand complexes of transthyretin (TTR) has been hindered by the low affinity of many compds. that bind to the central cavity of the tetramer. Because crystn. trials are carried out at protein and ligand concn. that approach the millimolar range, low affinity is less of a problem than the poor soly. of many compds. that have been shown to inhibit amyloid fibril formation. To achieve complete occupancy in co-crystn. expts., the minimal requirement is one ligand for each of the two sites within the TTR tetramer. Here we present a new strategy for the co-crystn. of TTR using high mol. wt. polyethylene glycol instead of high ionic strength precipitants, with ligands solubilized in multicomponent mixts. of compds. This strategy is applied to the crystn. of TTR complexes with curcumin and 16α-bromo-estradiol. Here we report the crystal structures with these compds. and with the ferulic acid that results from curcumin degrdn.
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78Irwin, J. J.; Duan, D.; Torosyan, H.; Doak, A. K.; Ziebart, K. T.; Sterling, T.; Tumanian, G.; Shoichet, B. K. An aggregation advisor for ligand discovery J. Med. Chem. 2015, 58, 7076– 7087 DOI: 10.1021/acs.jmedchem.5b0110578https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtlOqu7zM&md5=d3112f9f3a57a2ac61a4b32f31778b1dAn Aggregation Advisor for Ligand DiscoveryIrwin, John J.; Duan, Da; Torosyan, Hayarpi; Doak, Allison K.; Ziebart, Kristin T.; Sterling, Teague; Tumanian, Gurgen; Shoichet, Brian K.Journal of Medicinal Chemistry (2015), 58 (17), 7076-7087CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Colloidal aggregation of org. mols. is the dominant mechanism for artifactual inhibition of proteins, and controls against it are widely deployed. Notwithstanding an increasingly detailed understanding of this phenomenon, a method to reliably predict aggregation has remained elusive. Correspondingly, active mols. that act via aggregation continue to be found in early discovery campaigns and remain common in the literature. Over the past decade, over 12 thousand aggregating org. mols. have been identified, potentially enabling a precedent-based approach to match known aggregators with new mols. that may be expected to aggregate and lead to artifacts. We investigate an approach that uses lipophilicity, affinity, and similarity to known aggregators to advise on the likelihood that a candidate compd. is an aggregator. In prospective exptl. testing, five of seven new mols. with Tanimoto coeffs. (Tc's) between 0.95 and 0.99 to known aggregators aggregated at relevant concns. Ten of 19 with Tc's between 0.94 and 0.90 and three of seven with Tc's between 0.89 and 0.85 also aggregated. Another three of the predicted compds. aggregated at higher concns. This method finds that 61 827 or 5.1% of the ligands acting in the 0.1 to 10 μM range in the medicinal chem. literature are at least 85% similar to a known aggregator with these phys. properties and may aggregate at relevant concns. Intriguingly, only 0.73% of all drug-like com. available compds. resemble the known aggregators, suggesting that colloidal aggregators are enriched in the literature. As a percentage of the literature, aggregator-like compds. have increased 9-fold since 1995, partly reflecting the advent of high-throughput and virtual screens against mol. targets. Emerging from this study is an aggregator advisor database and tool (http://advisor.bkslab.org), free to the community, that may help distinguish between fruitful and artifactual screening hits acting by this mechanism.
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79Coan, K. E.; Shoichet, B. K. Stoichiometry and physical chemistry of promiscuous aggregate-based inhibitors J. Am. Chem. Soc. 2008, 130, 9606– 9612 DOI: 10.1021/ja802977h79https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXnvF2gsL8%253D&md5=6bb7b0d190db00bd872a2ba86a5d56efStoichiometry and Physical Chemistry of Promiscuous Aggregate-Based InhibitorsCoan, Kristin E. D.; Shoichet, Brian K.Journal of the American Chemical Society (2008), 130 (29), 9606-9612CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Many false positives in early drug discovery owe to nonspecific inhibition by colloid-like aggregates of org. mols. Despite their prevalence, little is known about aggregate concn., structure, or dynamic equil.; the binding mechanism, stoichiometry with, and affinity for enzymes remain uncertain. To investigate the elementary question of concn., we counted aggregate particles using flow cytometry. For seven aggregate-forming mols., aggregates were not obsd. until the concn. of monomer crossed a threshold, indicating a "crit. aggregation concn." (CAC). Above the CAC, aggregate count increased linearly with added org. material, while the particles dispersed when dild. below the CAC. The concn. of monomeric org. mol. is const. above the CAC, as is the size of the aggregate particles. For two compds. that form large aggregates, nicardipine and miconazole, we measured particle nos. directly by flow cytometry, detg. that the aggregate concn. just above the CAC ranged from 5 to 30 fM. By correlating inhibition of an enzyme with aggregate count for these two drugs, we detd. that the stoichiometry of binding is about 10 000 enzyme mols. per aggregate particle. Using measured vols. for nicardipine and miconazole aggregate particles (2.1 × 1011 and 4.7 × 1010 Å3, resp.), computed monomer vols., and the observation that past the CAC all addnl. monomer forms aggregate particles, we find that aggregates are densely packed particles. Finally, given their size and enzyme stoichiometry, all sequestered enzyme can be comfortably accommodated on the surface of the aggregate.
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80Coan, K. E. D.; Maltby, D. A.; Burlingame, A. L.; Shoichet, B. K. Promiscuous aggregate-based inhibitors promote enzyme unfolding J. Med. Chem. 2009, 52, 2067– 2075 DOI: 10.1021/jm801605r80https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXjtFKlsL4%253D&md5=d771ee54b647cf93efe5085c7977bb42Promiscuous Aggregate-Based Inhibitors Promote Enzyme UnfoldingCoan, Kristin E. D.; Maltby, David A.; Burlingame, Alma L.; Shoichet, Brian K.Journal of Medicinal Chemistry (2009), 52 (7), 2067-2075CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)One of the leading sources of false positives in early drug discovery is the formation of org. small mol. aggregates, which inhibit enzymes nonspecifically at micromolar concns. in aq. soln. The mol. basis for this widespread problem remains hazy. To investigate the mechanism of inhibition at a mol. level, we detd. changes in solvent accessibility that occur when an enzyme binds to an aggregate using hydrogen-deuterium exchange mass spectrometry. For AmpC β-lactamase, binding to aggregates of the small mol. rottlerin increased the deuterium exchange of all 10 reproducibly detectable peptides, which covered 41% of the sequence of β-lactamase. This suggested a global increase in proton accessibility upon aggregate binding, consistent with denaturation. We then investigated whether enzyme-aggregate complexes were more susceptible to proteolysis than uninhibited enzyme. For five aggregators, trypsin degrdn. of β-lactamase increased substantially when β-lactamase was inhibited by aggregates, whereas uninhibited enzyme was generally stable to digestion. Combined, these results suggest that the mechanism of action of aggregate-based inhibitors proceeds via partial protein unfolding when bound to an aggregate particle.
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81Winter, S.; Tortik, N.; Kubin, A.; Krammer, B.; Plaetzer, K. Back to the roots: Photodynamic inactivation of bacteria based on water-soluble curcumin bound to polyvinylpyrrolidone as a photosensitizer Photochem. Photobiol. Sci. 2013, 12, 1795– 1802 DOI: 10.1039/c3pp50095k81https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsVyqsLbM&md5=70702ca399d2d0d8395840f1dbc9ff53Back to the roots: photodynamic inactivation of bacteria based on water-soluble curcumin bound to polyvinylpyrrolidone as a photosensitizerWinter, Sandra; Tortik, Nicole; Kubin, Andreas; Krammer, Barbara; Plaetzer, KristjanPhotochemical & Photobiological Sciences (2013), 12 (10), 1795-1802CODEN: PPSHCB; ISSN:1474-905X. (Royal Society of Chemistry)Photodynamic inactivation (PDI), the light-induced and photosensitizer-mediated overprodn. of reactive oxygen species in microorganisms, represents a convincing approach to treat infections with (multi-resistant) pathogens. Due to its favorable photoactive properties combined with excellent biocompatibility, curcumin derived from the roots of turmeric (Curcuma longa) has been identified as an advantageous photosensitizer for PDI. To overcome the poor water soly. and the rapid decay of the natural substance at physiol. pH, we examd. the applicability of polyvinylpyrrolidone curcumin (PVP-C) in an acidified aq. soln. (soly. of PVP-C up to 2.7 mM) for photoinactivation of Gram(+) and Gram(-) bacteria. Five micromolar PVP-C incubated for 5 min and illuminated using a blue light LED array (435 ± 10 nm, 33.8 J cm-2) resulted in a >6 log10 redn. of the no. of viable Staphylococcus aureus. At this concn., longer incubation periods result in a lower phototoxicity, most likely due to degeneration of curcumin. Upon an increase of the PVP-C concn. to 50 μM (incubation for 15 or 25 min) a complete eradication of Staphylococcus aureus can be achieved. As expected for a non-cationic photosensitizer, cell wall permeabilization with CaCl2 prior to addn. of 50 μM PVP-C for 15 min is necessary to induce a drop in the count of the Gram(-) Escherichia coli for more than 3 log10. As both constituents of the formulation, curcumin (E no. E100) and polyvinylpyrrolidone (E1201), have been approved as food additives, a PDI based on PCP-C might allow for a very sparing clin. application (e.g. for disinfection of wounds) or even for employment in aseptic prodn. of foodstuffs.
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82Siviero, A.; Gallo, E.; Maggini, V.; Gori, L.; Mugelli, A.; Firenzuoli, F.; Vannacci, A. Curcumin, a golden spice with a low bioavailability Journal of Herbal Medicine 2015, 5, 57– 70 DOI: 10.1016/j.hermed.2015.03.001There is no corresponding record for this reference.
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83Lao, C. D.; Ruffin, M. T. I. V.; Normolle, D.; Heath, D. D.; Murray, S. I.; Bailey, J. M.; Boggs, M. E.; Crowell, J.; Rock, C. L.; Brenner, D. E. Dose escalation of a curcuminoid formulation BMC Complementary Altern. Med. 2006, 6, 10 DOI: 10.1186/1472-6882-6-1083https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD287ps12ksg%253D%253D&md5=468c392b27b48969ee5505e1bb5c059eDose escalation of a curcuminoid formulationLao Christopher D; Ruffin Mack T 4th; Normolle Daniel; Heath Dennis D; Murray Sandra I; Bailey Joanne M; Boggs Martha E; Crowell James; Rock Cheryl L; Brenner Dean EBMC complementary and alternative medicine (2006), 6 (), 10 ISSN:.BACKGROUND: Curcumin is the major yellow pigment extracted from turmeric, a commonly-used spice in India and Southeast Asia that has broad anticarcinogenic and cancer chemopreventive potential. However, few systematic studies of curcumin's pharmacology and toxicology in humans have been performed. METHODS: A dose escalation study was conducted to determine the maximum tolerated dose and safety of a single dose of standardized powder extract, uniformly milled curcumin (C3 Complextrade mark, Sabinsa Corporation). Healthy volunteers were administered escalating doses from 500 to 12,000 mg. RESULTS: Seven of twenty-four subjects (30%) experienced only minimal toxicity that did not appear to be dose-related. No curcumin was detected in the serum of subjects administered 500, 1,000, 2,000, 4,000, 6,000 or 8,000 mg. Low levels of curcumin were detected in two subjects administered 10,000 or 12,000 mg. CONCLUSION: The tolerance of curcumin in high single oral doses appears to be excellent. Given that achieving systemic bioavailability of curcumin or its metabolites may not be essential for colorectal cancer chemoprevention, these findings warrant further investigation for its utility as a long-term chemopreventive agent.
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84Wahlang, B.; Pawar, Y. B.; Bansal, A. K. Identification of permeability-related hurdles in oral delivery of curcumin using the Caco-2 cell model Eur. J. Pharm. Biopharm. 2011, 77, 275– 282 DOI: 10.1016/j.ejpb.2010.12.00684https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtlSktro%253D&md5=a948f9008184ecdefaa37c62b7ffb320Identification of permeability-related hurdles in oral delivery of curcumin using the Caco-2 cell modelWahlang, Banrida; Pawar, Yogesh B.; Bansal, Arvind K.European Journal of Pharmaceutics and Biopharmaceutics (2011), 77 (2), 275-282CODEN: EJPBEL; ISSN:0939-6411. (Elsevier B.V.)Curcumin a poly-phenolic compd. possesses diverse pharmacol. activities; however, its development as a drug has been severely impeded by extremely poor oral bioavailability. Poor aq. soly. and extensive metab. have been implicated for this but the role of membrane permeability has not been investigated. In the present study, permeability of curcumin was assessed using the Caco-2 cell line. Curcumin was poorly permeable with a Papp (A → B) value of 2.93 ± 0.94 × 10-6 cm/s. Papp value in (B → A) study was found out to be 2.55 ± 0.02 × 10-6 cm/s, thus ruling out the role of efflux pathways in poor oral bioavailability of curcumin. Studies using verapamil, a P-gp inhibitor, further confirmed this finding. Detailed mass balance studies showed loss of curcumin during transport. Further expts. using lysed cells revealed that 11.78% of curcumin was metabolized during transport. Studies using itraconazole, a CYP3A4 inhibitor, established its role in curcumin metab. Curcumin was also found to accumulate in cells as revealed by CLSM studies. Sorption and desorption kinetic studies further confirmed accumulation of curcumin inside the cells. Amt. accumulated was quantitated by HPLC and found to be >20%. Thus, intestinal first-pass metab. and intracellular accumulation played a role in poor permeability of curcumin. Based on its poor aq. soly. and intestinal permeability, curcumin can be classified as a BCS Class IV mol. This information can facilitate designing of drug delivery systems for enhancement of oral bioavailability of curcumin.
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85Volpe, D. A.; Faustino, P. J.; Ciavarella, A. B.; Asafu-Adjaye, E. B.; Ellison, C. D.; Yu, L. X.; Hussain, A. S. Classification of drug permeability with a Caco-2 cell monolayer assay Clin. Res. Regul. Aff. 2007, 24, 39– 47 DOI: 10.1080/10601330701273669There is no corresponding record for this reference.
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86Suresh, D.; Srinivasan, K. Tissue distribution & elimination of capsaicin, piperine & curcumin following oral intake in rats Indian J. Med. Res. 2010, 131, 682– 69186https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXpt1Olsbg%253D&md5=e7a1d76dfdb45452d86dc07357c12fc6Tissue distribution & elimination of capsaicin, piperine & curcumin following oral intake in ratsSuresh, D.; Srinivasan, K.Indian Journal of Medical Research (2010), 131 (5), 682-691CODEN: IMIREV; ISSN:0971-5916. (Indian Council of Medical Research)Curcumin, capsaicin and piperine, the bioactive compds. present in spices-turmeric (Curcuma longa), red pepper (Capsicum annuum), and black pepper (Piper nigrum) resp., have a considerable portion of structural homol. Tissue distribution and elimination of these three structurally similar bioactive compds. was examd. following their oral intake in rats. Sep. sets of animals (150-160 g) were orally administered the three spice principles at dosages of 30 mg (capsaicin), 170 mg (piperine) and 500 mg (curcumin)/kg body wt. The tissue concns. of administered spice compds. were detd. by HPLC. Maximum distribution of 24.4% of administered capsaicin was seen at 1 h, while no intact capsaicin was detectable after 4 days. Absorption of capsaicin was about 94% and very rapid relative to other two compds. A max. of 10.8% of administered piperine was seen in tissues at 6 h. Absorption of the administered piperine was about 96%. Curcumin concn. was max. in the intestine at 1 h; max. in blood at 6 h and remained at significantly higher level even at 24 h. About 63.5% of the curcumin dose was absorbed. Only a small portion of the administered dose of capsaicin (<0.1%) and curcumin (0.173%) was excreted in urine, whereas piperine was not detectable in urine. Enhanced bioavailability of curcumin was evidenced when the same was orally administered concomitant with piperine. Intestinal absorption of curcumin was relatively higher when administered concomitantly with piperine, and it stayed significantly longer in the body tissues. Intact curcumin was detected in brain at 24, 48, and 96 h with a max. at 48 h. Considerable difference exists in the bioavailability of the three test compds. Curcumin could be traced in the brain following its administration. Bioavailability of curcumin can be improved by co-administration with piperine.
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87Ravindranath, V.; Chandrasekhara, N. Absorption and tissue distribution of curcumin in rats Toxicology 1980, 16, 259– 265 DOI: 10.1016/0300-483X(80)90122-587https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL3cXmtFKhsL4%253D&md5=e28fca7f02c9bb9e5f5aa1cca65c9d7cAbsorption and tissue distribution of curcumin in ratsRavindranath, Vijayalakshmi; Chandrasekhara, NanjundiahToxicology (1980), 16 (3), 259-65CODEN: TXCYAC; ISSN:0300-483X.After oral administration of 400 mg curcumin [458-37-7] to rats, ∼60% of the dose was absorbed. No curcumin was detectable in urine. The urinary excretion of conjugated glucuronides and sulfates significantly increased. No curcumin was present in heart blood. Only traces (<5 μg/mL) in portal blood and negligible quantities in liver and kidney (<20 μg/tissue) were obsd. from 15 min up to 24 h after administration of curcumin. At the end of 24 h, the concn. of curcumin remaining in the lower part of the gut namely caecum and large intestine amounted to 38% of the quantity administered.
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88Ravindranath, V.; Chandrasekhara, N. Metabolism of curcumin - studies with [3H]curcumin Toxicology 1982, 22, 337– 344 DOI: 10.1016/0300-483X(81)90027-5There is no corresponding record for this reference.
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89Mathews, S.; Rao, M. N. A. Interaction of curcumin with glutathione Int. J. Pharm. (Amsterdam, Neth.) 1991, 76, 257– 259 DOI: 10.1016/0378-5173(91)90278-V89https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK38XjsVGitw%253D%253D&md5=a5a248a8d194eccf433182195de12007Interaction of curcumin with glutathioneMathews, Susan; Rao, M. N. A.International Journal of Pharmaceutics (1991), 76 (3), 257-9CODEN: IJPHDE; ISSN:0378-5173.Curcumin interacts with glutathione spontaneously and more rapidly in the presence of glutathione S-transferase. The interaction may involve Michael-type addn. reaction between the α,β-unsatd. chromophore of curcumin and the nucleophilic glutathione.
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90Asai, A.; Miyazawa, T. Occurrence of orally administered curcuminoid as glucuronide and glucuronide/sulfate conjugates in rat plasma Life Sci. 2000, 67, 2785– 2793 DOI: 10.1016/S0024-3205(00)00868-7There is no corresponding record for this reference.
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91Sharma, R. A.; McLelland, H. R.; Hill, K. A.; Ireson, C. R.; Euden, S. A.; Manson, M. M.; Pirmohamed, M.; Marnett, L. J.; Gescher, A. J.; Steward, W. P. Pharmacodynamic and pharmacokinetic study of oral Curcuma extract in patients with colorectal cancer Clin. Cancer Res. 2001, 7, 1894– 190091https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXlslaltbg%253D&md5=fbe43c34f827739bcbb6050824051cbbPharmacodynamic and pharmacokinetic study of oral Curcuma extract in patients with colorectal cancerSharma, Ricky A.; McLelland, Heather R.; Hill, Kirsti A.; Ireson, Christopher R.; Euden, Stephanie A.; Manson, Margaret M.; Pirmohamed, Munir; Marnett, Lawrence J.; Gescher, Andreas J.; Steward, William P.Clinical Cancer Research (2001), 7 (7), 1894-1900CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)Curcuma spp. exts., particularly the dietary polyphenol curcumin, prevent colon cancer in rodents. In view of the sparse information on the pharmacodynamics and pharmacokinetics of curcumin in humans, a dose-escalation pilot study of a novel standardized Curcuma ext. in proprietary capsule form was performed at doses between 440 and 2200 mg/day, contg. 36-180 mg of curcumin. Fifteen patients with advanced colorectal cancer refractory to std. chemotherapies received Curcuma ext. daily for up to 4 mo. Activity of glutathione S-transferase and levels of a DNA adduct (M1G) formed by malondialdehyde, a product of lipid peroxidn. and prostaglandin biosynthesis, were measured in patients' blood cells. Oral Curcuma ext. was well tolerated, and dose-limiting toxicity was not obsd. Neither curcumin nor its metabolites were detected in blood or urine, but curcumin was recovered from feces. Curcumin sulfate was identified in the feces of one patient. Ingestion of 440 mg of Curcuma ext. for 29 days was accompanied by a 59% decrease in lymphocytic glutathione S-transferase activity. At higher dose levels, this effect was not obsd. Leukocytic M1G levels were const. within each patient and unaffected by treatment. Radiol. stable disease was demonstrated in five patients for 2-4 mo of treatment. The results suggest that (a) Curcuma ext. can be administered safely to patients at doses of up to 2.2 g daily, equiv. to 180 mg of curcumin; (b) curcumin has low oral bioavailability in humans and may undergo intestinal metab.; and (c) larger clin. trials of Curcuma ext. are merited.
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92Garcea, G.; Berry, D. P.; Jones, D. J. L.; Singh, R.; Dennison, A. R.; Farmer, P. B.; Sharma, R. A.; Steward, W. P.; Gescher, A. J. Consumption of the putative chemopreventative agent curcumin by cancer patients: Assessment of curcumin levels in the colorectum and their pharmacodynamic consequences Cancer Epidemiol., Biomarkers Prev. 2005, 14, 120– 12592https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXmsVOntw%253D%253D&md5=d0e08edefda4f7529f22f6de0ab1a29fConsumption of the Putative Chemopreventive Agent Curcumin by Cancer Patients: Assessment of Curcumin Levels in the Colorectum and their Pharmacodynamic ConsequencesGarcea, Giuseppe; Berry, David P.; Jones, Donald J. L.; Singh, Raj; Dennison, Ashley R.; Farmer, Peter B.; Sharma, Ricky A.; Steward, William P.; Gescher, Andreas J.Cancer Epidemiology, Biomarkers & Prevention (2005), 14 (1), 120-125CODEN: CEBPE4; ISSN:1055-9965. (American Association for Cancer Research)Curcumin, a constituent of the spice turmeric, has been shown to reduce the adenoma burden in rodent models of colorectal cancer accompanied by a redn. of levels of the oxidative DNA adduct 3-(2-deoxy-β-di-erythro-pentafuranosyl)-pyr[1,2-α]-purin-10(3H)one (M1G) and of expression of the enzyme cyclooxygenase-2 (COX-2). We tested the hypothesis that pharmacol. active levels of curcumin can be achieved in the colorectum of humans as measured by effects on levels of M1G and COX-2 protein. Patients with colorectal cancer ingested curcumin capsules (3,600, 1,800, or 450 mg daily) for 7 days. Biopsy samples of normal and malignant colorectal tissue, resp., were obtained at diagnosis and at 6 to 7 h after the last dose of curcumin. Blood was taken 1 h after the last dose of curcumin. Curcumin and its metabolites were detected and quantitated by high-performance liq. chromatog. with detection by UV spectrophotometry or mass spectrometry. M1G levels and COX-2 protein expression were measured by immunoslot blot and Western blotting, resp. The concns. of curcumin in normal and malignant colorectal tissue of patients receiving 3,600 mg of curcumin were 12.7 ± 5.7 and 7.7 ± 1.8 nmol/g, resp. Curcumin sulfate and curcumin glucuronide were identified in the tissue of these patients. Trace levels of curcumin were found in the peripheral circulation. M1G levels were 2.5-fold higher in malignant tissue as compared with normal tissue (P < 0.05 by ANOVA). Administration of curcumin (3,600 mg) decreased M1G levels from 4.8 ± 2.9 adducts per 107 nucleotides in malignant colorectal tissue to 2.0 ± 1.8 adducts per 107 nucleotides (P < 0.05 by ANOVA). COX-2 protein levels in malignant colorectal tissue were not affected by curcumin. The results suggest that a daily dose of 3.6 g curcumin achieves pharmacol. efficacious levels in the colorectum with negligible distribution of curcumin outside the gut.
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93Johnson, J. J.; Mukhtar, H. Curcumin for chemoprevention of colon cancer Cancer Lett. (N. Y., NY, U. S.) 2007, 255, 170– 181 DOI: 10.1016/j.canlet.2007.03.00593https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXpsFKqurk%253D&md5=7dd80d117bf89bbcca9124a1616e3c7cCurcumin for chemoprevention of colon cancerJohnson, Jeremy James; Mukhtar, HasanCancer Letters (Amsterdam, Netherlands) (2007), 255 (2), 170-181CODEN: CALEDQ; ISSN:0304-3835. (Elsevier B.V.)A review. The most practical approach to reduce the morbidity and mortality of cancer is to delay the process of carcinogenesis through the use of chemopreventive agents. This necessitates that safer compds., esp. those derived from natural sources must be critically examd. for chemoprevention. A spice common to India and the surrounding regions, is turmeric, derived from the rhizome of Curcuma longa. Pre-clin. studies in a variety of cancer cell lines including breast, cervical, colon, gastric, hepatic, leukemia, oral epithelial, ovarian, pancreatic, and prostate have consistently shown that curcumin possesses anti-cancer activity in vitro and in pre-clin. animal models. The robust activity of curcumin in colorectal cancer has led to five phase I clin. trials being completed showing the safety and tolerability of curcumin in colorectal cancer patients. To date clin. trials have not identified a max. tolerated dose of curcumin in humans with clin. trials using doses up to 8000 mg per day. The success of these trials has led to the development of phase II trials that are currently enrolling patients. Overwhelming in vitro evidence and completed clin. trials suggests that curcumin may prove to be useful for the chemoprevention of colon cancer in humans. This review will focus on describing the pre-clin. and clin. evidence of curcumin as a chemopreventive compd. in colorectal cancer.
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94Vareed, S. K.; Kakarala, M.; Ruffin, M. T.; Crowell, J. A.; Normolle, D. P.; Djuric, Z.; Brenner, D. E. Pharmacokinetics of curcumin conjugate metabolites in healthy human subjects Cancer Epidemiol., Biomarkers Prev. 2008, 17, 1411– 1417 DOI: 10.1158/1055-9965.EPI-07-269394https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXnsVKgtL0%253D&md5=1176c76f0880b803c08a5ebceb10994aPharmacokinetics of Curcumin Conjugate Metabolites in Healthy Human SubjectsVareed, Shaiju K.; Kakarala, Madhuri; Ruffin, Mack T.; Crowell, James A.; Normolle, Daniel P.; Djuric, Zora; Brenner, Dean E.Cancer Epidemiology, Biomarkers & Prevention (2008), 17 (6), 1411-1417CODEN: CEBPE4; ISSN:1055-9965. (American Association for Cancer Research)Curcumin is a polyphenol, found in the spice turmeric, that has promising anticancer properties, but previous studies suggest that absorption of curcumin may be limited. This study examd. the pharmacokinetics of a curcumin prepn. in healthy human volunteers 0.25 to 72 h after a single oral dose. Curcumin was administered at doses of 10 g (n = 6) and 12 g (n = 6). Subjects were randomly allocated to dose level for a total of six subjects at each dose level. Serum samples were assayed for free curcumin, for its glucuronide, and for its sulfate conjugate. The data were fit to a one-compartment absorption and elimination model. Using a high-performance liq. chromatog. assay with a limit of detection of 50 ng/mL, only one subject had detectable free curcumin at any of the 14 time points assayed, but curcumin glucuronides and sulfates were detected in all subjects. Based on the pharmacokinetic model, the area under the curve for the 10 and 12 g doses was estd. (mean ± SE) to be 35.33 ± 3.78 and 26.57 ± 2.97 μg/mL x h, resp., whereas Cmax was 2.30 ± 0.26 and 1.73 ± 0.19 μg/mL. The Tmax and t1/2 were estd. to be 3.29 ± 0.43 and 6.77 ± 0.83 h. The ratio of glucuronide to sulfate was 1.92:1. The curcumin conjugates were present as either glucuronide or sulfate, not mixed conjugates. Curcumin is absorbed after oral dosing in humans and can be detected as glucuronide and sulfate conjugates in plasma. (Cancer Epidemiol Biomarkers Prev 2008;17(6):1411-7).
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95Chan, E.; Tan, M.; Xin, J.; Sudarsanam, S.; Johnson, D. E. Interactions between traditional Chinese medicines and western therapeutics Curr. Opin. Drug Discovery Dev. 2010, 13, 50– 6595https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXntVOqug%253D%253D&md5=dfc350826ee988f9a3cd84167f1581edInteractions between traditional Chinese medicines and Western therapeuticsChan, Elena; Tan, Marisela; Xin, Jianni; Sudarsanam, Sucha; Johnson, Dale E.Current Opinion in Drug Discovery & Development (2010), 13 (1), 50-65CODEN: CODDFF; ISSN:2040-3437. (BioMed Central Ltd.)A review. Traditional Chinese medicine (TCM) is a holistic approach to health that attempts to bring the body, mind and spirit into harmony. TCM is an essential part of the healthcare system in several Asian countries, and is considered a complementary or alternative medical system in most Western countries. An integration of the traditional Chinese and Western systems of medicine has begun in multiple medical centers internationally, and there is increasing evidence that several herbs and combinations of herbs used in TCM impart important pharmacol. effects. The no. of databases and compilations of herbs, herbal formulations, phytochem. constituents and mol. targets is increasing, primarily because of the widespread use of TCM in combination with Western drugs. The continued popularity of herbal remedies worldwide suggests that evidence-based research in this field, as well as information regarding the potential efficacy and safety of phytochem. constituents in herbs and TCM formulations, are essential, particularly when TCM is used in combination with other drugs. Herb-drug interactions are similar to drug-drug interactions in terms of their effects on ADME properties. Improvements in the knowledge of the mol. targets and metabolic pathways, as well as of the synergistic and inhibitory effects assocd. with important phytochems. from herbs and herbal formulations, will lead to the development of rational approaches for the safe combination of healthcare systems from different cultures.
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96Hong, D. H.; Son, Y. K.; Choi, I.-W.; Park, W. S. The inhibitory effect of curcumin on voltage-dependent K+ channels in rabbit coronary arterial smooth muscle cells Biochem. Biophys. Res. Commun. 2013, 430, 307– 312 DOI: 10.1016/j.bbrc.2012.10.132There is no corresponding record for this reference.
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97Bamba, Y.; Yun, Y. S.; Kunugi, A.; Inoue, H. Compounds isolated from Curcuma aromatica Salisb. inhibit human P450 enzymes J. Nat. Med. 2011, 65, 583– 587 DOI: 10.1007/s11418-011-0507-097https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXns12msLs%253D&md5=8f6641223031d7037ad50e134df2f8dbCompounds isolated from Curcuma aromatica Salisb. inhibit human P450 enzymesBamba, Yoshinori; Yun, Young Sook; Kunugi, Akira; Inoue, HideshiJournal of Natural Medicines (2011), 65 (3-4), 583-587CODEN: JNMOBN; ISSN:1861-0293. (Springer Japan)Curcuma species (Zingiberaceae) are used as both food and medicine in Asia. 10 Sesquiterpenes (1-10) and two curcuminoids (11 and 12) were isolated from the rhizomes of Curcuma aromatica Salisb. and identified. The compds. were evaluated for their ability to inhibit cytochrome P 450 (CYP). Among them, the sesquiterpene (4S,5S)-(+)-germacrone-4,5-epoxide (7) inhibited certain subtypes of CYP more potently than or at levels comparable to the curcuminoids curcumin (11) and demethoxycurcumin (12); 7 (IC50 = 1.0 ± 0.2 μM) > 12 (IC50 = 7.0 ± 1.7 μM) > 11 (IC50 = 14.9 ± 1.4 μM) for CYP3A4 inhibition; 12 (IC50 = 1.4 ± 0.2 μM) > 11 (IC50 = 6.0 ± 1.4 μM) > 7 (IC50 = 7.6 ± 2.5 μM) for CYP2C9 inhibition; and 7 (IC50 = 33.2 ± 3.6 μM) = 12 (IC50 = 34.0 ± 14.2 μM) > 11 (IC50 > 100 μM) for CYP1A2 inhibition. These results suggest the possibility that Curcuma aromatica Salisb. may cause food-drug interactions via cytochrome P 450 inhibition by sesquiterpene 7 and curcuminoids 11 and 12.
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98Gupta, S. C.; Kismali, G.; Aggarwal, B. B. Curcumin, a component of turmeric: From farm to pharmacy BioFactors 2013, 39, 2– 13 DOI: 10.1002/biof.1079There is no corresponding record for this reference.
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99Schramm, A.; Jahne, E. A.; Baburin, I.; Hering, S.; Hamburger, M. Natural products as potential human ether-a-go-go-related gene channel inhibitors - outcomes from a screening of widely used herbal medicines and edible plants Planta Med. 2014, 80, 1045– 1050 DOI: 10.1055/s-0034-1382907There is no corresponding record for this reference.
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100Xia, M.; Shahane, S. A.; Huang, R.; Titus, S. A.; Shum, E.; Zhao, Y.; Southall, N.; Zheng, W.; Witt, K. L.; Tice, R. R.; Austin, C. P. Identification of quaternary ammonium compounds as potent inhibitors of hERG potassium channels Toxicol. Appl. Pharmacol. 2011, 252, 250– 258 DOI: 10.1016/j.taap.2011.02.016100https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXkvVGhsLY%253D&md5=4f5007d47bd7d0ab8300e29c3ef0725cIdentification of quaternary ammonium compounds as potent inhibitors of hERG potassium channelsXia, Menghang; Shahane, Sampada A.; Huang, Ruili; Titus, Steven A.; Shum, Enoch; Zhao, Yong; Southall, Noel; Zheng, Wei; Witt, Kristine L.; Tice, Raymond R.; Austin, Christopher P.Toxicology and Applied Pharmacology (2011), 252 (3), 250-258CODEN: TXAPA9; ISSN:0041-008X. (Elsevier B.V.)The human ether-a-go-go-related gene (hERG) channel, a member of a family of voltage-gated potassium (K+) channels, plays a crit. role in the repolarization of the cardiac action potential. The redn. of hERG channel activity as a result of adverse drug effects or genetic mutations may cause QT interval prolongation and potentially leads to acquired long QT syndrome. Thus, screening for hERG channel activity is important in drug development. Cardiotoxicity assocd. with the inhibition of hERG channels by environmental chems. is also a public health concern. To assess the inhibitory effects of environmental chems. on hERG channel function, we screened the National Toxicol. Program (NTP) collection of 1408 compds. by measuring thallium influx into cells through hERG channels. Seventeen compds. with hERG channel inhibition were identified with IC50 potencies ranging from 0.26 to 22 μM. Twelve of these compds. were confirmed as hERG channel blockers in an automated whole cell patch clamp expt. In addn., we investigated the structure-activity relationship of seven compds. belonging to the quaternary ammonium compd. (QAC) series on hERG channel inhibition. Among four active QAC compds., tetra-n-octylammonium bromide was the most potent with an IC50 value of 260 nM in the thallium influx assay and 80 nM in the patch clamp assay. The potency of this class of hERG channel inhibitors appears to depend on the no. and length of their aliph. side-chains surrounding the charged nitrogen. Profiling environmental compd. libraries for hERG channel inhibition provides information useful in prioritizing these compds. for cardiotoxicity assessment in vivo.
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101Hu, C.-W.; Sheng, Y.; Zhang, Q.; Liu, H.-B.; Xie, X.; Ma, W.-C.; Huo, R.; Dong, D.-L. Curcumin inhibits hERG potassium channels in vitro Toxicol. Lett. 2012, 208, 192– 196 DOI: 10.1016/j.toxlet.2011.11.005101https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhs1CitrnF&md5=53ec4e92c26b06df45ae21abc9840565Curcumin inhibits hERG potassium channels in vitroHu, Chao-Wei; Sheng, Yue; Zhang, Qin; Liu, Hui-Bin; Xie, Xin; Ma, Wen-Chao; Huo, Rong; Dong, De-LiToxicology Letters (2012), 208 (2), 192-196CODEN: TOLED5; ISSN:0378-4274. (Elsevier Ireland Ltd.)Curcumin is reported to exert antioxidant, anti-inflammatory, antiviral, antibacterial, antifungal, and anti-tumor activities. The human ether-a-go-go related gene (hERG) encodes the rapid component of the delayed rectifier K+ currents. Inhibition of hERG K+ channels leads to cardiac repolarization prolongation, which contributes to either the anti-arrhythmic effects of anti-arrhythmic drugs, or the pro-arrhythmic effects (induction of long QT syndrome) of some drugs not used for anti-arrhythmias. Since curcumin shows multiple beneficial effects and clin. significance, the aim of the present study is to investigate the effect of curcumin on hERG K+ channels, elucidating its potential cardiac therapeutic or toxic effects. In whole-cell patch-clamp expts., we found that curcumin inhibited hERG K+ currents in HEK293 cells stably expressing hERG channels in a dose-dependent manner, with IC50 value of 5.55 μM. The deactivation, inactivation, and the recovery time from inactivation of hERG channels were significantly changed by acute treatment of 10 μM curcumin. Incubation of 20 μM curcumin for 24 h reduced the HEK293 cell viability. I.v. injection of maximal amt. of curcumin in rabbits (20 mg/animal) did not affect the cardiac repolarization manifested with QTc value. We conclude that curcumin inhibits hERG K+ channels in vitro.
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102Zhang, G.; Nitteranon, V.; Chan, L. Y.; Parkin, K. L. Glutathione conjugation attenuates biological activities of 6-dehydroshogaol from ginger Food Chem. 2013, 140, 1– 8 DOI: 10.1016/j.foodchem.2013.02.073There is no corresponding record for this reference.
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103McFadden, R.-M. T.; Larmonier, C. B.; Shehab, K. W.; Midura-Kiela, M.; Ramalingam, R.; Harrison, C. A.; Besselsen, D. G.; Chase, J. H.; Caporaso, J. G.; Jobin, C.; Ghishan, F. K.; Kiela, P. R. The role of curcumin in modulating colonic microbiota during colitis and colon cancer prevention Inflamm Bowel Dis. 2015, 21, 2483– 2494 DOI: 10.1097/MIB.0000000000000522103https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28%252Fnt1Kjug%253D%253D&md5=8b5ee2d67cfb8334eb405c0804af37b9The Role of Curcumin in Modulating Colonic Microbiota During Colitis and Colon Cancer PreventionMcFadden Rita-Marie T; Larmonier Claire B; Shehab Kareem W; Midura-Kiela Monica; Ramalingam Rajalakshmy; Harrison Christy A; Besselsen David G; Chase John H; Caporaso J Gregory; Jobin Christian; Ghishan Fayez K; Kiela Pawel RInflammatory bowel diseases (2015), 21 (11), 2483-94 ISSN:.BACKGROUND: Intestinal microbiota influences the progression of colitis-associated colorectal cancer. With diet being a key determinant of the gut microbial ecology, dietary interventions are an attractive avenue for the prevention of colitis-associated colorectal cancer. Curcumin is the most active constituent of the ground rhizome of the Curcuma longa plant, which has been demonstrated to have anti-inflammatory, antioxidative, and antiproliferative properties. METHODS: Il10 mice on 129/SvEv background were used as a model of colitis-associated colorectal cancer. Starting at 10 weeks of age, wild-type or Il10 mice received 6 weekly intraperitoneal injections of azoxymethane (AOM) or phosphate-buffered saline (PBS) and were started on either a control or a curcumin-supplemented diet. Stools were collected every 4 weeks for microbial community analysis. Mice were killed at 30 weeks of age. RESULTS: Curcumin-supplemented diet increased survival, decreased colon weight/length ratio, and, at 0.5%, entirely eliminated tumor burden. Although colonic histology indicated improvement with curcumin, no effects of mucosal immune responses have been observed in PBS/Il10 mice and limited effects were seen in AOM/Il10 mice. In wild-type and in Il10 mice, curcumin increased bacterial richness, prevented age-related decrease in alpha diversity, increased the relative abundance of Lactobacillales, and decreased Coriobacterales order. Taxonomic profile of AOM/Il10 mice receiving curcumin was more similar to those of wild-type mice than those fed control diet. CONCLUSIONS: In AOM/Il10 model, curcumin reduced or eliminated colonic tumor burden with limited effects on mucosal immune responses. The beneficial effect of curcumin on tumorigenesis was associated with the maintenance of a more diverse colonic microbial ecology.
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104Gupta, S. C.; Prasad, S.; Kim, J. H.; Patchva, S.; Webb, L. J.; Priyadarsini, I. K.; Aggarwal, B. B. Multitargeting by curcumin as revealed by molecular interaction studies Nat. Prod. Rep. 2011, 28, 1937– 1955 DOI: 10.1039/c1np00051a104https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsVOjt7rF&md5=0b57191439e921d89a2695aa49b602e5Multitargeting by curcumin as revealed by molecular interaction studiesGupta, Subash C.; Prasad, Sahdeo; Kim, Ji Hye; Patchva, Sridevi; Webb, Lauren J.; Priyadarsini, Indira K.; Aggarwal, Bharat B.Natural Product Reports (2011), 28 (12), 1937-1955CODEN: NPRRDF; ISSN:0265-0568. (Royal Society of Chemistry)A review. Curcumin (diferuloylmethane), the active ingredient in turmeric (Curcuma longa), is a highly pleiotropic mol. with anti-inflammatory, anti-oxidant, chemopreventive, chemosensitization, and radiosensitization activities. The pleiotropic activities attributed to curcumin come from its complex mol. structure and chem., as well as its ability to influence multiple signaling mols. Curcumin has been shown to bind by multiple forces directly to numerous signaling mols., such as inflammatory mols., cell survival proteins, protein kinases, protein reductases, histone acetyltransferase, histone deacetylase, glyoxalase I, xanthine oxidase, proteasome, HIV1 integrase, HIV1 protease, sarco (endo) plasmic reticulum Ca2+ ATPase, DNA methyltransferases 1, FtsZ protofilaments, carrier proteins, and metal ions. Curcumin can also bind directly to DNA and RNA. Owing to its β-diketone moiety, curcumin undergoes keto-enol tautomerism that has been reported as a favorable state for direct binding. The functional groups on curcumin found suitable for interaction with other macromols. include the α, β-unsatd. β-diketone moiety, carbonyl and enolic groups of the β-diketone moiety, methoxy and phenolic hydroxyl groups, and the Ph rings. Various biophys. tools have been used to monitor direct interaction of curcumin with other proteins, including absorption, fluorescence, Fourier transform IR (FTIR) and CD (CD) spectroscopy, surface plasmon resonance, competitive ligand binding, Forster type fluorescence resonance energy transfer (FRET), radiolabeling, site-directed mutagenesis, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), immunopptn., phage display biopanning, electron microscopy, 1-anilino-8-naphthalene-sulfonate (ANS) displacement, and co-localization. Mol. docking, the most commonly employed computational tool for calcg. binding affinities and predicting binding sites, has also been used to further characterize curcumin's binding sites. Furthermore, the ability of curcumin to bind directly to carrier proteins improves its soly. and bioavailability. In this review, we focus on how curcumin directly targets signaling mols., as well as the different forces that bind the curcumin-protein complex and how this interaction affects the biol. properties of proteins. We will also discuss various analogs of curcumin designed to bind selective targets with increased affinity.
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105Ghosh, S.; Banerjee, S.; Sil, P. C. The beneficial role of curcumin on inflammation, diabetes and neurodegenerative disease: A recent update Food Chem. Toxicol. 2015, 83, 111– 124 DOI: 10.1016/j.fct.2015.05.022105https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtVWgu7fJ&md5=f8e58560062b009bf029808ca161750aThe beneficial role of curcumin on inflammation, diabetes and neurodegenerative disease: A recent updateGhosh, Shatadal; Banerjee, Sharmistha; Sil, Parames C.Food and Chemical Toxicology (2015), 83 (), 111-124CODEN: FCTOD7; ISSN:0278-6915. (Elsevier Ltd.)The concept of using phytochems. has ushered in a new revolution in pharmaceuticals. Naturally occurring polyphenols (like curcumin, morin, resveratrol, etc.) have gained importance because of their minimal side effects, low cost and abundance. Curcumin (diferuloylmethane) is a component of turmeric isolated from the rhizome of Curcuma longa. Research for more than two decades has revealed the pleiotropic nature of the biol. effects of this mol. More than 7000 published articles have shed light on the various aspects of curcumin including its antioxidant, hypoglycemic, anti-inflammatory and anti-cancer activities. Apart from these well-known activities, this natural polyphenolic compd. also exerts its beneficial effects by modulating different signalling mols. including transcription factors, chemokines, cytokines, tumor suppressor genes, adhesion mols., microRNAs, etc. Oxidative stress and inflammation play a pivotal role in various diseases like diabetes, cancer, arthritis, Alzheimer's disease and cardiovascular diseases. Curcumin, therefore, could be a therapeutic option for the treatment of these diseases, provided limitations in its oral bioavailability can be overcome. The current review provides an updated overview of the metab. and mechanism of action of curcumin in various organ pathophysiologies. The review also discusses the potential for multifunctional therapeutic application of curcumin and its recent progress in clin. biol.
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106Oliveira, A. S.; Sousa, E.; Vasconcelos, M. H.; Pinto, M. Curcumin: A natural lead for potential new drug candidates Curr. Med. Chem. 2015, 22, 4196– 4232 DOI: 10.2174/0929867322666151029104611106https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXitVagur3K&md5=195c850b38a74c1f86c80819cfd88f48Curcumin: A Natural Lead for Potential New Drug CandidatesOliveira, Ana Sofia; Sousa, Emilia; Vasconcelos, Maria Helena; Pinto, MadalenaCurrent Medicinal Chemistry (2015), 22 (36), 4196-4232CODEN: CMCHE7; ISSN:0929-8673. (Bentham Science Publishers Ltd.)Curcumin (1) is a secondary metabolite of turmeric, derived from Curcuma longa L. and was shown to have many biol. activities. One of the most interesting properties of curcumin (1) is the antitumor activity allied with the ability to act as a multidrug resistance (MDR) modulator. Several curcumin derivs. have been synthesized with the purpose of discovering more information about the mechanisms of action, to establish structure-activity relationships (SAR), and to overcome pharmacokinetic problems. Over the past few decades, more potent and more stable curcumin derivs. have emerged with potential as drug candidates. Some important SAR studies pointed out that the unstable ,-unsatd. diketone linker present in curcumin (1) may not be necessary for the antitumor activity; generally, shorter linkers result in more potent compds. than curcumin (1); the type of substituents and their substitution pattern are crucial regarding the biol. activities of interest. Overall, the structure of curcumin (1) may represent an important basis for the development of more effective therapeutic agents, particularly in chemotherapy, as reflected by ongoing clin. trials. This article aims to review the synthesis and biol. activities of curcumin (1) and derivs., highlighting the MDR modulation properties of curcumin (1), since these effects makes this natural product a promising lead compd. for the development of new anticancer drugs.
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107Kundu, P.; Mohanty, C.; Sahoo, S. K. Antiglioma activity of curcumin-loaded lipid nanoparticles and its enhanced bioavailability in brain tissue for effective glioblastoma therapy Acta Biomater. 2012, 8, 2670– 2687 DOI: 10.1016/j.actbio.2012.03.048There is no corresponding record for this reference.
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108Dilnawaz, F.; Singh, A.; Sahoo, S. K. Transferrin-conjugated curcumin-loaded superparamagnetic iron oxide nanoparticles induce augmented cellular uptake and apoptosis in K562 cells Acta Biomater. 2012, 8, 704– 719 DOI: 10.1016/j.actbio.2011.10.022There is no corresponding record for this reference.
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109Ni, Z.; Xing, F.; Wang, P.; Cao, G. Retracted: Synthesis, characterization and release of curcumin-intercalated Mg–Al-layered double hydroxides Appl. Clay Sci. 2008, 40, 72– 80 DOI: 10.1016/j.clay.2007.07.008There is no corresponding record for this reference.
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110Tomita, M.; Kawakami, H.; Uchihara, J. N.; Okudaira, T.; Masuda, M.; Takasu, N.; Matsuda, T.; Ohta, T.; Tanaka, Y.; Mori, N. Curcumin suppresses constitutive activation of AP-1 by downregulation of Jund protein in HTLV-1-infected T-cell lines Leuk. Res. 2006, 30, 313– 321 DOI: 10.1016/j.leukres.2005.08.004110https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XksFGhtw%253D%253D&md5=a6652fe29782705ee5b39fe42d2f7f73Curcumin suppresses constitutive activation of AP-1 by downregulation of JunD protein in HTLV-1-infected T-cell linesTomita, Mariko; Kawakami, Hirochika; Uchihara, Jun-Nosuke; Okudaira, Taeko; Masuda, Masato; Takasu, Nobuyuki; Matsuda, Takehiro; Ohta, Takao; Tanaka, Yuetsu; Mori, NaokiLeukemia Research (2006), 30 (3), 313-321CODEN: LEREDD; ISSN:0145-2126. (Elsevier B.V.)Activation of the activator protein 1 (AP-1) plays a crit. role in oncogenesis by human T-cell leukemia virus type 1 (HTLV-1), the etiol. agent of adult T-cell leukemia (ATL), and is required for maintenance of the malignant phenotype. Curcumin (diferuloylmethane), the major pigment of the spice turmeric, has anti-tumor activity; however, the effect of curcumin against ATL has not been elucidated. In this study, we examd. the effects of curcumin on AP-1 activity in HTLV-1-infected T-cell lines. Curcumin suppressed the constitutive AP-1 DNA-binding and transcriptional activity in HTLV-1-infected T-cell line. Curcumin also inhibited HTLV-1 Tax-induced AP-1 transcriptional activity. JunD was detectable as a major component of the AP-1-DNA complex in HTLV-1-infected T-cell lines using the supershift assay. The expression of JunD was suppressed by curcumin treatment. Curcumin inhibited the growth of HTLV-1-infected T-cell lines by inducing cell cycle arrest followed by apoptosis. Our results suggest that suppression of the constitutively active AP-1 by curcumin is due to, at least in-part, reducing the expression of JunD by curcumin. Inhibition of AP-1 activity by curcumin may be one of the mechanisms responsible for the anti-ATL effect of curcumin. We propose that curcumin is a potentially promising compd. for the treatment of ATL.
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111Mishra, A.; Kumar, R.; Tyagi, A.; Kohaar, I.; Hedau, S.; Bharti, A. C.; Sarker, S.; Dey, D.; Saluja, D.; Das, B. Curcumin modulates cellular AP-1, NF-kB, and HPV16 E6 proteins in oral cancer ecancer 2015, 9, 525 DOI: 10.3332/ecancer.2015.525There is no corresponding record for this reference.
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112Tomita, M. Retraction: Curcumin targets Akt cell survival signaling pathway in HTLV-I-infected T-cell lines Cancer Sci. 2011, 102, 499 DOI: 10.1111/j.1349-7006.2010.01831.x112https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXitFSmu70%253D&md5=696d442e2dd7ae4601e65fc3fc72b816Anti-adult T-cell leukemia effects of a novel synthetic retinoid, Am80 (Tamibarotene). [Retraction of document cited in CA149:548495]Nakazato, Tetsuro; Okudaira, Taeko; Ishikawa, Chie; Nakama, Shinji; Sawada, Shigeki; Tomita, Mariko; Uchihara, Jun-nosuke; Taira, Naoya; Masuda, Masato; Tanaka, Yuetsu; Ohshiro, Kazuiku; Takasu, Nobuyuki; Mori, NaokiCancer Science (2011), 102 (2), 499CODEN: CSACCM; ISSN:1347-9032. (Wiley-Blackwell)This article has been retracted by the authors, the journal Editor-in-Chief, Yusuke Nakamura, and Blackwell Publishing Asia Pty Ltd., due to inappropriate image utilization in three of the figures within the article.
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113Balasubramanyam, K.; Varier, R. A.; Altaf, M.; Swaminathan, V.; Siddappa, N. B.; Ranga, U.; Kundu, T. K. Curcumin, a novel p300/CREB-binding protein-specific inhibitor of acetyltransferase, represses the acetylation of histone/nonhistone proteins and histone acetyltransferase-dependent chromatin transcription J. Biol. Chem. 2004, 279, 51163– 51171 DOI: 10.1074/jbc.M409024200There is no corresponding record for this reference.
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114Simon, R. P.; Robaa, D.; Alhalabi, Z.; Sippl, W.; Jung, M. Katching-up on small molecule modulators of lysine acetyltransferases J. Med. Chem. 2016, 59, 1249– 1270 DOI: 10.1021/acs.jmedchem.5b01502114https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXitVygt7rK&md5=afcf613db1cfa04320b93aed8b25cec1KATching-Up on Small Molecule Modulators of Lysine AcetyltransferasesSimon, Roman P.; Robaa, Dina; Alhalabi, Zayan; Sippl, Wolfgang; Jung, ManfredJournal of Medicinal Chemistry (2016), 59 (4), 1249-1270CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The reversible acetylation of lysines is one of the best characterized epigenetic modifications. Its involvement in many key physiol. and pathol. processes has been documented in numerous studies. Lysine deacetylases (KDACs) and acetyltransferases (KATs) maintain the acetylation equil. at histones but also many other proteins. Besides acetylation, also other acyl groups are reversibly installed at the side chain of lysines in proteins. Because of their involvement in disease, KDACs and KATs were proposed to be promising drug targets, and for KDACs, indeed, five inhibitors are now approved for human use. While there is a similar level of evidence for the potential of KATs as drug targets, no inhibitor is in clin. trials. Here, we review the evidence for the diverse roles of KATs in disease pathol., provide an overview of structural features and the available modulators, including those targeting the bromodomains of KATs, and present an outlook.
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115Lu, X.; Deng, Y.; Yu, D.; Cao, H.; Wang, L.; Liu, L.; Yu, C.; Zhang, Y.; Guo, X.; Yu, G. Histone acetyltransferase p300 mediates histone acetylation of PS1 and BACE1 in a cellular model of Alzheimer’s disease PLoS One 2014, 9, e103067 DOI: 10.1371/journal.pone.0103067There is no corresponding record for this reference.
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116Cui, L.; Miao, J.; Cui, L. Cytotoxic effect of curcumin on malaria parasite Plasmodium falciparum: Inhibition of histone acetylation and generation of reactive oxygen species Antimicrob. Agents Chemother. 2007, 51, 488– 494 DOI: 10.1128/AAC.01238-06116https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhsVOqurg%253D&md5=580eac24ab97fc225fc588f88091b5aeCytotoxic effect of curcumin on malaria parasite Plasmodium falciparum: inhibition of histone acetylation and generation of reactive oxygen speciesCui, Long; Miao, Jun; Cui, LiwangAntimicrobial Agents and Chemotherapy (2007), 51 (2), 488-494CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)The emergence of multidrug-resistant parasites is a major concern for malaria control, and development of novel drugs is a high priority. Curcumin, a natural polyphenolic compd., possesses diverse pharmacol. properties. Among its antiprotozoan activities, curcumin was potent against both chloroquine-sensitive and -resistant Plasmodium falciparum strains. Consistent with findings in mammalian cell lines, curcumin's prooxidant activity promoted the prodn. in P. falciparum of reactive oxygen species (ROS), whose cytotoxic effect could be antagonized by coincubation with antioxidants and ROS scavengers. Curcumin treatment also resulted in damage of both mitochondrial and nuclear DNA, probably due to the elevation of intracellular ROS. Furthermore, we have demonstrated that curcumin inhibited the histone acetyltransferase (HAT) activity of the recombinant P. falciparum general control nonderepressed 5 (PfGCN5) in vitro and reduced nuclear HAT activity of the parasite in culture. Curcumin-induced hypoacetylation of histone H3 at K9 and K14, but not H4 at K5, K8, K12, and K16, suggested that curcumin caused specific inhibition of the PfGCN5 HAT. Taken together, these results indicated that at least the generation of ROS and down-regulation of PfGCN5 HAT activity accounted for curcumin's cytotoxicity for malaria parasites.
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117Kutluay, S. B.; Doroghazi, J.; Roemer, M. E.; Triezenberg, S. J. Curcumin inhibits herpes simplex virus immediate-early gene expression by a mechanism independent of p300/CBP histone acetyltransferase activity Virology 2008, 373, 239– 247 DOI: 10.1016/j.virol.2007.11.028There is no corresponding record for this reference.
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118Kang, S.-K.; Cha, S.-H.; Jeon, H.-G. Curcumin-induced histone hypoacetylation enhances caspase-3-dependent glioma cell death and neurogenesis of neural progenitor cells Stem Cells Dev. 2006, 15, 165– 174 DOI: 10.1089/scd.2006.15.165There is no corresponding record for this reference.
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119Chen, W.; Bacanamwo, M.; Harrison, D. G. Activation of p300 histone acetyltransferase activity is an early endothelial response to laminar shear stress and is essential for stimulation of endothelial nitric-oxide synthase mRNA transcription J. Biol. Chem. 2008, 283, 16293– 16298 DOI: 10.1074/jbc.M801803200There is no corresponding record for this reference.
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120Chiu, J.; Khan, Z. A.; Farhangkhoee, H.; Chakrabarti, S. Curcumin prevents diabetes-associated abnormalities in the kidneys by inhibiting p300 and nuclear factor-kappaB Nutrition 2009, 25, 964– 972 DOI: 10.1016/j.nut.2008.12.007There is no corresponding record for this reference.
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121Collins, H. M.; Abdelghany, M. K.; Messmer, M.; Yue, B.; Deeves, S. E.; Kindle, K. B.; Mantelingu, K.; Aslam, A.; Winkler, G. S.; Kundu, T. K.; Heery, D. M. Differential effects of garcinol and curcumin on histone and p53 modifications in tumour cells BMC Cancer 2013, 13, 37 DOI: 10.1186/1471-2407-13-37There is no corresponding record for this reference.
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122Dahlin, J. L.; Nissink, J. W. M.; Strasser, J. M.; Francis, S.; Higgins, L.; Zhou, H.; Zhang, Z.; Walters, M. A. PAINS in the assay: Chemical mechanisms of assay interference and promiscuous enzymatic inhibition observed during a sulfhydryl-scavenging HTS J. Med. Chem. 2015, 58, 2091– 2113 DOI: 10.1021/jm5019093122https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhvVeisbY%253D&md5=3f77702544cea2ec4c8184b60dd38b8aPAINS in the Assay: Chemical Mechanisms of Assay Interference and Promiscuous Enzymatic Inhibition Observed during a Sulfhydryl-Scavenging HTSDahlin, Jayme L.; Nissink, J. Willem M.; Strasser, Jessica M.; Francis, Subhashree; Higgins, LeeAnn; Zhou, Hui; Zhang, Zhiguo; Walters, Michael A.Journal of Medicinal Chemistry (2015), 58 (5), 2091-2113CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Significant resources in early drug discovery are spent unknowingly pursuing artifacts and promiscuous bioactive compds., while understanding the chem. basis for these adverse behaviors often goes unexplored in pursuit of lead compds. Nearly all the hits from our recent sulfhydryl-scavenging high-throughput screen (HTS) targeting the histone acetyltransferase Rtt109 were such compds. Herein, we characterize the chem. basis for assay interference and promiscuous enzymic inhibition for several prominent chemotypes identified by this HTS, including some pan-assay interference compds. (PAINS). Protein mass spectrometry and ALARM NMR confirmed these compds. react covalently with cysteines on multiple proteins. Unfortunately, compds. contg. these chemotypes have been published as screening actives in reputable journals and even touted as chem. probes or preclin. candidates. Our detailed characterization and identification of such thiol-reactive chemotypes should accelerate triage of nuisance compds., guide screening library design, and prevent follow-up on undesirable chem. matter.
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123Bora-Tatar, G.; Dayangac-Erden, D.; Demir, A. S.; Dalkara, S.; Yelekci, K.; Erdem-Yurter, H. Molecular modifications on carboxylic acid derivatives as potent histone deacetylase inhibitors: Activity and docking studies Bioorg. Med. Chem. 2009, 17, 5219– 5228 DOI: 10.1016/j.bmc.2009.05.042123https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXosVyqsr4%253D&md5=16c0ee960291fadf786fbb4f099ff3beMolecular modifications on carboxylic acid derivatives as potent histone deacetylase inhibitors: Activity and docking studiesBora-Tatar, Gamze; Dayangac-Erden, Didem; Demir, Ayhan S.; Dalkara, Sevim; Yelekci, Kemal; Erdem-Yurter, HayatBioorganic & Medicinal Chemistry (2009), 17 (14), 5219-5228CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)In the light of known HDAC inhibitors, 33 carboxylic acid derivs. were tested to understand the structural requirements for HDAC inhibition activity. Several modifications were applied to develop the structure-activity relationships of carboxylic acid HDAC inhibitors. HDAC inhibition activities were investigated in vitro by using HeLa nuclear ext. in a fluorimetric assay. Mol. docking was also carried out for the human HDAC8 enzyme in order to predict inhibition activity and the 3D poses of inhibitor-enzyme complexes. Of these compds., caffeic acid derivs. such as chlorogenic acid and curcumin were found to be highly potent compared to sodium butyrate, which is a well-known HDAC inhibitor.
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124Wang, S.-H.; Lin, P.-Y.; Chiu, Y.-C.; Huang, J.-S.; Kuo, Y.-T.; Wu, J.-C.; Chen, C.-C. Curcumin-mediated HDAC inhibition suppresses the DNA damage response and contributes to increased DNA damage sensitivity PLoS One 2015, 10, e0134110/0134111– e0134110/0134119 DOI: 10.1371/journal.pone.0134110There is no corresponding record for this reference.
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125Link, A.; Balaguer, F.; Goel, A. Cancer chemoprevention by dietary polyphenols: Promising role for epigenetics Biochem. Pharmacol. (Amsterdam, Neth.) 2010, 80, 1771– 1792 DOI: 10.1016/j.bcp.2010.06.036There is no corresponding record for this reference.
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126Rajendran, P.; Ho, E.; Williams, D. E.; Dashwood, R. H. Dietary phytochemicals, HDAC inhibition, and DNA damage/repair defects in cancer cells Clin. Epigenet. 2011, 3, 4 DOI: 10.1186/1868-7083-3-4126https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsFSrur%252FN&md5=51eb4a6b37e6448f267c47ff625fe92bDietary phytochemicals, HDAC inhibition, and DNA damage/repair defects in cancer cellsRajendran, Praveen; Ho, Emily; Williams, David E.; Dashwood, Roderick H.Clinical Epigenetics (2011), 3 (), 4CODEN: CELPCI; ISSN:1868-7083. (BioMed Central Ltd.)A review. Genomic instability is a common feature of cancer etiol. This provides an avenue for therapeutic intervention, since cancer cells are more susceptible than normal cells to DNA damaging agents. However, there is growing evidence that the epigenetic mechanisms that impact DNA methylation and histone status also contribute to genomic instability. The DNA damage response, for example, is modulated by the acetylation status of histone and non-histone proteins, and by the opposing activities of histone acetyltransferase and histone deacetylase (HDAC) enzymes. Many HDACs overexpressed in cancer cells have been implicated in protecting such cells from genotoxic insults. Thus, HDAC inhibitors, in addn. to unsilencing tumor suppressor genes, also can silence DNA repair pathways, inactivate non-histone proteins that are required for DNA stability, and induce reactive oxygen species and DNA double-strand breaks. This review summarizes how dietary phytochems. that affect the epigenome also can trigger DNA damage and repair mechanisms. Where such data is available, examples are cited from studies in vitro and in vivo of polyphenols, organosulfur/organoselenium compds., indoles, sesquiterpene lactones, and misc. agents such as anacardic acid. Finally, by virtue of their genetic and epigenetic mechanisms, cancer chemopreventive agents are being redefined as chemo- or radio-sensitizers. A sustained DNA damage response coupled with insufficient repair may be a pivotal mechanism for apoptosis induction in cancer cells exposed to dietary phytochems. Future research, including appropriate clin. investigation, should clarify these emerging concepts in the context of both genetic and epigenetic mechanisms dysregulated in cancer, and the pros and cons of specific dietary intervention strategies.
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127Bustanji, Y.; Taha, M. O.; Almasri, I. M.; Al-Ghussein, M. A. S.; Mohammad, M. K.; Alkhatib, H. S. Inhibition of glycogen synthase kinase by curcumin: Investigation by simulated molecular docking and subsequent in vitro/in vivo evaluation J. Enzyme Inhib. Med. Chem. 2009, 24, 771– 778 DOI: 10.1080/14756360802364377127https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXmtl2qsrk%253D&md5=fdbbd01680853a24049aa61bc73dd3fdInhibition of glycogen synthase kinase by curcumin: Investigation by simulated molecular docking and subsequent in vitro/in vivo evaluationBustanji, Yasser; Taha, Mutasem O.; Almasri, Ihab M.; Al-Ghussein, Mohamed A. S.; Mohammad, Mohammad K.; Alkhatib, Hatim S.Journal of Enzyme Inhibition and Medicinal Chemistry (2009), 24 (3), 771-778CODEN: JEIMAZ; ISSN:1475-6366. (Informa Healthcare)Curcumin was investigated as an inhibitor of glycogen synthase kinase-3β (GSK-3β) in an attempt to explain some of its interesting multiple pharmacol. effects, such as its anti-diabetic, anti-inflammatory, anti-cancer, anti-malarial and anti-alzheimer's properties. The investigation included simulated docking expts. to fit curcumin within the binding pocket of GSK-3β followed by exptl. in vitro and in vivo validations. Curcumin was found to optimally fit within the binding pocket of GSK-3β via several attractive interactions with key amino acids. Exptl., curcumin was found to potently inhibit GSK-3β (IC50 = 66.3 nM). Furthermore, our in vivo expts. illustrated that curcumin significantly increases liver glycogen in fasting Balb/c mice. Our findings strongly suggest that the diverse pharmacol. activities of curcumin are at least partially mediated by inhibition of GSK-3β.
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128Di Martino, R. M.; De Simone, A.; Andrisano, V.; Bisignano, P.; Bisi, A.; Gobbi, S.; Rampa, A.; Fato, R.; Bergamini, C.; Perez, D. I.; Martinez, A.; Bottegoni, G.; Cavalli, A.; Belluti, F. Versatility of the curcumin scaffold: Discovery of potent and balanced dual BACE-1 and GSK-3beta inhibitors J. Med. Chem. 2016, 59, 531– 544 DOI: 10.1021/acs.jmedchem.5b00894128https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXitVGrsLrJ&md5=349916a940c9cc8d87ca817c689756f1Versatility of the Curcumin Scaffold: Discovery of Potent and Balanced Dual BACE-1 and GSK-3β InhibitorsDi Martino, Rita Maria Concetta; De Simone, Angela; Andrisano, Vincenza; Bisignano, Paola; Bisi, Alessandra; Gobbi, Silvia; Rampa, Angela; Fato, Romana; Bergamini, Christian; Perez, Daniel I.; Martinez, Ana; Bottegoni, Giovanni; Cavalli, Andrea; Belluti, FedericaJournal of Medicinal Chemistry (2016), 59 (2), 531-544CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The multitarget approach has gained increasing acceptance as a useful tool to address complex and multifactorial maladies such as Alzheimer's disease (AD). The concurrent inhibition of the validated AD targets β-secretase (BACE-1) and glycogen synthase kinase-3β (GSK-3β) by attacking both β-amyloid and tau protein cascades has been identified as a promising AD therapeutic strategy. In our study, curcumin was identified as a lead compd. for the simultaneous inhibition of both targets; therefore, synthetic efforts were dedicated to obtaining a small library of novel curcumin-based analogs, and a no. of potent and balanced dual-target inhibitors were obtained. In particular, 2, 6, and 7 emerged as promising drug candidates endowed with neuroprotective potential and brain permeability. Notably, for some new compds. the sym. diketo and the β-keto-enol tautomeric forms were purposely isolated and tested in vitro, allowing us to gain insight into the key requirements for BACE-1 and GSK-3β inhibition.
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129Zhang, X.; Yin, W. K.; Shi, X. D.; Li, Y. Curcumin activates Wnt/beta-catenin signaling pathway through inhibiting the activity of GSK-3beta in APPswe transfected SY5Y cells Eur. J. Pharm. Sci. 2011, 42, 540– 546 DOI: 10.1016/j.ejps.2011.02.009129https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXkvFamu7w%253D&md5=a97d1ccf76a14e414519873d8b34b606Curcumin activates Wnt/β-catenin signaling pathway through inhibiting the activity of GSK-3β in APPswe transfected SY5Y cellsZhang, Xiong; Yin, Wen-ke; Shi, Xiao-dong; Li, YuEuropean Journal of Pharmaceutical Sciences (2011), 42 (5), 540-546CODEN: EPSCED; ISSN:0928-0987. (Elsevier B.V.)Wnt/β-catenin signaling pathway plays an important role in the genesis and development of Alzheimer's disease. The study aims to investigate the effect of Curcumin on the expression of GSK-3β, β-catenin and CyclinD1 in vitro, which are tightly correlated with Wnt/β-catenin signaling pathway, and also to explore the mechanisms, which will provide a novel therapeutic intervention for treatment of Alzheimer's disease. Plasmid APPswe and BACE1-mychis were transiently co-transfected into SHSY5Y cells by Liposfectamin 2000. The cells were treated with Curcumin at 0, 1.25, 5.0, 20.0 μmol/L for 24 h, or with Curcumin at 5.0 μmol/L for 0, and 12, 24 and 48 h for time course assay. Cell lysates were collected for RT-PCR, Western blot assay and immunofluorescent staining were carried out for detecting the effect of Curcumin on the expression of GSK-3β, β-catenin and CyclinD1. RT-PCR and Western blot results showed that the expression of GSK-3β mRNA and protein significantly decreased in the transfected cells treated with Curcumin, and that the changes were in a dose and time-dependent manner (P < 0.05); however, the protein expression of GSK-3β-Ser9 was increased (P < 0.05). Meanwhile, the expressions of β-catenin and transcriptional factors CyclinD1 mRNA and protein increased and the changes were also in a dose and time-dependent manner (P < 0.05). Immunofluorescent staining results not only confirmed the above changes, but also showed that β-catenin had translocated into the nucleus gradually with the increased dosage of Curcumin. Therefore, GSK-3β is a potential target for treatment of AD. Curcumin could activate the Wnt/β-catenin signaling pathway through inhibiting the expression of GSK-3β and inducing the expression of β-catenin and CyclinD1, which will provide a new theory for treatment of neurodegenerative diseases by Curcumin.
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130Yun, J. H.; Park, Y. G.; Lee, K. M.; Kim, J.; Nho, C. W. Curcumin induces apoptotic cell death via Oct4 inhibition and GSK-3beta activation in NCCIT cells Mol. Nutr. Food Res. 2015, 59, 1053– 1062 DOI: 10.1002/mnfr.201400739130https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXnt1Wlsbw%253D&md5=a44051729c7c6e42393b5d1b4db9b325Curcumin induces apoptotic cell death via Oct4 inhibition and GSK-3β activation in NCCIT cellsYun, Ji Ho; Park, Young Gyun; Lee, Kyung-Mi; Kim, Jungho; Nho, Chu WonMolecular Nutrition & Food Research (2015), 59 (6), 1053-1062CODEN: MNFRCV; ISSN:1613-4125. (Wiley-VCH Verlag GmbH & Co. KGaA)Scope : Octamer-binding transcription factor 4 (Oct4) is a key regulator of pluripotent embryonic stem cell maintenance. However, increasing evidence has suggested that Oct4 is also expressed in cancer stem cells (CSCs) and is assocd. with tumor progression and chemoresistance. Curcumin (CUR) is a widely used cancer chemopreventive agent, and it has been used to treat several diseases including cancers. Here, we investigated whether CUR-induced apoptotic cell death by inhibiting Oct4 levels and examg. mol. mechanisms in NCCIT human embryonic carcinoma cells. Methods and results : CUR significantly inhibited Oct4 transcription levels in a dose-dependent manner by dual luciferase expt., also decreased mRNA and protein levels in NCCIT human embryonic carcinoma cells, which express high levels of endogenous Oct4. Interestingly, we found that CUR treatment increased apoptotic cell death including subG0/G1 contents, cleavage caspases, and pro-apoptotic protein, as confirmed with a series of loss-of-function expts. using Oct4 siRNA. Furthermore, CUR induced marked total level of glycogen synthase kinase 3 beta (GSK-3β), resulting in an increase in apoptotic cell death, was evaluated using chem. inhibitor of GSK3-3β. Conclusion : These data suggest that CUR induces apoptotic cell death through Oct4 inhibition and GSK-3β activation. Thus, CUR may be a useful cancer chemopreventive agent to suppress tumor progression or to improve chemoresistance by eliminating CSCs.
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131Xiong, Z.; Hongmei, Z.; Lu, S.; Yu, L. Curcumin mediates presenilin-1 activity to reduce β-amyloid production in a model of Alzheimer’s disease Pharmacol. Rep. 2011, 63, 1101– 1108 DOI: 10.1016/S1734-1140(11)70629-6131https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC38%252FotlKrsw%253D%253D&md5=0c236679133b5c777f1fc92e77feeb84Curcumin mediates presenilin-1 activity to reduce β-amyloid production in a model of Alzheimer's DiseaseXiong Zhang; Hongmei Zhang; Lu Si; Yu LiPharmacological reports : PR (2011), 63 (5), 1101-8 ISSN:1734-1140.Curcumin has been reported to inhibit the generation of Aβ, but the underlying mechanisms by which this occurs remain unknown. Aβ is thought to play an important role in the pathogenesis of Alzheimer's disease (AD). The amyloid hypothesis argues that aggregates of Aβ trigger a complex pathological cascade that leads to neurodegeneration. Aβ is generated by the processing of APP (amyloid precursor protein) by β- and γ-secretases. Presenilin 1 (PS1) is central to γ-secretase activity and is a substrate for GSK-3β, both of which are implicated in the pathogenesis of AD. The present study aimed to investigate the effects of curcumin on the generation of Aβ in cultured neuroblastoma cells and on the in vitro expression of PS1 and GSK-3β. To stimulate Aβ production, a plasmid expressing APP was transfected into human SH-SY5Y neuroblastoma cells. The transfected cells were then treated with curcumin at 0-20 μM for 24 h or with 5 μM curcumin for 0-48 h, and the extracellular levels of Aβ(40/42) were determined by ELISA. The levels of PS1 and GSK-3β mRNA were measured by RT-PCR, and the expression of the PS1 and GSK-3β proteins (including the phosphorylated form of GSK-3β, p-GSK-3β-Ser9) were evaluated by western blotting. Curcumin treatment was found to markedly reduce the production of Aβ(40/42). Treatment with curcumin also decreased both PS1 and GSK-3β mRNA and protein levels in a dose- and time-dependent manner. Furthermore, curcumin increased the inhibitory phosphorylation of GSK-3β protein at Ser9. Therefore, we propose that curcumin decreases Aβ production by inhibiting GSK-3β-mediated PS1 activation.
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132Dahlin, J. L.; Inglese, J.; Walters, M. A. Mitigating risk in academic preclinical drug discovery Nat. Rev. Drug Discovery 2015, 14, 279– 294 DOI: 10.1038/nrd4578132https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXls1artLg%253D&md5=9c7548364bfe54e25e013985436ba876Mitigating risk in academic preclinical drug discoveryDahlin, Jayme L.; Inglese, James; Walters, Michael A.Nature Reviews Drug Discovery (2015), 14 (4), 279-294CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)The no. of academic drug discovery centers has grown considerably in recent years, providing new opportunities to couple the curiosity-driven research culture in academia with rigorous preclin. drug discovery practices used in industry. To fully realize the potential of these opportunities, it is important that academic researchers understand the risks inherent in preclin. drug discovery, and that translational research programs are effectively organized and supported at an institutional level. In this article, we discuss strategies to mitigate risks in several key aspects of preclin. drug discovery at academic drug discovery centers, including organization, target selection, assay design, medicinal chem. and preclin. pharmacol.
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133Yang, F.; Lim, G. P.; Begum, A. N.; Ubeda, O. J.; Simmons, M. R.; Ambegaokar, S. S.; Chen, P. P.; Kayed, R.; Glabe, C. G.; Frautschy, S. A.; Cole, G. M. Curcumin inhibits formation of amyloid beta oligomers and fibrils, binds plaques, and reduces amyloid in vivo J. Biol. Chem. 2005, 280, 5892– 5901 DOI: 10.1074/jbc.M404751200133https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtlClt7w%253D&md5=5f8f6fb0c3529ba9dbeae5f8af096250Curcumin Inhibits Formation of Amyloid β Oligomers and Fibrils, Binds Plaques, and Reduces Amyloid in VivoYang, Fusheng; Lim, Giselle P.; Begum, Aynun N.; Ubeda, Oliver J.; Simmons, Mychica R.; Ambegaokar, Surendra S.; Chen, Pingping P.; Kayed, Rakez; Glabe, Charles G.; Frautschy, Sally A.; Cole, Gregory M.Journal of Biological Chemistry (2005), 280 (7), 5892-5901CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)Alzheimer's disease (AD) involves amyloid β (Aβ) accumulation, oxidative damage, and inflammation, and risk is reduced with increased antioxidant and anti-inflammatory consumption. The phenolic yellow curry pigment curcumin has potent anti-inflammatory and antioxidant activities and can suppress oxidative damage, inflammation, cognitive deficits, and amyloid accumulation. Since the mol. structure of curcumin suggested potential Aβ binding, we investigated whether its efficacy in AD models could be explained by effects on Aβ aggregation. Under aggregating conditions in vitro, curcumin inhibited aggregation (IC50 = 0.8 μM) as well as disaggregated fibrillar Aβ40 (IC50 = 1 μM), indicating favorable stoichiometry for inhibition. Curcumin was a better Aβ40 aggregation inhibitor than ibuprofen and naproxen, and prevented Aβ42 oligomer formation and toxicity between 0.1 and 1.0 μM. Under EM, curcumin decreased dose dependently Aβ fibril formation beginning with 0.125 μM. The effects of curcumin did not depend on Aβ sequence but on fibril-related conformation. AD and Tg2576 mice brain sections incubated with curcumin revealed preferential labeling of amyloid plaques. In vivo studies showed that curcumin injected peripherally into aged Tg mice crossed the blood-brain barrier and bound plaques. When fed to aged Tg2576 mice with advanced amyloid accumulation, curcumin labeled plaques and reduced amyloid levels and plaque burden. Hence, curcumin directly binds small β-amyloid species to block aggregation and fibril formation in vitro and in vivo. These data suggest that low dose curcumin effectively disaggregates Aβ as well as prevents fibril and oligomer formation, supporting the rationale for curcumin use in clin. trials preventing or treating AD.
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134Hudson, S. A.; Ecroyd, H.; Kee, T. W.; Carver, J. A. The thioflavin T fluorescence assay for amyloid fibril detection can be biased by the presence of exogenous compounds FEBS J. 2009, 276, 5960– 5972 DOI: 10.1111/j.1742-4658.2009.07307.x134https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXht12qs7rI&md5=2ea6162d19419134f3ff894be6686d78The thioflavin T fluorescence assay for amyloid fibril detection can be biased by the presence of exogenous compoundsHudson, Sean A.; Ecroyd, Heath; Kee, Tak W.; Carver, John A.FEBS Journal (2009), 276 (20), 5960-5972CODEN: FJEOAC; ISSN:1742-464X. (Wiley-Blackwell)Thioflavin T (ThT) dye fluorescence is used regularly to quantify the formation and inhibition of amyloid fibrils in the presence of anti-amyloidogenic compds. such as polyphenols. However, in this study, it was shown, using three polyphenolics (curcumin, quercetin and resveratrol), that ThT fluorescence should be used with caution in the presence of such exogenous compds. The strong absorptive and fluorescent properties of quercetin and curcumin were found to significantly bias the ThT fluorescence readings in both in situ real-time ThT assays and single time-point diln. ThT-type assays. The presence of curcumin at concns. as low as 0.01 and 1 μM was sufficient to interfere with the ThT fluorescence assocd. with fibrillar amyloid-β(1-42) (0.5 μM) and fibrillar reduced and carboxymethylated κ-casein (50 μM), resp. The ThT fluorescence assocd. with fibrillar amyloid-β(1-42) was also biased using higher concns. of resveratrol, a polyphenol that is not spectroscopically active at the wavelengths of ThT fluorescence, implying that there can be direct interactions between ThT and the exogenous compd. and/or competitive binding with ThT for the fibrils. Thus, in all cases where ThT is used in the presence of an exogenous compd., biases for amyloid-assocd. ThT fluorescence should be tested, regardless of whether the additive is spectroscopically active. Simple methods to conduct these tests were described. The Congo red spectral shift assay is demonstrated as a more viable spectrophotometric alternative to ThT, but allied methods, such as TEM, should also be used to assess fibril formation independently of dye-based assays.
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135Thapa, A.; Jett, S. D.; Chi, E. Y. Curcumin attenuates amyloid-β aggregate toxicity and modulates amyloid-β aggregation pathway ACS Chem. Neurosci. 2016, 7, 56– 68 DOI: 10.1021/acschemneuro.5b00214135https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhslGms7bP&md5=8da11a9c15080af82688e26ed5ec639eCurcumin Attenuates Amyloid-β Aggregate Toxicity and Modulates Amyloid-β Aggregation PathwayThapa, Arjun; Jett, Stephen D.; Chi, Eva Y.ACS Chemical Neuroscience (2016), 7 (1), 56-68CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)The abnormal misfolding and aggregation of amyloid-β (Aβ) peptides into β-sheet enriched insol. deposits initiates a cascade of events leading to pathol. processes and culminating in cognitive decline in Alzheimer's disease (AD). In particular, sol. oligomeric/prefibrillar Aβ have been shown to be potent neurotoxins. The naturally occurring polyphenol curcumin has been shown to exert a neuroprotective effect against age-related neurodegenerative diseases such as AD. However, its protective mechanism remains unclear. In this study, we investigated the effects of curcumin on the aggregation of Aβ40 as well as Aβ40 aggregate induced neurotoxicity. Our results show that the curcumin does not inhibit Aβ fibril formation, but rather enriches the population of "off-pathway" sol. oligomers and prefibrillar aggregates that were nontoxic. Curcumin also exerted a nonspecific neuroprotective effect, reducing toxicities induced by a range of Aβ conformers, including monomeric, oligomeric, prefibrillar, and fibrillar Aβ. The neuroprotective effect is possibly membrane-mediated, as curcumin reduced the extent of cell membrane permeabilization induced by Aβ aggregates. Taken together, our study shows that curcumin exerts its neuroprotective effect against Aβ induced toxicity through at least two concerted pathways, modifying the Aβ aggregation pathway toward the formation of nontoxic aggregates and ameliorating Aβ-induced toxicity possibly through a nonspecific pathway.
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136Kayed, R.; Head, E.; Thompson, J. L.; McIntire, T. M.; Milton, S. C.; Cotman, C. W.; Glabe, C. G. Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis Science (Washington, DC, U. S.) 2003, 300, 486– 489 DOI: 10.1126/science.1079469136https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXivFyms7k%253D&md5=028225aa14803cc25c308d6b77679412Common Structure of Soluble Amyloid Oligomers Implies Common Mechanism of PathogenesisKayed, Rakez; Head, Elizabeth; Thompson, Jennifer L.; McIntire, Theresa M.; Milton, Saskia C.; Cotman, Carl W.; Glabe, Charles G.Science (Washington, DC, United States) (2003), 300 (5618), 486-489CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)Sol. oligomers are common to most amyloids and may represent the primary toxic species of amyloids, like the Aβ peptide in Alzheimer's disease (AD). Here the authors show that all of the sol. oligomers tested display a common conformation-dependent structure that is unique to sol. oligomers regardless of sequence. The in vitro toxicity of sol. oligomers is inhibited by oligomer-specific antibody. Sol. oligomers have a unique distribution in human AD brain that is distinct from fibrillar amyloid. These results indicate that different types of sol. amyloid oligomers have a common structure and suggest they share a common mechanism of toxicity.
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137Feng, B. Y.; Shoichet, B. K. A detergent-based assay for the detection of promiscuous inhibitors Nat. Protoc. 2006, 1, 550– 553 DOI: 10.1038/nprot.2006.77137https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhtFOitLjO&md5=8aa7562b5f69c896af7e133ecc35e6deA detergent-based assay for the detection of promiscuous inhibitorsFeng, Brian Y.; Shoichet, Brian K.Nature Protocols (2006), 1 (2), 550-553CODEN: NPARDW; ISSN:1750-2799. (Nature Publishing Group)At micromolar concns., many small mols. self-assoc. into colloidal aggregates that non-specifically inhibit enzymes and other proteins. Here the authors describe a protocol for identifying aggregate-based inhibitors and distinguishing them from small mols. that inhibit via specific mechanisms. As a convenient proxy for promiscuous, aggregate-based inhibition, the authors monitor inhibition of β-lactamase in the absence and presence of detergent. Inhibition that is attenuated in the presence of detergent is characteristic of an aggregate-based mechanism. In the 96-well-format assay described here, about 200 mols. can be tested, in duplicate, per h for detergent-dependent sensitivity. Furthermore, the authors also describe simple expts. that can offer addnl. confirmation of aggregate-based inhibition.
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138Egan, M. E.; Pearson, M.; Weiner, S. A.; Rajendran, V.; Rubin, D.; Gloeckner-Pagel, J.; Canny, S.; Du, K.; Lukacs, G. L.; Caplan, M. J. Curcumin, a major constituent of turmeric, corrects cystic fibrosis defects Science (Washington, DC, U. S.) 2004, 304, 600– 602 DOI: 10.1126/science.1093941138https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXjt1Crsrs%253D&md5=00a8ab6438aee2d6198965e41f1fb379Curcumin, a major constituent of turmeric, corrects cystic fibrosis defectsEgan, Marie E.; Pearson, Marilyn; Weiner, Scott A.; Rajendran, Vanathy; Rubin, Daniel; Gloeckner-Pagel, Judith; Canny, Susan; Du, Kai; Lukacs, Gergely L.; Caplan, Michael J.Science (Washington, DC, United States) (2004), 304 (5670), 600-602CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)Cystic fibrosis is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). The most common mutation, ΔF508, results in the prodn. of a misfolded CFTR protein that is retained in the endoplasmic reticulum and targeted for degrdn. Curcumin is a nontoxic Ca-ATPase pump inhibitor that can be administered to humans safely. Oral administration of curcumin to homozygous ΔF508 CFTR mice in doses comparable, on a wt.-per-wt. basis, to those well tolerated by humans cor. these animals' characteristic nasal p.d. defect. These effects were not obsd. in mice homozygous for a complete knockout of the CFTR gene. Curcumin also induced the functional appearance of ΔF508 CFTR protein in the plasma membranes of transfected baby hamster kidney cells. Thus, curcumin treatment may be able to correct defects assocd. with the homozygous expression of ΔF508 CFTR.
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139Song, Y.; Sonawane, N. D.; Salinas, D.; Qian, L.; Pedemonte, N.; Galietta, L. J. V.; Verkman, A. S. Evidence against the rescue of defective ΔF508-CFTR cellular processing by curcumin in cell culture and mouse models J. Biol. Chem. 2004, 279, 40629– 40633 DOI: 10.1074/jbc.M407308200There is no corresponding record for this reference.
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140Dey, I.; Shah, K.; Bradbury, N. A. Natural compounds as therapeutic agents in the treatment cystic fibrosis J. Genet. Syndr. Gene Ther. 2016, 7, 284 DOI: 10.4172/2157-7412.1000284There is no corresponding record for this reference.
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141Seely, K. A.; Levi, M. S.; Prather, P. L. The dietary polyphenols trans-resveratrol and curcumin selectively bind human CB1 cannabinoid receptors with nanomolar affinities and function as antagonists/inverse agonists J. Pharmacol. Exp. Ther. 2009, 330, 31– 39 DOI: 10.1124/jpet.109.151654141https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXosFGhsbk%253D&md5=fdee663c3bd88a2f808e31e6a118d1c3The dietary polyphenols trans-resveratrol and curcumin selectively bind human CB1 cannabinoid receptors with nanomolar affinities and function as antagonists/inverse agonistsSeely, Kathryn A.; Levi, Mark S.; Prather, Paul L.Journal of Pharmacology and Experimental Therapeutics (2009), 330 (1), 31-39CODEN: JPETAB; ISSN:0022-3565. (American Society for Pharmacology and Experimental Therapeutics)The dietary polyphenols trans-resveratrol [5-[(1E)-2-(4-hydroxyphenyl)ethenyl]-1,3-benzenediol; found in red wine] and curcumin [1,7-bis(4-hydroxy-3-methoxyphenyl)-1E,6E-heptadiene-3,5-dione] (found in curry powders) exert anti-inflammatory and antioxidant effects via poorly defined mechanisms. It is interesting that cannabinoids, derived from the marijuana plant (Cannabis sativa), produce similar protective effects via CB1 and CB2 receptors. We examd. whether trans-resveratrol, curcumin, and ASC-J9 [1,7-bis(3,4-dimethoxyphenyl)-5-hydroxy-1E,4E,6E-heptatriene-3-one] (a curcumin analog) act at ligands at cannabinoid receptors. All three bind to human (h) CB1 and mouse CB1 receptors with nanomolar affinities, displaying only micromolar affinities for hCB2 receptors. Characteristic of inverse agonists, the polyphenols inhibit basal G-protein activity in membranes prepd. from Chinese hamster ovary (CHO)-hCB1 cells or mouse brain that is reversed by a neutral CB1 antagonist. Furthermore, they competitively antagonize G-protein activation produced by a CB1 agonist. In intact CHO-hCB1 cells, the polyphenols act as neutral antagonists, producing no effect when tested alone, whereas competitively antagonizing CB1 agonist mediated inhibition of adenylyl cyclase activity. Confirming their neutral antagonist profile in cells, the polyphenols similarly attenuate stimulation of adenylyl cyclase activity produced by a CB1 inverse agonist. In mice, the polyphenols dose-dependently reverse acute hypothermia produced by a CB1 agonist. Upon repeated administration, the polyphenols also reduce body wt. in mice similar to that produced by a CB1 antagonist/inverse agonist. Finally, transresveratrol and curcumin share common structural motifs with other known cannabinoid receptor ligands. Collectively, we suggest that trans-resveratrol and curcumin act as antagonists/inverse agonists at CB1 receptors at dietary relevant concns. Therefore, these polyphenols and their derivs. might be developed as novel, nontoxic CB1 therapeutics for obesity and/or drug dependence.
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142Prather, P. L.; Seely, K. A.; Levi, M. S. Notice of retraction J. Pharmacol. Exp. Ther. 2009, 331, 1147142https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhsFaqsLjL&md5=843e2d615d3727f76083e4e0fe5b7caePolyphenols and cannabinoid receptor functional agonismPrather, Paul L.; Seely, Kathryn A.; Levi, Mark S.Journal of Pharmacology and Experimental Therapeutics (2009), 331 (3), 1147CODEN: JPETAB; ISSN:0022-3565. (American Society for Pharmacology and Experimental Therapeutics)There is no expanded citation for this reference.
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143Sharma, C.; Sadek, B.; Goyal, S. N.; Sinha, S.; Kamal, M. A.; Ojha, S. Small molecules from nature targeting G-protein coupled cannabinoid receptors: Potential leads for drug discovery and development Evidence-Based Complementary Altern. Med. 2015, 2015, 238482 DOI: 10.1155/2015/238482143https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28rhvVClsA%253D%253D&md5=e59ce0b82e5722e4de576e51f037076cSmall Molecules from Nature Targeting G-Protein Coupled Cannabinoid Receptors: Potential Leads for Drug Discovery and DevelopmentSharma Charu; Sadek Bassem; Ojha Shreesh; Goyal Sameer N; Sinha Satyesh; Kamal Mohammad AmjadEvidence-based complementary and alternative medicine : eCAM (2015), 2015 (), 238482 ISSN:1741-427X.The cannabinoid molecules are derived from Cannabis sativa plant which acts on the cannabinoid receptors types 1 and 2 (CB1 and CB2) which have been explored as potential therapeutic targets for drug discovery and development. Currently, there are numerous cannabinoid based synthetic drugs used in clinical practice like the popular ones such as nabilone, dronabinol, and Δ(9)-tetrahydrocannabinol mediates its action through CB1/CB2 receptors. However, these synthetic based Cannabis derived compounds are known to exert adverse psychiatric effect and have also been exploited for drug abuse. This encourages us to find out an alternative and safe drug with the least psychiatric adverse effects. In recent years, many phytocannabinoids have been isolated from plants other than Cannabis. Several studies have shown that these phytocannabinoids show affinity, potency, selectivity, and efficacy towards cannabinoid receptors and inhibit endocannabinoid metabolizing enzymes, thus reducing hyperactivity of endocannabinoid systems. Also, these naturally derived molecules possess the least adverse effects opposed to the synthetically derived cannabinoids. Therefore, the plant based cannabinoid molecules proved to be promising and emerging therapeutic alternative. The present review provides an overview of therapeutic potential of ligands and plants modulating cannabinoid receptors that may be of interest to pharmaceutical industry in search of new and safer drug discovery and development for future therapeutics.
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144Code of Federal Regulations Title 21. Part 182: Substances Generally Recognized as Safe. Section 182.20 Essential oils, oleoresins (solvent-free), and natural extractives (including distillates). U.S. Food and Drug Administration, 2016.There is no corresponding record for this reference.
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145Ringman, J. M.; Bardens, J.; Apostolova, L. G.; Frautschy, S. A.; Teng, E.; Cole, G. M.; Begum, A. N.; Beigi, M.; Gylys, K. H.; Badmaev, V.; Heath, D. D.; Porter, V.; Vanek, Z.; Marshall, G. A.; Hellemann, G.; Sugar, C.; Masterman, D. L.; Montine, T. J.; Cummings, J. L. Oral curcumin for Alzheimer’s disease: Tolerability and efficacy in a 24-week randomized, double blind, placebo-controlled study Alzheimer's Res. Ther. 2012, 4, 43 DOI: 10.1186/alzrt146145https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXit1CntLw%253D&md5=a2478f2b60ca63a95de1da293fe2b2deOral curcumin for Alzheimer's disease: tolerability and efficacy in a 24-week randomized, double blind, placebo-controlled studyRingman, John M.; Frautschy, Sally A.; Teng, Edmond; Begum, Aynun N.; Bardens, Jenny; Beigi, Maryam; Gylys, Karen H.; Badmaev, Vladimir; Heath, Dennis D.; Apostolova, Liana G.; Porter, Verna; Vanek, Zeba; Marshall, Gad A.; Hellemann, Gerhard; Sugar, Catherine; Masterman, Donna L.; Montine, Thomas J.; Cummings, Jeffrey L.; Cole, Greg M.Alzheimer's Research & Therapy (2012), 4 (5), 43CODEN: ARTLCD; ISSN:1758-9193. (BioMed Central Ltd.)Introduction: Curcumin is a polyphenolic compd. derived from the plant Curcuma Long Lin that has been demonstrated to have antioxidant and anti-inflammatory effects as well as effects on reducing beta-amyloid aggregation. It reduces pathol. in transgenic models of Alzheimer's disease (AD) and is a promising candidate for treating human AD. The purpose of the current study is to generate tolerability and preliminary clin. and biomarker efficacy data on curcumin in persons with AD. Methods: We performed a 24-wk randomized, double blind, placebo-controlled study of Curcumin C3 Complex with an open-label extension to 48 wk. Thirty-six persons with mild-to-moderate AD were randomized to receive placebo, 2 g/day, or 4 g/day of oral curcumin for 24 wk. For weeks 24 through 48, subjects that were receiving curcumin continued with the same dose, while subjects previously receiving placebo were randomized in a 1:1 ratio to 2 g/day or 4 g/day. The primary outcome measures were incidence of adverse events, changes in clin. lab. tests and the Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) at 24 wk in those completing the study. Secondary outcome measures included the Neuropsychiatric Inventory (NPI), the Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) scale, levels of Aβ1-40 and Aβ1-42 in plasma and levels of Aβ1-42, t-tau, p-tau181 and F2-isoprostanes in cerebrospinal fluid. Plasma levels of curcumin and its metabolites up to four hours after drug administration were also measured. Results: Mean age of completers (n = 30) was 73.5 years and mean Mini-Mental Status Examn. (MMSE) score was 22.5. One subject withdrew in the placebo (8%, worsened memory) and 5/24 subjects withdrew in the curcumin group (21%, 3 due to gastrointestinal symptoms). Curcumin C3 Complex was assocd. with lowered hematocrit and increased glucose levels that were clin. insignificant. There were no differences between treatment groups in clin. or biomarker efficacy measures. The levels of native curcumin measured in plasma were low (7.32 ng/mL). Conclusions: Curcumin was generally well-tolerated although three subjects on curcumin withdrew due to gastrointestinal symptoms. We were unable to demonstrate clin. or biochem. evidence of efficacy of Curcumin C3 Complex in AD in this 24-wk placebo-controlled trial although preliminary data suggest limited bioavailability of this compd.
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146Pfizer. Bioequivalence study comparing a new 10 mg atorvastatin tablet to a 10 mg atorvastatin commercial tablet. https://clinicaltrials.gov/ct2/show/NCT00917579, 2009There is no corresponding record for this reference.
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147Sharma, R. A.; Euden, S. A.; Platton, S. L.; Cooke, D. N.; Shafayat, A.; Hewitt, H. R.; Marczylo, T. H.; Morgan, B.; Hemingway, D.; Plummer, S. M.; Pirmohamed, M.; Gescher, A. J.; Steward, W. P. Phase I clinical trial of oral curcumin: Biomarkers of systemic activity and compliance Clin. Cancer Res. 2004, 10, 6847– 6854 DOI: 10.1158/1078-0432.CCR-04-0744147https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXpslGltLg%253D&md5=9fde9f88cfcfca6a6e10a339d8596029Phase I Clinical Trial of Oral Curcumin: Biomarkers of Systemic Activity and ComplianceSharma, Ricky A.; Euden, Stephanie A.; Platton, Sharon L.; Cooke, Darren N.; Shafayat, Aisha; Hewitt, Heather R.; Marczylo, Timothy H.; Morgan, Bruno; Hemingway, David; Plummer, Simon M.; Pirmohamed, Munir; Gescher, Andreas J.; Steward, William P.Clinical Cancer Research (2004), 10 (20), 6847-6854CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)Curcumin, a polyphenolic antioxidant derived from a dietary spice, exhibits anticancer activity in rodents and in humans. Its efficacy appears to be related to induction of glutathione S-transferase enzymes, inhibition of prostaglandin E2 (PGE2) prodn., or suppression of oxidative DNA adduct (M1G) formation. We designed a dose-escalation study to explore the pharmacol. of curcumin in humans. Fifteen patients with advanced colorectal cancer refractory to std. chemotherapies consumed capsules compatible with curcumin doses between 0.45 and 3.6 g daily for up to 4 mo. Levels of curcumin and its metabolites in plasma, urine, and feces were analyzed by high-pressure liq. chromatog. and mass spectrometry. Three biomarkers of the potential activity of curcumin were translated from preclin. models and measured in patient blood leukocytes: glutathione S-transferase activity, levels of M1G, and PGE2 prodn. induced ex vivo. Dose-limiting toxicity was not obsd. Curcumin and its glucuronide and sulfate metabolites were detected in plasma in the 10 nmol/L range and in urine. A daily dose of 3.6 g curcumin engendered 62% and 57% decreases in inducible PGE2 prodn. in blood samples taken 1 h after dose on days 1 and 29, resp., of treatment compared with levels obsd. immediately predose (P < 0.05). A daily oral dose of 3.6 g of curcumin is advocated for Phase II evaluation in the prevention or treatment of cancers outside the gastrointestinal tract. PGE2 prodn. in blood and target tissue may indicate biol. activity. Levels of curcumin and its metabolites in the urine can be used to assess general compliance.
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148Dhillon, N.; Aggarwal, B. B.; Newman, R. A.; Wolff, R. A.; Kunnumakkara, A. B.; Abbruzzese, J. L.; Ng, C. S.; Badmaev, V.; Kurzrock, R. Phase II trial of curcumin in patients with advanced pancreatic cancer Clin. Cancer Res. 2008, 14, 4491– 4499 DOI: 10.1158/1078-0432.CCR-08-0024148https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXosFGitLw%253D&md5=9e2760727409ab572fb37a21fc2f619fPhase II Trial of Curcumin in Patients with Advanced Pancreatic CancerDhillon, Navneet; Aggarwal, Bharat B.; Newman, Robert A.; Wolff, Robert A.; Kunnumakkara, Ajaikumar B.; Abbruzzese, James L.; Ng, Chaan S.; Badmaev, Vladimir; Kurzrock, RazelleClinical Cancer Research (2008), 14 (14), 4491-4499CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)Pancreatic cancer is almost always lethal, and the only U.S. Food and Drug Administration-approved therapies for it, gemcitabine and erlotinib, produce objective responses in <10% of patients. We evaluated the clin. biol. effects of curcumin (diferuloylmethane), a plant-derived dietary ingredient with potent nuclear factor-κB (NF-κB) and tumor inhibitory properties, against advanced pancreatic cancer. Patients received 8 g curcumin by mouth daily until disease progression, with restaging every 2 mo. Serum cytokine levels for interleukin (IL)-6, IL-8, IL-10, and IL-1 receptor antagonists and peripheral blood mononuclear cell expression of NF-κB and cyclooxygenase-2 were monitored. Twenty-five patients were enrolled, with 21 evaluable for response. Circulating curcumin was detectable as drug in glucuronide and sulfate conjugate forms, albeit at low steady-state levels, suggesting poor oral bioavailability. Two patients showed clin. biol. activity. One had ongoing stable disease for >18 mo; interestingly, one addnl. patient had a brief, but marked, tumor regression (73%) accompanied by significant increases (4- to 35-fold) in serum cytokine levels (IL-6, IL-8, IL-10, and IL-1 receptor antagonists). No toxicities were obsd. Curcumin down-regulated expression of NF-κB, cyclooxygenase-2, and phosphorylated signal transducer and activator of transcription 3 in peripheral blood mononuclear cells from patients (most of whom had baseline levels considerably higher than those found in healthy volunteers). Whereas there was considerable interpatient variation in plasma curcumin levels, drug levels peaked at 22 to 41 ng/mL and remained relatively const. over the first 4 wk. Oral curcumin is well tolerated and, despite its limited absorption, has biol. activity in some patients with pancreatic cancer.
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149Asher, G. N.; Spelman, K. Clinical utility of curcumin extract Altern. Ther. Health Med. 2013, 19, 20– 22149https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3srmtFynsg%253D%253D&md5=6d8271d065a5272093b7d7f50850ae81Clinical utility of curcumin extractAsher Gary N; Spelman KevinAlternative therapies in health and medicine (2013), 19 (2), 20-2 ISSN:1078-6791.Turmeric root has been used medicinally in China and India for thousands of years. The active components are thought to be the curcuminoids, primarily curcumin, which is commonly available worldwide as a standardized extract. This article reviews the pharmacology of curcuminoids, their use and efficacy, potential adverse effects, and dosage and standardization. Preclinical studies point to mechanisms of action that are predominantly anti-inflammatory and antineoplastic, while early human clinical trials suggest beneficial effects for dyspepsia, peptic ulcer, inflammatory bowel disease, rheumatoid arthritis, osteoarthritis, uveitis, orbital pseudotumor, and pancreatic cancer. Curcumin is well-tolerated; the most common side effects are nausea and diarrhea. Theoretical interactions exist due to purported effects on metabolic enzymes and transport proteins, but clinical reports do not support any meaningful interactions. Nonetheless, caution, especially with chemotherapy agents, is advised. Late-phase clinical trials are still needed to confirm most beneficial effects.
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150Gupta, S. C.; Patchva, S.; Aggarwal, B. B. Therapeutic roles of curcumin: Lessons learned from clinical trials AAPS J. 2013, 15, 195– 218 DOI: 10.1208/s12248-012-9432-8150https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXktFWmsA%253D%253D&md5=c4da4ca00682052f5a273b89c0a7404aTherapeutic Roles of Curcumin: Lessons Learned from Clinical TrialsGupta, Subash C.; Patchva, Sridevi; Aggarwal, Bharat B.AAPS Journal (2013), 15 (1), 195-218CODEN: AJAOB6; ISSN:1550-7416. (Springer)A review. Extensive research over the past half century has shown that curcumin (diferuloylmethane), a component of the golden spice turmeric (Curcuma longa), can modulate multiple cell signaling pathways. Extensive clin. trials over the past quarter century have addressed the pharmacokinetics, safety, and efficacy of this nutraceutical against numerous diseases in humans. Some promising effects have been obsd. in patients with various pro-inflammatory diseases including cancer, cardiovascular disease, arthritis, uveitis, ulcerative proctitis, Crohn's disease, ulcerative colitis, irritable bowel disease, tropical pancreatitis, peptic ulcer, gastric ulcer, idiopathic orbital inflammatory pseudotumor, oral lichen planus, gastric inflammation, vitiligo, psoriasis, acute coronary syndrome, atherosclerosis, diabetes, diabetic nephropathy, diabetic microangiopathy, lupus nephritis, renal conditions, acquired immunodeficiency syndrome, β-thalassemia, biliary dyskinesia, Dejerine-Sottas disease, cholecystitis, and chronic bacterial prostatitis. Curcumin has also shown protection against hepatic conditions, chronic arsenic exposure, and alc. intoxication. Dose-escalating studies have indicated the safety of curcumin at doses as high as 12 g/day over 3 mo. Curcumin's pleiotropic activities emanate from its ability to modulate numerous signaling mols. such as pro-inflammatory cytokines, apoptotic proteins, NF-κB, cyclooxygenase-2, 5-LOX, STAT3, C-reactive protein, prostaglandin E2, prostate-specific antigen, adhesion mols., phosphorylase kinase, transforming growth factor-β, triglyceride, ET-1, creatinine, HO-1, AST, and ALT in human participants. In clin. trials, curcumin has been used either alone or in combination with other agents. Various formulations of curcumin, including nanoparticles, liposomal encapsulation, emulsions, capsules, tablets, and powder, have been examd. In this review, we discuss in detail the various human diseases in which the effect of curcumin has been investigated.
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151Hsu, C.-H.; Cheng, A.-L. Clinical studies with curcumin Adv. Exp. Med. Biol. 2007, 595, 471– 480 DOI: 10.1007/978-0-387-46401-5_21151https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2szlslGmsg%253D%253D&md5=d4df9c648b604f1401e1c72e96e7ebedClinical studies with curcuminHsu Chih-Hung; Cheng Ann-LiiAdvances in experimental medicine and biology (2007), 595 (), 471-80 ISSN:0065-2598.Curcumin has long been expected to be a therapeutic or preventive agent for several major human diseases because of its antioxidative, anti-inflammatory, and anticancerous effects. In phase I clinical studies, curcumin with doses up to 3600-8000 mg daily for 4 months did not result in discernible toxicities except mild nausea and diarrhea. The pharmacokinetic studies of curcumin indicated in general a low bioavailability of curcumin following oral application. Nevertheless, the pharmacologically active concentration of curcumin could be achieved in colorectal tissue in patients taking curcumin orally and might also be achievable in tissues such as skin and oral mucosa, which are directly exposed to the drugs applied locally or topically. The effect of curcumin was studied in patients with rheumatoid arthritis, inflammatory eye diseases, inflammatory bowel disease, chronic pancreatitis, psoriasis, hyperlipidemia, and cancers. Although the preliminary results did support the efficacy of curcumin in these diseases, the data to date are all preliminary and not conclusive. It is imperative that well-designed clinical trials, supported by better formulations of curcumin or novel routes of administration, be conducted in the near future.
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152Oppenheimer, A. Turmeric (curcumin) in biliary diseases Lancet 1937, 229, 619– 621 DOI: 10.1016/S0140-6736(00)98193-5There is no corresponding record for this reference.
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153National Institutes of Health. "ClinicalTrials.gov." Registry and results database of clinical studies of human participants. http://clinicaltrials.gov (accessed October 6, 2016) .There is no corresponding record for this reference.
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154Hurlstone, D. P.; Karajeh, M.; Sanders, D. S.; Drew, S. K.; Cross, S. S. Rectal aberrant crypt foci identified using high-magnification-chromoscopic colonoscopy: Biomarkers for flat and depressed neoplasia Am. J. Gastroenterol. 2005, 100, 1283– 1289 DOI: 10.1111/j.1572-0241.2005.40891.x154https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2M3osVOrsw%253D%253D&md5=6734217544f4bb9e1067c1b7f6595346Rectal aberrant crypt foci identified using high-magnification-chromoscopic colonoscopy: biomarkers for flat and depressed neoplasiaHurlstone David P; Karajeh Mohammed; Sanders David S; Drew Sister K; Cross Simon SThe American journal of gastroenterology (2005), 100 (6), 1283-9 ISSN:0002-9270.BACKGROUND: Aberrant crypt foci may represent preneoplastic lesions in the human colon. The prevalence of aberrant crypt foci detected using magnification chromoscopic colonoscopy is known to follow a stepwise progression from normal subjects to those with exophytic adenomas and colon cancer. No studies have addressed the prevalence of rectal aberrant crypt foci in patients with flat and depressed colonic lesions that cluster within the right hemi-colon and may undergo de novo neoplastic transformation. METHODS: All patients underwent total colonoscopy by a single endoscopist using the Olympus CF240Z magnifying colonoscope. Flat and depressed lesions were diagnosed using targeted indigo carmine chromoscopy. Prior to extubation, pan high-magnification-chromoscopy using indigo carmine was applied to the rectum and the distal 10 cm of mucosa examined using forward and retroflexed views. Aberrant crypt foci were defined as two or more crypts with dilated or slit-like openings that were raised above the adjacent mucosa. Using high-magnification chromoscopic colonoscopy we assessed the prevalence and dysplastic features of aberrant crypt foci in three groups: endoscopically "normal" subjects, patients with flat/depressed adenoma, and flat/depressed cancer. RESULTS: Two thousand five hundred and fifty-nine patients underwent colonoscopy of which 1,000 were eligible for inclusion. The median number of aberrant crypt foci per patient in the endoscopically normal, adenoma, and cancer group was 1 (range: 0-5), 9 (range: 0-22), and 38 (range: 14-64), respectively. The estimated relative risk of dysplastic aberrant crypt foci when comparing the flat adenoma group with the endoscopically "normal" group was 4.68 (95% CI: 2.23-9.91) with the relative risk for flat cancer versus endoscopically normal group being 21.8 (95% CI: 10.9-23.8). Patients with >5 flat adenomas had higher crypt foci densities than those with <5 adenomas (r=0.53; p<0.001). CONCLUSIONS: The number of aberrant crypt foci in normal patients, patients with flat adenoma, and flat cancer follow a stepwise incremental change as previously observed for exophytic adenomas and cancer. Detection of aberrant crypt foci in the rectum may be a useful biomarker for proximal colonic flat neoplasia and could be used at index flexible sigmoidoscopic screening to stratify risk of proximal colonic neoplasia. Patients with dysplastic aberrant crypt foci of high density should receive total colonoscopy.
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155Mattson, M. P.; Cheng, A. Neurohormetic phytochemicals: Low-dose toxins that induce adaptive neuronal stress responses Trends Neurosci. 2006, 29, 632– 639 DOI: 10.1016/j.tins.2006.09.001There is no corresponding record for this reference.
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156Brondino, N.; Re, S.; Boldrini, A.; Cuccomarino, A.; Lanati, N.; Barale, F.; Politi, P. Curcumin as a therapeutic agent in dementia: A mini systematic review of human studies Sci. World J. 2014, 2014, 174282 DOI: 10.1155/2014/174282There is no corresponding record for this reference.
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157Chandra, V.; Pandav, R.; Dodge, H. H.; Johnston, J. M.; Belle, S. H.; DeKosky, S. T.; Ganguli, M. Incidence of Alzheimer’s disease in a rural community in India: The Indo-US study Neurology 2001, 57, 985– 989 DOI: 10.1212/WNL.57.6.985157https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3MrisVemsQ%253D%253D&md5=42734f49b011dc09f7c1c6c5ca9e690dIncidence of Alzheimer's disease in a rural community in India: the Indo-US studyChandra V; Pandav R; Dodge H H; Johnston J M; Belle S H; DeKosky S T; Ganguli MNeurology (2001), 57 (6), 985-9 ISSN:0028-3878.OBJECTIVE: To determine overall and age-specific incidence rates of AD in a rural, population-based cohort in Ballabgarh, India, and to compare them with those of a reference US population in the Monongahela Valley of Pennsylvania. METHODS: A 2-year, prospective, epidemiologic study of subjects aged > or =55 years utilizing repeated cognitive and functional ability screening, followed by standardized clinical evaluation using the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, and the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria for the diagnosis, and the Clinical Dementia Rating scale for the staging, of dementia and AD. RESULTS: Incidence rates per 1000 person-years for AD with CDR > or =0.5 were 3.24 (95% CI: 1.48-6.14) for those aged > or =65 years and 1.74 (95% CI: 0.84-3.20) for those aged > or =55 years. Standardized against the age distribution of the 1990 US Census, the overall incidence rate in those aged > or =65 years was 4.7 per 1000 person-years, substantially lower than the corresponding rate of 17.5 per 1000 person-years in the Monongahela Valley. CONCLUSION: These are the first AD incidence rates to be reported from the Indian subcontinent, and they appear to be among the lowest ever reported. However, the relatively short duration of follow-up, cultural factors, and other potential confounders suggest caution in interpreting this finding.
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158Ng, T.-P.; Chiam, P.-C.; Lee, T.; Chua, H.-C.; Lim, L.; Kua, E.-H. Curry consumption and cognitive function in the elderly Am. J. Epidemiol. 2006, 164, 898– 906 DOI: 10.1093/aje/kwj267158https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD28nhvVKqsw%253D%253D&md5=bfca5b72527ef9b1d78a3bb8da672c1bCurry consumption and cognitive function in the elderlyNg Tze-Pin; Chiam Peak-Chiang; Lee Theresa; Chua Hong-Choon; Lim Leslie; Kua Ee-HeokAmerican journal of epidemiology (2006), 164 (9), 898-906 ISSN:0002-9262.Curcumin, from the curry spice turmeric, has been shown to possess potent antioxidant and antiinflammatory properties and to reduce beta-amyloid and plaque burden in experimental studies, but epidemiologic evidence is lacking. The authors investigated the association between usual curry consumption level and cognitive function in elderly Asians. In a population-based cohort (n = 1,010) of nondemented elderly Asian subjects aged 60-93 years in 2003, the authors compared Mini-Mental State Examination (MMSE) scores for three categories of regular curry consumption, taking into account known sociodemographic, health, and behavioral correlates of MMSE performance. Those who consumed curry "occasionally" and "often or very often" had significantly better MMSE scores than did subjects who "never or rarely" consumed curry. The authors reported tentative evidence of better cognitive performance from curry consumption in nondemented elderly Asians, which should be confirmed in future studies.
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159Li, S.; Yuan, W.; Deng, G.; Wang, P.; Yang, P.; Aggarwal, B. B. Chemical composition and product quality control of turmeric (Curcuma longa l.) Pharm. Crops 2011, 2, 28– 54 DOI: 10.2174/2210290601102010028159https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXht1GjtbfO&md5=c80633c79db31449ddb1511f394084faChemical composition and product quality control of turmeric (Curcuma longa L.)Li, Shiyou; Yuan, Wei; Deng, Guangrui; Wang, Ping; Yang, Peiying; Aggarwal, Bharat B.Pharmaceutical Crops (2011), 2 (), 28-54CODEN: PCHRBU; ISSN:2210-2906. (Bentham Science Publishers Ltd.)A review. Chem. constituents of various tissues of turmeric (Curcuma longa L.) have been extensively investigated. To date, at least 235 compds., primarily phenolic compds. and terpenoids have been identified from the species, including 22 diarylheptanoids and diarylpentanoids, eight phenylpropene and other phenolic compds., 68 monoterpenes, 109 sesquiterpenes, five diterpenes, three triterpenoids, four sterols, two alkaloids, and 14 other compds. Curcuminoids (diarylheptanoids) and essential oils are major bioactive ingredients showing various bioactivities in in vitro and in vivo bioassays. Curcuminoids in turmeric are primarily accumulated in rhizomes. The essential oils from leaves and flowers are usually dominated by monoterpenes while those from roots and rhizomes primarily contained sesquiterpenes. The contents of curcuminoids in turmeric rhizomes vary often with varieties, locations, sources, and cultivation conditions, while there are significant variations in compn. of essential oils of turmeric rhizomes with varieties and geog. locations. Further, both curcuminoids and essential oils vary in contents with different extn. methods and are unstable with extn. and storage processes. As a result, the quality of com. turmeric products can be markedly varied. While curcumin (1), demethoxycurcumin (2), and bisdemethoxycurcumin (5) have been used as marker compds. for the quality control of rhizomes, powders, and ext. ("curcumin") products, Ar-turmerone (99), α-turmerone (100), and β-turmerone (101) may be used to control the product quality of turmeric oil and oleoresin products. Authentication of turmeric products can be achieved by chromatog. and NMR techniques, DNA markers, with morphol. and anat. data as well as GAP and other information available.
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160Clark, C. M.; Sheppard, L.; Fillinbaum, G. G.; Galasko, D.; Morris, J. C.; Koss, E.; Mohs, R.; Heyman, A. Variability in annual mini-mental state examination score in patients with probable Alzheimer’s disease Arch. Neurol. (Chicago) 1999, 56, 857– 862 DOI: 10.1001/archneur.56.7.857There is no corresponding record for this reference.
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161Dahlin, J. L.; Walters, M. A. The essential roles of chemistry in high-throughput screening triage Future Med. Chem. 2014, 6, 1265– 1290 DOI: 10.4155/fmc.14.60161https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsVeisbjF&md5=4ca8e43d7a85a1f67be930d40bfefad4The essential roles of chemistry in high-throughput screening triageDahlin, Jayme L.; Walters, Michael A.Future Medicinal Chemistry (2014), 6 (11), 1265-1290CODEN: FMCUA7; ISSN:1756-8919. (Future Science Ltd.)It is increasingly clear that academic high-throughput screening (HTS) and virtual HTS triage suffers from a lack of scientists trained in the art and science of early drug discovery chem. Many recent publications report the discovery of compds. by screening that are most likely artifacts or promiscuous bioactive compds., and these results are not placed into the context of previous studies. For HTS to be most successful, it is our contention that there must exist an early partnership between biologists and medicinal chemists. Their combined skill sets are necessary to design robust assays and efficient workflows that will weed out assay artifacts, false positives, promiscuous bioactive compds. and intractable screening hits, efforts that ultimately give projects a better chance at identifying truly useful chem. matter. Expertise in medicinal chem., chemoinformatics and purifn. sciences (anal. chem.) can enhance the post-HTS triage process by quickly removing these problematic chemotypes from consideration, while simultaneously prioritizing the more promising chem. matter for follow-up testing. It is only when biologists and chemists collaborate effectively that HTS can manifest its full promise.
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162Atanasov, A. G.; Waltenberger, B.; Pferschy-Wenzig, E. M.; Linder, T.; Wawrosch, C.; Uhrin, P.; Temml, V.; Wang, L.; Schwaiger, S.; Heiss, E. H.; Rollinger, J. M.; Schuster, D.; Breuss, J. M.; Bochkov, V.; Mihovilovic, M. D.; Kopp, B.; Bauer, R.; Dirsch, V. M.; Stuppner, H. Discovery and resupply of pharmacologically active plant-derived natural products: A review Biotechnol. Adv. 2015, 33, 1582– 1614 DOI: 10.1016/j.biotechadv.2015.08.001162https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhvFGjsbjJ&md5=e1f2296576f1f80b984d99adbf83a20dDiscovery and resupply of pharmacologically active plant-derived natural products: A reviewAtanasov, Atanas G.; Waltenberger, Birgit; Pferschy-Wenzig, Eva-Maria; Linder, Thomas; Wawrosch, Christoph; Uhrin, Pavel; Temml, Veronika; Wang, Limei; Schwaiger, Stefan; Heiss, Elke H.; Rollinger, Judith M.; Schuster, Daniela; Breuss, Johannes M.; Bochkov, Valery; Mihovilovic, Marko D.; Kopp, Brigitte; Bauer, Rudolf; Dirsch, Verena M.; Stuppner, HermannBiotechnology Advances (2015), 33 (8), 1582-1614CODEN: BIADDD; ISSN:0734-9750. (Elsevier)A review. Medicinal plants have historically proven their value as a source of mols. with therapeutic potential, and nowadays still represent an important pool for the identification of novel drug leads. In the past decades, pharmaceutical industry focused mainly on libraries of synthetic compds. as drug discovery source. They are comparably easy to produce and resupply, and demonstrate good compatibility with established high throughput screening (HTS) platforms. However, at the same time there has been a declining trend in the no. of new drugs reaching the market, raising renewed scientific interest in drug discovery from natural sources, despite of its known challenges. In this survey, a brief outline of historical development is provided together with a comprehensive overview of used approaches and recent developments relevant to plant-derived natural product drug discovery. Assocd. challenges and major strengths of natural product-based drug discovery are critically discussed. A snapshot of the advanced plant-derived natural products that are currently in actively recruiting clin. trials is also presented. Importantly, the transition of a natural compd. from a "screening hit" through a "drug lead" to a "marketed drug" is assocd. with increasingly challenging demands for compd. amt., which often cannot be met by re-isolation from the resp. plant sources. In this regard, existing alternatives for resupply are also discussed, including different biotechnol. approaches and total org. synthesis. While the intrinsic complexity of natural product-based drug discovery necessitates highly integrated interdisciplinary approaches, the reviewed scientific developments, recent technol. advances, and research trends clearly indicate that natural products will be among the most important sources of new drugs also in the future.
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163Wagner, H. Synergy research: Approaching a new generation of phytopharmaceuticals Fitoterapia 2011, 82, 34– 37 DOI: 10.1016/j.fitote.2010.11.016There is no corresponding record for this reference.
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164Gertsch, J. The metabolic plant feedback hypothesis: How plant secondary metabolites nonspecifically impact human health Planta Med. 2016, 82, 920– 929 DOI: 10.1055/s-0042-108340164https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XpslyltLo%253D&md5=2df35d563676ad519af5828c5a0f3dbcThe Metabolic Plant Feedback Hypothesis: How Plant Secondary Metabolites Nonspecifically Impact Human Health*Gertsch, JurgPlanta Medica (2016), 82 (11/12), 920-929CODEN: PLMEAA; ISSN:0032-0943. (Georg Thieme Verlag)A review. Humans can ingest gram amts. of plant secondary metabolites daily through diet. Many of these phytochems. are bioactive beyond our current understanding because they act through weak neg. biol. feedback mechanisms, undetectable in vitro. Homeostatic-type assessments shed light on the evolutionary implications of the human diet from plants, giving rise to the metabolic plant feedback hypothesis. The hypothesis states that ancient diets rich in carbohydrates coincide with bulk dietary phytochems. that act as nonspecific inhibitors of metabolic and inflammatory processes. Consequently, food-derived phytochems. are likely to be equally effective as herbal medicines for these indications. In addn. to the ubiquitous flavonoids, terpenoids, and fatty acids in the diet, the likely impact of chronic chlorophyll ingestion on human health is discussed, and data on its modulation of blood glucose levels are presented. A major deduction of this hypothesis is that starchy diets lacking plant secondary metabolites are assocd. with multimorbidity (lifestyle diseases) including obesity, type 2 diabetes, and cardiovascular disease. It is proposed that the intake of leafy vegetables, spices, and herbal remedies rich in phytochems. matches the transition and genetic adaptation to early agriculture, playing a compensatory role in the mismatch of old genes and new diets.
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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.6b00975.
Supplemental Tables 1, 2, and 3 of assays, half-lives, and activities, along with a discussion of covalent protein modification by 1 (PDF)
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