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Potential Antiosteoporotic Natural Product Lead Compounds That Inhibit 17β-Hydroxysteroid Dehydrogenase Type 2

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† Division of Molecular & Systems Toxicology, University of Basel, Klingelbergstraße 50, 4056 Basel, Switzerland
‡ ‡Computer-Aided Molecular Design Group, Institute of Pharmacy/Pharmaceutical Chemistry and Center for Molecular Biosciences Innsbruck, and ∥Institute of Pharmacy/Pharmacognosy and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria
§ Department of Pharmacognosy, University of Vienna, Althanstraße 14, 1090 Vienna, Austria
⊥ Institute of Genetics and Animal Breeding of the Polish Academy of Sciences, Postępu 36A Street, 05-552, Jastrzebiec, Poland
Laboratory of Animal Physiology, Department of Animal Biology and Physiology, Faculty of Science, University of Yaounde I, P.O. Box 812, Yaounde, Cameroon
□ Griffith Institute for Drug Discovery, Griffith University, Brisbane, QLD 4111, Australia
*Biochemistry: A. Odermatt, Tel: +41 (0)61 267 15 30. Fax: +41 (0)61 267 15 15. E-mail: [email protected]
*Molecular modeling: D. Schuster, Tel: +43-512-507-58253. Fax: +43-512-507-58299. E-mail: [email protected]
Cite this: J. Nat. Prod. 2017, 80, 4, 965–974
Publication Date (Web):March 20, 2017
https://doi.org/10.1021/acs.jnatprod.6b00950

Copyright © 2017 The American Chemical Society and American Society of Pharmacognosy. This publication is licensed under CC-BY.

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Abstract

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17β-Hydroxysteroid dehydrogenase type 2 (17β-HSD2) converts the active steroid hormones estradiol, testosterone, and 5α-dihydrotestosterone into their weakly active forms estrone, Δ4-androstene-3,17-dione, and 5α-androstane-3,17-dione, respectively, thereby regulating cell- and tissue-specific steroid action. As reduced levels of active steroids are associated with compromised bone health and onset of osteoporosis, 17β-HSD2 is considered a target for antiosteoporotic treatment. In this study, a pharmacophore model based on 17β-HSD2 inhibitors was applied to a virtual screening of various databases containing natural products in order to discover new lead structures from nature. In total, 36 hit molecules were selected for biological evaluation. Of these compounds, 12 inhibited 17β-HSD2 with nanomolar to low micromolar IC50 values. The most potent compounds, nordihydroguaiaretic acid (1), IC50 0.38 ± 0.04 μM, (−)-dihydroguaiaretic acid (4), IC50 0.94 ± 0.02 μM, isoliquiritigenin (6), IC50 0.36 ± 0.08 μM, and ethyl vanillate (12), IC50 1.28 ± 0.26 μM, showed 8-fold or higher selectivity over 17β-HSD1. As some of the identified compounds belong to the same structural class, structure–activity relationships were derived for these molecules. Thus, this study describes new 17β-HSD2 inhibitors from nature and provides insights into the binding pocket of 17β-HSD2, offering a promising starting point for further research in this area.

17β-Hydroxysteroid dehydrogenase type 2 (17β-HSD2) belongs to a large family of short-chain dehydrogenase/reductase (SDR) enzymes with the systematic name SDR9C2. (1) It is mainly expressed in the placenta, endometrium, breast, prostate, small intestine, liver, and bone. (2-5) This NAD+-dependent enzyme converts active sex steroid hormones such as estradiol, testosterone, and 5α-dihydrotestosterone into their respective inactive forms, namely, estrone, Δ4-androstene-3,17-dione (androstenedione), and 5α-androstane-3,17-dione (androstanedione), thereby protecting tissues from excessive sex steroid hormone action (Figure 1). (6, 7) Furthermore, 17β-HSD2 catalyzes the oxidation of Δ5-androstene-3β,17β-diol (androstenediol) to dehydroepiandrosterone (DHEA). The enzyme shares considerable structural and functional similarity with other extensively studied SDR enzymes such as 17β-HSD1 and 17β-HSD3. (8) In contrast to 17β-HSD2, the enzymes 17β-HSD1, 17β-HSD3, and the aldo-keto-reductase 17β-HSD5 (also known as AKR1C3) are oxidoreductases converting the weak estrogen estrone to the potent estradiol and the weak androgens androstenedione and androstanedione to testosterone and 5α-dihydrotestosterone, respectively. (9-11) Whereas 17β-HSD3 is responsible for the last step of testosterone synthesis in the testes, 17β-HSD5 is responsible for the production of extratesticular testosterone and plays a crucial role in androgen maintenance in the elderly. (9, 10)

Figure 1

Figure 1. Enzymatic reactions catalyzed by 17β-HSD2 and reverse reactions catalyzed by other HSD enzymes.

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Owing to its favorable localization and its role as a main contributor to the inactivation of estradiol, testosterone, and 5α-dihydrotestosterone in bone cells, (2) 17β-HSD2 has been proposed as a promising target for the treatment of osteoporosis. (12) This condition, where decreased bone density leads to an increased fracture risk, is in the majority of cases linked with the age-related decrease of sex steroid hormones. (13) The age-related onset of osteoporosis in postmenopausal women (14) and men with low testosterone levels (15) can be explained, at least in part, by a decline in the concentrations of estradiol and testosterone, which inhibit bone degradation. (16) Thus, by inhibiting 17β-HSD2, the amount of active steroids can be locally increased in the bones, thereby improving bone health. This hypothesis is supported by an in vivo study, where a 17β-HSD2 inhibitor was administered to ovariectomized cynomolgus monkeys. (17) In this study, the 17β-HSD2 inhibitor was shown to improve bone strength by increasing bone formation and decreasing bone resorption, although the effects were rather weak and only observed at the highest dose of 25 mg/kg/day.
Although multiple synthetic 17β-HSD2 inhibitors have already been reported, (18-21) natural products inhibiting this enzyme are currently underexplored. There are only a few reports on natural product inhibitors of 17β-HSD2 and other steroid-metabolizing enzymes, and the majority of these compounds are flavonoids. (22-24) Flavonoids share certain functional similarities with steroids and can be considered as steroid mimetics (Figure S1, Supporting Information). However, most of these compounds are not selective. They also inhibit other members of the SDR enzyme family, and, additionally, they frequently show activity toward estrogen and androgen receptors. Nevertheless, natural compounds play an important role in providing new structures as potential lead candidates in drug discovery, and hence they are of high general interest. (25, 26) Remarkably, from 1999 to 2008, 28% of all new FDA-approved, first-in-class small-molecule drugs were natural products or compounds derived thereof. (27)
Despite the fact that osteoporosis is not well represented among the conditions treated with plants and phytotherapy, (28) there are many other conditions related to bone homeostasis and fractures that are reported in the literature on ethnopharmacology. Interestingly, an ethnopharmacological study has been reported that shows that plants such as Pholidota articulate Lindl. and Coelogyne cristata Lindl. (both of the Orchidaceae family) contain several flavonoids that are used to treat bone fractures in India. (29) Even though part of the observed effects of these compounds may be due to direct modulation of estrogen and androgen receptor activities, the mechanism of action of these compounds in the treatment of bone-related conditions is largely unknown. Accordingly, 17β-HSD2 inhibition might well contribute to the effects of these herbal remedies.
As natural compounds represent a rich source of potential lead structures, novel 17β-HSD2 inhibitors of natural origin were searched using in silico methods. Previously, a procedure to discover new synthetic chemicals that inhibit 17β-HSD2 was established. (19) In this previous study, pharmacophore models representing the chemical functionalities and steric requirements essential for the activity of small molecules toward 17β-HSD2 were constructed and employed for virtual screening of a commercial synthetic chemical database. From this previous experimental validation, the two pharmacophore models 1 and 2 (Figure 2) showed good predictive power, with positive hit rates of 50% and 10%, respectively. Although the models are very similar in feature types and distribution, they differ slightly in feature location, which is why they may lead to somewhat different virtual hits. Thus, both of these models were selected for virtual screening of selected natural product databases.

Figure 2

Figure 2. Pharmacophore models for 17β-HSD2 inhibitors. (A) Chemical features of models 1 and 2 describing the types, locations, and tolerance spheres of inhibitory chemical functionalities. Pharmacophore features are colored as follows: red, hydrogen-bond acceptor; green, hydrogen-bond donor; yellow, hydrophobic; and blue, aromatic ring. Optional features are depicted in scattered style. (B) Full versions of models 1 and 2 with gray exclusion volumes as steric restraints for inhibitor size (forbidden areas). A 3D video view of model 1 is available as Supporting Information.

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Results and Discussion

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In-house natural product databases based on input from several academic institutions (total of 439 entries) and the Sigma-Aldrich catalogue (Sigma-Aldrich, St. Louis, MO, USA), containing natural products and synthetic compounds, were screened virtually using the two pharmacophore models. The virtual screening procedure and its results are described in detail in the Supporting Information (text and Table S1). As the full models were quite restrictive, most databases were also screened in models where one omitted feature (omf) was applied during the pharmacophore mapping.
The 36 selected virtual hits were evaluated in an in vitro assay using lysates of cells expressing the recombinant human enzyme 17β-HSD2. Initially, all compounds were tested at a final concentration of 20 μM. Compounds showing more than 50% inhibition at that concentration are shown in Tables 1 and 2 as well as Figures 3 and 4. For all compounds inhibiting 17β-HSD2 activity by at least 70% (remaining activity ≤30% of vehicle control), IC50 values were determined. The complete list of the compounds tested is provided in Table S2, Supporting Information.
Table 1. Active Hit Compounds of Natural Origin, Databases, Mapping Pharmacophore Models, and Activities against 17β-HSD2
compound database pharmacophore models remaining activity at 20 μM (% of control) or IC50
nordihydroguaiaretic acid (1) Atanasov models 1 and 2 0.38 ± 0.04 μM
oleanolic acid (2) Atanosov model 1 omfa 49 ± 6%
curcumin (3) Atanosov models 1 and 2 omf 1.73 ± 0.2 μM
(−)-dihydroguaiaretic acid (4) Davis models 1 and 2 0.94 ± 0.02 μM
jaceosidin (5) Davis models 1 and 2 omf 9.3 ± 2.3 μM
isoliquiritigenin (6) Davis models 1 and 2 0.36 ± 0.08 μM
pinoresinol (7) Waltenberger models 1 and 2 42 ± 5%
lupinalbin A (8) Krenn model 2 omf 1.52 ± 0.15 μM
2′-hydroxygenistein (9) Krenn model 2 omf 2.03 ± 0.37 μM
butein (10) Sigma model 1 7.3 ± 2.7 μM
rosmarinic acid (11) Sigma model 1 3.72 ± 0.17 μM
ethyl vanillate (12) Sigma model 1 1.28 ± 0.26 μM
a

omf, screening by allowing one omitted feature.

Figure 3

Figure 3. Structures of natural products identified in this study that inhibit 17β-HSD2.

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Table 2. Active Semisynthetic Fungal Natural Products, Origin, Mapping Pharmacophore Models, and Activities against 17β-HSD2
compound database pharmacophore models remaining activity at 20 μM (% of control) or IC50
2-(3-chloro-4-hydroxyphenyl)-N-phenethylacetamide (13) Davis model 1 1.57 ± 0.16 μM
2-(3-chloro-4-hydroxyphenyl)-N-(2-methoxyethyl)acetamide (14) Davis model 1 omfa 37 ± 3%
N-butyl-2-(3-chloro-4-hydroxyphenyl)acetamide (15) Davis model 1 33 ± 6%
N-benzyl-2-(3-chloro-4-hydroxyphenyl)acetamide (16) Davis model 1 3.42 ± 0.74 μM
N-(2-(1H-indol-3-yl)ethyl)-2-(3-chloro-4-hydroxyphenyl)acetamide (17) Davis model 1 0.98 ± 0.24 μM
2-(3-chloro-4-hydroxyphenyl)-N-(2-chlorobenzyl)acetamide (18) Davis model 1 0.78 ± 0.16 μM
a

omf, screening by allowing one omitted feature.

Figure 4

Figure 4. Semisynthetic fungal natural products that inhibit 17β-HSD2.

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From the selected 36 tested compounds, 12 were active with IC50 values of <5 μM, six were moderately active showing at least 50% inhibition at a compound concentration of 20 μM, and the remaining compounds were considered inactive. Altogether, this corresponds to a 50% hit rate, indicating that the pharmacophore models performed explicitly well, not only for synthetic molecules but also for natural compounds. This is an important aspect, because natural products often differ from synthetic drug-like structures. From the 33 in-house database-derived test compounds, 10 fit into model 1 and four into model 2, respectively, without omitted features during the screening (Tables 1 and 2). Remarkably, all these hits were active in vitro. Additionally, the strategy of allowing one pharmacophore feature to be left out during the natural product database screening proved successful: The hits obtained by allowing one omitted feature additionally included the active compounds oleanolic acid (2), curcumin (3), jaceosidin (5), lupinalbin A (8), 2′-hydroxygenistein (9), and the semisynthetic derivative 2-(3-chloro-4-hydroxyphenyl)-N-(2-methoxyethyl)acetamide (14). Although, admittedly, all inactive compounds from this study have also been identified in the screenings with one omitted feature, these additional active hits encourage this screening mode, when a wider range of chemically diverse 17β-HSD2 inhibitors is sought and a higher number of false positive virtual hits is acceptable.
For a possible therapeutic use of a 17β-HSD2 inhibitor, a compound must be selective over 17β-HSD1, which catalyzes the reverse reaction. Therefore, the most active newly identified 17β-HSD2 inhibitors were screened at a final concentration of 20 μM in vitro using lysates of cells expressing the recombinant human 17β-HSD1 enzyme. For all compounds inhibiting 17β-HSD1 by 70% or more, IC50 values and corresponding selectivity factors were determined. The results are shown in Table 3. Follow-up experiments should include additional SDR enzymes such as 11β-HSDs, 3α/β-HSDs, and retinol dehydrogenases as well as a careful assessment of the cytotoxic potential of the identified compounds.
Table 3. Selectivity of the Most Active 17β-HSD2 Inhibitors toward 17β-HSD1
compound 17β-HSD2 activity (IC50) 17β-HSD1 activity (IC50 or remaining activity at 20 μM) selectivity factor
nordihydroguaiaretic acid (1) 0.38 ± 0.04 μM 5.5 ± 1.3 μM 15
curcumin (3) 1.73 ± 0.20 μM 52.2 ± 7.1% ∼12
(−)-dihydroguaiaretic acid (4) 0.94 ± 0.02 μM 7.7 ± 2.2 μM 8
isoliquiritigenin (6) 0.36 ± 0.08 μM 2.83 ± 0.80 μM 8
lupinalbin A (8) 1.52 ± 0.15 μM 0.049 ± 0.019 μM 0.03
2′-hydroxygenistein (9) 2.03 ± 0.37 μM 1.09 ± 0.06 μM 0.5
rosmarinic acid (11) 3.72 ± 0.17 μM n.i.a >5
ethyl vanillate (12) 1.28 ± 0.26 μM n.i. >15
2-(3-chloro-4-hydroxyphenyl)-N-phenethylacetamide (13) 1.57 ± 0.16 μM n.i. >12
N-benzyl-2-(3-chloro-4-hydroxyphenyl)acetamide (16) 3.42 ± 0.74 μM n.i. >5
N-(2-(1H-indol-3-yl)ethyl)-2-(3-chloro-4-hydroxyphenyl)acetamide (17) 0.98 ± 0.24 μM n.i. >20
2-(3-chloro-4-hydroxyphenyl)-N-(2-chlorobenzyl)acetamide (18) 0.78 ± 0.16 μM 54.8 ± 5.8% ∼25
a

n.i., no inhibition.

Most of the active hits found in this study belong to compound classes associated with steroidogenic activities. This includes the triterpene oleanolic acid (2), which belongs to a compound class containing several 11β-HSD inhibitors. (30-33) Compounds 5, 8, and 9 are flavonoids, a class known to have estrogenic activity. Nordihydroguaiaretic acid (1) is a lignan found at high concentrations in the leaves of Larrea tridentata (Sessé & Moc. ex DC.) Coville, a common shrub in the United States and in Mexico. (34) The leaves have been used in the preparation of a tea for the treatment of cancer, arthritis, and tuberculosis. Compound 1 is an antioxidant that also inhibits lipoxygenase, thus influencing the leukotriene cascade and suppressing ovulation in rats. (35) Thereby, it may pose a potential risk for reproductive toxicity if ingested in large amounts. Compound 1 was proposed to be converted into a phytoestrogen by gut flora. (36) In addition, it was shown to have estrogenic effects, being an ERα-agonist, with a tendency to be selective over ERβ. (37) Additionally, compound 1 was shown to inhibit the formation of β-amyloid fibrils in the central nervous system and the accumulation of β-peptides. These properties suggest that 1 is an interesting compound for the development of potential anti-Alzheimer disease (AD) pharmaceuticals. (38) Similar anti-amyloidogenic effects were also reported in studies with mice for 1, 3, and 11, supporting the potential preventive properties of these natural compounds against AD. (39)
Curcumin (3) is a tautomeric diarylheptanoid compound that is found in the roots of Curcuma longa L. and has a great variety of potential therapeutic activities. (40, 41) It is one of the main ingredients of curry spice mixtures and is responsible for the yellow color. (42) Many papers have been published in the past few decades describing anti-inflammatory, (43) anticancer, (44, 45) and antioxidant properties of 3. (40) In Asian medicine, 3 was used for topical or oral application to treat a variety of diseases for thousands of years. Despite the low bioavailability and rapid hepatic metabolism, 3 was shown to be therapeutically active against several diseases. (46) There is debate as to whether 3 may be an invalid bioactive compound because of its PAINS properties (47-49) or may still have some potential as a lead structure candidate for certain conditions. (50) According to the experiments and observations from this study, 3 directly and specifically inhibits 17β-HSD2 and 17β-HSD1. A detailed discussion on this issue is provided in the Supporting Information (p S9). Although 3 may not be a suitable lead compound for various reasons, it still reflects the ability of the virtual screening workflow to detect structurally diverse 17β-HSD2 inhibitors.
Dihydroguaiaretic acid (4) is another lignan that is present in various plant extracts, such as those derived from the bark of Machilus thunbergii (51) Siebold & Zucc. and the seeds of Myristica fragrans Houtt. (52) These plants are found predominantly in tropical and subtropical Asian countries. Compound 4 was reported to possess antibacterial, (53) antioxidative, (54) and potential anticancer properties. (55) Little is known about the potential interference of 4 with estrogen-metabolizing hormones. In 2001, Filleur et al. reported that 4 showed no effects on 17β-HSD activity in placenta microsomes. (56) This is in contrast with the potent inhibition (IC50, 940 ± 20 nM) of 17β-HSD2 by 4 found in the present study. The reason for this discrepancy is unclear but may be due to experimental differences, as in the present study recombinant human enzyme was used. In contrast, in the study by Filleur et al. placenta microsomes that also express other steroid-metabolizing enzymes were applied.
Isoliquiritigenin (6) is a hydroxylated chalcone found in Glycyrrhiza uralensis Fisch. ex. DC. (57) and other various plant preparations. Many pharmacological effects of 6 have been described in the literature such as antitumor, antioxidative, and antibacterial properties. (58) Using a recombinant protein, it was reported that 6 inhibits aromatase activity with an IC50 value of 3.8 μM. (59) This would lower the amount of estrogens produced from androgens, which may aggravate osteoporosis. Nevertheless, 6 is a moderately potent inhibitor of aromatase, and efficient inhibition of 17β-HSD2 was achieved at concentrations 10 times lower. Importantly, 6 did not inhibit 17β-HSD1. Using yeast strains expressing human receptors, 6 was shown to bind to ERα (IC50 to displace estradiol of 1.87 μM) and ERβ (IC50 of 269 nM), however, with much lower affinity than estradiol. (60)
Compounds 8 and 9 are major constituents contained in a methanolic extract of the aerial parts of Eriosema laurentii De Wild, which was shown to have protective effects against femur mass loss and significantly increased calcium and inorganic phosphorus content in the femur in ovariectomized rats. (61, 62) Inhibition of 17β-HSD2 by these compounds may enhance local levels of estradiol, thereby potentiating estrogen receptor α (ERα)-mediated signaling. However, some of these effects may be explained by direct effects of the compounds on steroid receptors and/or helix–loop–helix transcription factors. In yeast systems expressing the human ERα and the human aryl hydrocarbon receptor, 8 showed agonistic effects with EC50 values of 21.4 nM and 1.34 μM, respectively. (63) Additionally, 9 was reported to activate ERα with an EC50 value of 6.1 μM. Regarding 8 and 9, it needs to be noted that these compounds exert more potent inhibitory effects against 17β-HSD1 than 17β-HSD2. In fact, 8 potently inhibited 17β-HSD1 with an IC50 of 49 ± 19 nM and an approximately 30-fold selectivity over 17β-HSD2. This in vitro information suggests that 8 most potently activates ERα and potently inhibits estrone to estradiol conversion by 17β-HSD1 but shows weaker effects on 17β-HSD2-mediated estradiol inactivation. Depending on the tissue and cell type, ERα is expressed together with either 17β-HSD1 or 17β-HSD2, which may result in cell-specific estrogenic effects of 8.
Rosmarinic acid (11) was first isolated from an extract of Rosmarinus officinalis L. (64) This compound was studied for many years and showed antinociceptive and anti-inflammatory effects in animal studies. (65) In addition, several clinical trials showed positive effects of comfrey roots containing 11 as a topical treatment against pain. (66) Antinociceptive effects would clearly be beneficial in the treatment of osteoporosis because of increasing pain with progression of the disease. Compound 11 selectively inhibited 17β-HSD2 over 17β-HSD1, although with rather moderate activity. It therefore remains to be seen whether such concentrations can be reached in bone cells. Alternatively, paracrine effects from neighboring cells may affect estrogen availability and therefore bone metabolism.
Ethyl vanillate (12) is an antioxidative (67) compound that has been found in hedge mustard [Sisymbrium officinale (L.) Scop.] and also in Pinot noir wine. (68) Although 12 has been known for quite some time, due to its intense vanilla taste and its use as a flavoring additive, its biological properties remain poorly investigated.
Most of the newly discovered 17β-HSD2 inhibitors were already known as phytoestrogens or compounds that are converted into phytoestrogen by gut flora (e.g., pinoresinol (7) and 1). (36) The rationale why the pharmacophore model found these ER-active compounds was that the substrate (estradiol) of 17β-HSD2 is the endogenous ER agonist, and thus the binding pockets of ER and 17β-HSD2 are obviously able to accommodate similar compounds that may be considered as steroid mimetics. This was reflected by the pharmacophore model that is based on the properties of compounds binding to 17β-HSD2: the compounds that share features needed for binding to 17β-HSD2 are likely to bind to ERα and ERβ as well.
Many of the active hits share considerable structural similarity. Interestingly, the most active substance, 6, has one phenolic hydroxy group less than 10. This difference led to a drastic effect on the activity of these compounds: 6 gave an IC50 value of 0.36 ± 0.08 μM, whereas 10 was 20-fold less active, with an IC50 of 7.3 ± 2.7 μM. However, the difference in the overall lipophilicity of these compounds may also play a role in their different activities.
The semisynthetic fungal natural products (13–18 (69)) followed a clear structure–activity relationship (SAR), with the activity shown to increase when a second aromatic ring was present. The parent compound (i.e., natural product) for this semisynthetic series, 2-(3-chloro-4-hydroxyphenyl)acetamide (S11), and the related natural products 2-(3-chloro-4-hydroxyphenyl)acetic acid (S15) and 2-(4-hydroxyphenyl)acetamide (S16) (see Table S1, Supporting Information, for their chemical structures), did not inhibit 17β-HSD2, whereas compounds 2-(3-chloro-4-hydroxyphenyl)-N-(2-methoxyethyl)acetamide (14) and N-butyl-2-(3-chloro-4-hydroxyphenyl)acetamide (15) were moderately active. The most active compounds from this series were 2-(3-chloro-4-hydroxyphenyl)-N-phenethylacetamide (13) and 16–18, which all shared a similar interaction pattern (Figure 5A). However, if the acetamide fragment is extended with, for example, an N-butyl chain, the compound can form additional hydrophobic interactions with the enzyme, resulting in an increased activity (Figure 5B). In addition to the alkyl chain, the most active compounds have a second aryl ring that can form aromatic interactions with the enzyme (Figure 5C). On the basis of the activities of these compounds, it can be proposed that 17β-HSD2 has a hydrophobic ligand binding pocket and aromatic amino acid residues in the active site that may contribute to the affinities of these ligands.

Figure 5

Figure 5. Illustration of the SAR of semisynthetic natural product derivatives (Table 3). (A) The core structure with compounds S12 (gray), S15 (red), and S11 (blue) with a pharmacophore model illustrating the interaction pattern. (B) The moderately active compounds 14 (yellow) and 15 (gray) with the additional hydrophobic feature. (C) The most active compounds 13 (orange), N-benzyl-2-(3-chloro-4-hydroxyphenyl)acetamide (16, green), N-(2-(1H-indol-3-yl)ethyl)-2-(3-chloro-4-hydroxyphenyl) (17, purple), and 18 (gray) with the additional aromatic ring feature.

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Most of the tested compounds inhibited selectively 17β-HSD2 over 17β-HSD1, except for compounds 8 and 9. The semisynthetic compounds 13 and 16–18 also showed good selectivity in terms of the inhibition of 17β-HSD2. The two most potent compounds, 1 and 6, were 15 and 8 times more active toward 17β-HSD2 than 17β-HSD1. Both compounds are potential natural lead structures that could be used for the development of 17β-HSD2 drug candidates. Unlike many other related compounds that are possibly rapidly metabolized due to the presence of several hydroxy groups, 2-(3-chloro-4-hydroxyphenyl)-N-(2-chlorobenzyl)acetamide (18) has only a single hydroxy group and might therefore be less prone to rapid biotransformation. Compound 18 still potently and selectively inhibited 17β-HSD2 with an IC50 of 0.78 ± 0.16 μM.
Among the most active compounds identified during these studies were also the flavonoids 5 and 9. Schuster et al. earlier reported several flavonoids inhibiting 17β-HSD2. Taking the data together (Table 4), (24) a SAR model for the flavonoids that inhibit this enzyme could be established (Figure 6).
Table 4. Flavonoid Structures and Activities Used for Deriving a Flavonoid SAR Model of 17β-HSD2 Inhibitors

Figure 6

Figure 6. SAR of the flavonoids inhibiting 17β-HSD2. (A) The three most active compounds, 9 (2′-hydroxygenistein, blue), kaempferol (30, red), and quercetin (31, green), share a combined hydrogen bond acceptor/donor at position C-4′, a hydrophobic (aromatic) ring (ring B), two neighboring hydrogen bond acceptors on rings A and C, and the aromatic ring A. (B) The moderately active inhibitors 5 (magenta), naringenin (23, gray), genistein (32, black), and biochanin A (33, yellow) fit into the SAR-pharmacophore illustrating the importance of the hydrogen bond acceptor features on the B and C rings, respectively. (C) For comparison, the general flavonoid model not distinguishing active from inactive compounds is shown with all 17 flavonoids from Table 4.

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In general, the active flavonoids share a typical pharmacophore model containing hydrogen bond acceptors and donors and hydrophobic and aromatic features (Figure 6A). The hydrogen bond acceptor in position C-3 (scaffold A) was found to be beneficial for activity, as the most active flavonoids, 30 and 31, contain a hydroxy group at this position (Figure 6B). If this feature was absent, the activity decreased or the compound was inactive. Furthermore, the hydrogen bond acceptor unit at the C-4′-position is important and shared by all active compounds. If the hydrogen-bonding feature at this position was deleted, active and inactive compounds were no longer distinguished (Figure 6C).
To learn more about the general properties of 17β-HSD2 inhibitors, model 1 and the flavonoid model were aligned (Figure 7). Every model contains an aromatic ring feature next to a hydrogen bond donor/acceptor feature. Among the compounds mapped, this combination was often represented by a phenolic hydroxy group. Another common feature was the hydrophobic/aromatic group in a certain distance from the first feature group. Interestingly, in between these aligned hydrophobic/aromatic features, there were hydrogen bond acceptor features. These indicate that in the binding pocket there may be two hydrophobic regions that tolerate aromatic interactions, and in between these pockets, there was most likely a hydrogen-bonding partner. This feature arrangement is in line with the architecture of already crystallized 11β-HSD1 and 17β-HSD1, where inhibitors are anchored to the catalytically active amino acids by central hydrogen bonds and form further, adjacent hydrophobic contacts (e.g., the PDB structures 4c7j (70) and 3hb5 (71)).

Figure 7

Figure 7. Alignment of the 17β-HSD2 inhibitor model 1 from Vuorinen et al. (19) and the SAR model (features highlighted by grid) for highly active flavonoids. The pharmacophore features are color-coded: hydrogen bond acceptor, red; hydrogen bond donor, green; hydrophobic, yellow; aromatic ring, blue. The alignment centers are indicated with orange spheres.

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The present virtual screening approach for the identification of natural products-derived 17β-HSD2 inhibitors was productive. Thus, only 38 compounds had to be tested to yield 17 active hits with sub- and low-micromolar IC50 values. The most potent bioactive compound, 6, exhibited an IC50 value of 360 ± 80 nM. Thus, the present approach had a success rate of 47% within the virtual hit lists. The fact that so many interesting 17β-HSD2 inhibitors were obtained within this relatively small natural product collection points toward the probable presence of more potent active compounds among other natural products.
Furthermore, SAR information was derived for two compound classes, providing more detailed insight into the binding pocket of the enzyme. Only 8 and 9, which were identified by model 2 with one omitted feature, were not selective and even preferentially inhibited 17β-HSD1. Consequently, both compounds seem not to be suitable lead structures for further development as antiosteoporosis leads. All other newly discovered 17β-HSD2 inhibitors were preferentially selective over 17β-HSD1, and therefore they could serve as lead structures for further optimization. It needs to be noted that the activities of these compounds toward 17β-HSD2 are at least an order of magnitude lower than that of reported synthetic, chemically optimized compounds. (18, 20, 21) To further develop potential lead candidates, additional investigations into the bioavailability, metabolism, and tissue distribution of the identified natural compounds are needed. Inhibition of 17β-HSD2 is expected to result in tissue-specific elevated levels of estradiol, and potential adverse effects include endometrial hyperplasia and impaired growth control of the glandular epithelium of the breast. (72-74) Thus, compounds that are primarily active in the bone would be preferred for future drug development.

Experimental Section

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Databases

The Davis Compound Library (Griffith Institute for Drug Discovery, Griffith University) consisted of 352 compounds, of which the majority were obtained from Australian natural sources, such as endophytic fungi, (75) macrofungi, (76) plants, (77) and marine invertebrates. (78, 79) Approximately 15% of the entries of this library were semisynthetic natural product analogues, (80, 76) while a small percentage (∼5%) are known commercial drugs or synthetic compounds inspired by natural products. The Atanasov and Krenn databases consisted of 51 and 13 in-house available natural products, respectively, from the Department of Pharmacognosy at the University of Vienna, Austria. From the University of Innsbruck, 23 selected plant- and lichen-derived compounds (81-84, 62) available in-house at the Institute of Pharmacy/Pharmacognosy were collected in the Waltenberger database. Finally, the Sigma-Aldrich catalogue was also screened, as it includes some commercially available natural products.

Virtual Screening

The databases were prepared for virtual screening by deleting counterions and generating multiconformational databases using OMEGA implemented in LigandScout 3.03b. For the relatively small in-house databases used, BEST settings were employed with a maximum of 500 conformers per molecule. For the larger Sigma-Aldrich database, FAST settings were used, which allowed for a maximum of 50 conformations per compound.

Origin, Isolation, and Purification of the Natural Compounds

All natural products from the Davis Compound Library were isolated from plants, marine invertebrates, or endophytic fungi archived at the Griffith Institute for Drug Discovery, Griffith University, Australia, or purchased from Sigma-Aldrich. The extraction and isolation of the natural products featured in this paper have been previously reported by Davis et al. (69, 85-88) The synthesis and characterization of the semisynthetic fungal analogues 13–18 have also been previously reported in the literature. (69) All compounds from the Davis collection were analyzed for purity prior to screening and were shown by LC-MS or 1H NMR analysis to have purities of >95%. The compounds from the Atanasov library were obtained from Sigma-Aldrich, except for 2, 3, and butyl gallate (S3), which were purchased from Fisher, Molekula, and ABCR GmbH & Co. KG, respectively. All compounds were purchased at a purity of ≥90%. Compounds 8 and 9 were isolated in an activity-guided approach from a MeOH extract from Eriosema laurentii de Wild and unambiguously identified by following MS and NMR analysis. HPLC was applied to determine purity and resulted in 98.7% purity for 8 and 92.1% purity for 9. The compounds from the Waltenberger library were isolated from different plant and lichen species in the course of the project “Drugs from Nature Targeting Inflammation” (DNTI). (89) Compound 7 was isolated from a MeOH extract of the bark material of Himatanthus sucuuba (Spruce) Woodson as described elsewhere. (62) The purity of this compound was determined by HPLC and NMR experiments as >95%.

Activity Assays for 17β-HSD1 and 17β-HSD2 Using Cell Lysates

The 17β-HSD1 and 17β-HSD2 activity assays were performed as described previously. (19) Briefly, lysates of human embryonic kidney cells (HEK-293, ATCC, Manassas, VA, USA) expressing either human 17β-HSD1 or human 17β-HSD2 were incubated for 10 min at 37 °C in TS2 buffer (100 mM NaCl, 1 mM EGTA, 1 mM EDTA, 1 mM MgCl2, 250 mM sucrose, 20 mM Tris-HCl, pH 7.4) in a final volume of 22 μL containing either solvent (0.1% DMSO) or the inhibitor at the respective concentration. 17β-HSD1 activity was measured in the presence of 200 nM estrone, containing 50 nCi of [2,4,6,7-3H]-estrone, and 500 μM NADPH. In contrast, 17β-HSD2 activity was determined in the presence of 200 nM estradiol, containing 50 nCi of [2,4,6,7-3H]-estradiol, and 500 μM NAD+. Reactions were stopped after 10 min by adding an excess of unlabeled estradiol and estrone (2 mM of each in methanol). Unlabeled steroids and cofactors were purchased from Sigma-Aldrich and radiolabeled compounds from PerkinElmer (Boston, MA, USA). The steroids were separated by TLC, followed by scintillation counting and calculation of substrate conversion. Data were collected from at least three independent measurements. Compound 29 (24) was used as a positive control for 17β-HSD1 assays and compound 22 from Vuorinen et al. (19) as a positive control for 17β-HSD2 tests.

Structure–Activity-Relationship Modeling

The SAR models were generated using LigandScout 4.09 with default settings (Wolber 2005 JCIM; (90) LigandScout 4.09, 2005–2016, Inte:Ligand GmbH, Vienna, Austria, www.inteligand.com). For all compounds, BEST conformational models using iCon (max 500 conformers per entry) were calculated and overlaid by chemical features using the pharmacophore-based alignment algorithm of the program.

Supporting Information

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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jnatprod.6b00950.

  • Additional information (PDF)

  • 3D video view of model 1 (AVI)

Terms & Conditions

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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  • Corresponding Authors
    • Alex Odermatt - Division of Molecular & Systems Toxicology, University of Basel, Klingelbergstraße 50, 4056 Basel, Switzerland;  Email: [email protected]
    • Daniela Schuster - Division of Molecular & Systems Toxicology, University of Basel, Klingelbergstraße 50, 4056 Basel, Switzerland;  ‡Computer-Aided Molecular Design Group, Institute of Pharmacy/Pharmaceutical Chemistry and Center for Molecular Biosciences Innsbruck, and ∥Institute of Pharmacy/Pharmacognosy and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria;  Department of Pharmacognosy, University of Vienna, Althanstraße 14, 1090 Vienna, Austria;  Institute of Genetics and Animal Breeding of the Polish Academy of Sciences, Postępu 36A Street, 05-552, Jastrzebiec, Poland;  Laboratory of Animal Physiology, Department of Animal Biology and Physiology, Faculty of Science, University of Yaounde I, P.O. Box 812, Yaounde, Cameroon;  Griffith Institute for Drug Discovery, Griffith University, Brisbane, QLD 4111, Australia;  Orcidhttp://orcid.org/0000-0002-9933-8938;  Email: [email protected]
  • Authors
    • Anna Vuorinen - Division of Molecular & Systems Toxicology, University of Basel, Klingelbergstraße 50, 4056 Basel, Switzerland
    • Roger T. Engeli - Division of Molecular & Systems Toxicology, University of Basel, Klingelbergstraße 50, 4056 Basel, Switzerland
    • Susanne Leugger - Division of Molecular & Systems Toxicology, University of Basel, Klingelbergstraße 50, 4056 Basel, Switzerland
    • Fabio Bachmann - Division of Molecular & Systems Toxicology, University of Basel, Klingelbergstraße 50, 4056 Basel, Switzerland
    • Muhammad Akram - Division of Molecular & Systems Toxicology, University of Basel, Klingelbergstraße 50, 4056 Basel, Switzerland;  ‡Computer-Aided Molecular Design Group, Institute of Pharmacy/Pharmaceutical Chemistry and Center for Molecular Biosciences Innsbruck, and ∥Institute of Pharmacy/Pharmacognosy and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria;  Department of Pharmacognosy, University of Vienna, Althanstraße 14, 1090 Vienna, Austria;  Institute of Genetics and Animal Breeding of the Polish Academy of Sciences, Postępu 36A Street, 05-552, Jastrzebiec, Poland;  Laboratory of Animal Physiology, Department of Animal Biology and Physiology, Faculty of Science, University of Yaounde I, P.O. Box 812, Yaounde, Cameroon;  Griffith Institute for Drug Discovery, Griffith University, Brisbane, QLD 4111, Australia
    • Atanas G. Atanasov - Department of Pharmacognosy, University of Vienna, Althanstraße 14, 1090 Vienna, Austria;  Institute of Genetics and Animal Breeding of the Polish Academy of Sciences, Postępu 36A Street, 05-552, Jastrzebiec, Poland
    • Birgit Waltenberger - Division of Molecular & Systems Toxicology, University of Basel, Klingelbergstraße 50, 4056 Basel, Switzerland;  ‡Computer-Aided Molecular Design Group, Institute of Pharmacy/Pharmaceutical Chemistry and Center for Molecular Biosciences Innsbruck, and ∥Institute of Pharmacy/Pharmacognosy and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria;  Department of Pharmacognosy, University of Vienna, Althanstraße 14, 1090 Vienna, Austria;  Institute of Genetics and Animal Breeding of the Polish Academy of Sciences, Postępu 36A Street, 05-552, Jastrzebiec, Poland;  Laboratory of Animal Physiology, Department of Animal Biology and Physiology, Faculty of Science, University of Yaounde I, P.O. Box 812, Yaounde, Cameroon;  Griffith Institute for Drug Discovery, Griffith University, Brisbane, QLD 4111, Australia
    • Veronika Temml - Division of Molecular & Systems Toxicology, University of Basel, Klingelbergstraße 50, 4056 Basel, Switzerland;  ‡Computer-Aided Molecular Design Group, Institute of Pharmacy/Pharmaceutical Chemistry and Center for Molecular Biosciences Innsbruck, and ∥Institute of Pharmacy/Pharmacognosy and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria;  Department of Pharmacognosy, University of Vienna, Althanstraße 14, 1090 Vienna, Austria;  Institute of Genetics and Animal Breeding of the Polish Academy of Sciences, Postępu 36A Street, 05-552, Jastrzebiec, Poland;  Laboratory of Animal Physiology, Department of Animal Biology and Physiology, Faculty of Science, University of Yaounde I, P.O. Box 812, Yaounde, Cameroon;  Griffith Institute for Drug Discovery, Griffith University, Brisbane, QLD 4111, Australia
    • Hermann Stuppner - Division of Molecular & Systems Toxicology, University of Basel, Klingelbergstraße 50, 4056 Basel, Switzerland;  ‡Computer-Aided Molecular Design Group, Institute of Pharmacy/Pharmaceutical Chemistry and Center for Molecular Biosciences Innsbruck, and ∥Institute of Pharmacy/Pharmacognosy and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria;  Department of Pharmacognosy, University of Vienna, Althanstraße 14, 1090 Vienna, Austria;  Institute of Genetics and Animal Breeding of the Polish Academy of Sciences, Postępu 36A Street, 05-552, Jastrzebiec, Poland;  Laboratory of Animal Physiology, Department of Animal Biology and Physiology, Faculty of Science, University of Yaounde I, P.O. Box 812, Yaounde, Cameroon;  Griffith Institute for Drug Discovery, Griffith University, Brisbane, QLD 4111, Australia
    • Liselotte Krenn - Department of Pharmacognosy, University of Vienna, Althanstraße 14, 1090 Vienna, Austria
    • Sylvin B. Ateba - Laboratory of Animal Physiology, Department of Animal Biology and Physiology, Faculty of Science, University of Yaounde I, P.O. Box 812, Yaounde, Cameroon
    • Dieudonné Njamen - Laboratory of Animal Physiology, Department of Animal Biology and Physiology, Faculty of Science, University of Yaounde I, P.O. Box 812, Yaounde, Cameroon
    • Rohan A. Davis - Griffith Institute for Drug Discovery, Griffith University, Brisbane, QLD 4111, Australia
  • Notes
    The authors declare no competing financial interest.

Acknowledgment

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This study was supported by the Swiss National Science Foundation (31003A-159454 to A.O.), the Novartis Research Foundation (A.O.), the Austrian Science Fund (P26782 to D.S. and P25971-B23 to A.G.A.), the Hochschuljubiläumsfond (H-297322/2014 to A.G.A.), the Ernst Mach Stipendium (to S.B.A.), the National Health and Medical Research Council (NHMRC) (APP1024314 to R.A.D.), and the Australian Research Council (ARC) (LE0668477, LE0237908, LP120200339 to R.A.D.). D.S. is an Ingeborg Hochmair professor of the University of Innsbruck. We thank P. Schuster and G. Begg for help in preparing the manuscript and Inte:Ligand GmbH for providing LigandScout software free of charge.

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    Molecular mechanisms of estrogen recognition and 17-keto reduction by human 17β-hydroxysteroid dehydrogenase 1
    Ghosh, D.; Vihko, P.
    Chemico-Biological Interactions (2001), 130-132 (1-3), 637-650CODEN: CBINA8; ISSN:0009-2797. (Elsevier Science Ireland Ltd.)
    A review with 34 refs. The redn. of inactive estrone (E1) to the active estrogen 17β-estradiol (E2) is catalyzed by type 1 17β-hydroxysteroid dehydrogenase (17HSD1). Crystallog. studies, modeling and activity measurement of mutants and chimeric enzymes have led to the understanding of its mechanism of action and the mol. basis for the estrogenic specificity. An electrophilic attack on the C17-keto oxygen by the Tyr 155 hydroxyl is proposed for initiation of the transition state. The active site is a hydrophobic pocket with catalytic residues at one end and the recognition machinery on the other. Tyr 155, Lys 159 and Ser 142 are essential for the activity. The presence of certain other amino acids near the substrate recognition end of the active site including His 152 and Pro 187 is crit. to the shape complementarity of estrogenic ligands. His 221 and Glu 282 form hydrogen bonds with 3-hydroxyl of the arom. A-ring of the ligand. This mechanism of recognition of E1 by 17HSD1 is similar to that of E2 by estrogen receptor α. In a ternary complex with NADP+ and equilin, an equine estrogen with C7=C8 double bond, the orientation of C17=O of equilin relative to the C4-hydride is more acute than the near normal approach of the hydride for the substrate. In the apo-enzyme structure, a substrate-entry loop (residues 186-201) is in an open conformation. The loop is closed in this complex and Phe 192 and Met 193 make contacts with the ligand. Residues of the entry loop could be partially responsible for the estrogenic specificity.
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    Soubhye, J.; Alard, I. C.; van Antwerpen, P.; Dufrasne, F. Future Med. Chem. 2015, 7, 1431– 1456 DOI: 10.4155/fmc.15.74
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    Type 2 17-β hydroxysteroid dehydrogenase as a novel target for the treatment of osteoporosis
    Soubhye, Jalal; Alard, Ibaa Chikh; van Antwerpen, Pierre; Dufrasne, Francois
    Future Medicinal Chemistry (2015), 7 (11), 1431-1456CODEN: FMCUA7; ISSN:1756-8919. (Future Science Ltd.)
    Low estradiol level in postmenopausal women is implicated in osteoporosis, which occurs because of the high bone resorption rate. Estrogen formation is controlled by 17-β hydroxysteroid dehydrogenase 17-β HSD enzymes, where 17-β HSD type 1 contributes in the formation of estradiol, while type 2 catalyzes its catabolism. Inhibiting 17-β HSD2 can help in increasing estradiol concn. Several promising 17-β HSD2 inhibitors that can act at low nanomolar range have been identified. However, there are some specific challenges assocd. with the application of these compds. Our review provides an up-to-date summary of the current status and recent progress in the prodn. of 17-β HSD2 inhibitors as well as the future challenges in their clin. application.
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    Compston, J. E. Physiol. Rev. 2001, 81, 419– 447
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    Riggs, B. L.; Khosla, S.; Melton, L. J. J. Bone Miner. Res. 1998, 13, 763– 773 DOI: 10.1359/jbmr.1998.13.5.763
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    A unitary model for involutional osteoporosis: estrogen deficiency causes both type I and type II osteoporosis in postmenopausal women and contributes to bone loss in aging men
    Riggs B L; Khosla S; Melton L J 3rd
    Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research (1998), 13 (5), 763-73 ISSN:0884-0431.
    We propose here a new unitary model for the pathophysiology of involutional osteoporosis that identifies estrogen (E) deficiency as the cause of both the early, accelerated and the late, slow phases of bone loss in postmenopausal women and as a contributing cause of the continuous phase of bone loss in aging men. The accelerated phase in women is most apparent during the first decade after menopause, involves disproportionate loss of cancellous bone, and is mediated mainly by loss of the direct restraining effects of E on bone cell function. The ensuing slow phase continues throughout life in women, involves proportionate losses of cancellous and cortical bone, and is associated with progressive secondary hyperparathyroidism. This phase is mediated mainly by loss of E action on extraskeletal calcium homeostasis which results in net calcium wasting and increases in the level of dietary calcium intake required to maintain bone balance. Because elderly men have low circulating levels of both bioavailable E and bioavailable testosterone (T) and because recent data suggest that E is at least as important as T in determining bone mass in aging men, E deficiency may also contribute substantially to the continuous bone loss of aging men. In both genders, E deficiency increases bone resorption and may also impair a compensatory increase in bone formation. For the most part, this unitary model is well supported by observational and experimental data and provides plausible explanations to traditional objections to a unitary hypothesis.
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    Chin, K.-Y.; Ima-Nirwana, S. Int. J. Endocrinol. 2012, 2012, 208719 DOI: 10.1155/2012/208719
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    Sex steroids and bone health status in men
    Chin Kok-Yong; Ima-Nirwana Soelaiman
    International journal of endocrinology (2012), 2012 (), 208719 ISSN:.
    Male osteoporosis is a health problem which deserves more attention as nearly 30% of osteoporotic fractures happen in men aged 50 years and above. Although men do not experience an accelerated bone loss phase and testosterone deficiency is not a universal characteristic for aged men, osteoporosis due to age-related testosterone deficiency does have a negative impact on bone health status of men. Observations from epidemiological studies indicate that elderly men with higher testosterone can preserve their BMD better and thus are less prone to fracture. Observations on men with estrogen resistance or aromatase deficiency indicate that estrogen is equally important in the maintenance of bone health status. This had been validated in several epidemiological studies which found that the relationships between estrogen and bone health indices are significant and sometimes stronger than testosterone. Studies on the relationship between quantitative ultrasound and bone remodeling markers suggest that testosterone and estrogen may have differential effects on bone, but further evidence was needed. In conclusion, both testosterone and estrogen are important in the maintenance of bone health in men.
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    Michael, H.; Härkönen, P. L.; Väänänen, H. K.; Hentunen, T. A. J. Bone Miner. Res. 2005, 20, 2224– 2232 DOI: 10.1359/JBMR.050803
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    Estrogen and testosterone use different cellular pathways to inhibit osteoclastogenesis and bone resorption
    Michael, Husheem; Harkonen, Pirkko L.; Vaananen, H. Kalervo; Hentunen, Teuvo A.
    Journal of Bone and Mineral Research (2005), 20 (12), 2224-2232CODEN: JBMREJ; ISSN:0884-0431. (American Society for Bone and Mineral Research)
    Using human peripheral blood CD14+ osteoclast precursors, we show that testosterone directly inhibits osteoclast formation and bone resorption at physiol. concns. Instead, estrogen has no direct effects, whereas its action seems to be mediated through osteoblasts by producing osteoprotegerin. Both estrogen and testosterone acts through their cognate receptors. Introduction: Estrogen (E2) deficiency is assocd. with both the development of postmenopausal and senile form of osteoporosis in elderly women. Testosterone (Te) deficiency, on the other hand, may cause osteoporosis in men. In both sexes, osteoporosis is assocd. with disturbed bone turnover, including increased bone resorption caused by enhanced osteoclast formation and increased osteoclast activity. However, the mechanisms by which E2 or Te act on bone are not fully understood, and one of the central questions is whether these hormones act directly on osteoclast precursors or whether their action is mediated through osteoblastic cells. Materials and Methods: We cultured human peripheral blood CD14+ osteoclast precursors in the presence of RANKL, macrophage-colony stimulating factor (M-CSF), TNF-α, and dexamethasone to induce them to differentiate into osteoclasts. To study the possible osteoblast-mediated effects, osteoclast precursors were also co-cultured either with human MG-63 or SaOS-2 osteoblast-derived osteosarcoma cells. These cultures were treated with 10-8-10-12 M of E2 or Te for 7 days. Results: E2 did not have any direct effect on osteoclast formation, whereas testosterone inhibited osteoclast formation and bone resorption in a dose-dependent manner. In co-cultures, where MG-63 or SaOS-2 cells were present, E2 and Te inhibited osteoclast formation in a dose-dependent manner. At the same time, E2 and Te treatment in MG-63 or SaOS-2 cell-contg. cultures stimulated significantly the formation of osteoprotegerin (OPG) compared with untreated cultures measured by ELISA assay from the culture medium. The effects of E2 and Te on osteoclast formation and bone resorption were completely antagonized by an E2 receptor (ER) antagonist, ICI 182,780, and an androgen receptor (AR) antagonist, flutamide, suggesting ER- and AR-mediated mechanisms, resp., in these cultures. Conclusions: Te is likely to have direct and indirect inhibitory effects on human osteoclast formation and bone resorption, whereas the effect of E2 on osteoclast precursors and osteoclasts seems to be mediated by osteoblastic cells. Inhibitory effect of E2 is assocd. with the stimulated secretion of OPG by osteoblast-derived osteosarcoma cells. Mechanism of action of E2 and Te is mediated by ER and AR, resp.
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    Bagi, C. M.; Wood, J.; Wilkie, D.; Dixon, B. J. Musculoskelet. Neuronal. Interact. 2008, 8, 267– 280
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    Effect of 17β-hydroxysteroid dehydrogenase type 2 inhibitor on bone strength in ovariectomized cynomolgus monkeys
    Bagi, C. M.; Wood, J.; Wilkie, D.; Dixon, B.
    Journal of Musculoskeletal & Neuronal Interactions (2008), 8 (3), 267-280CODEN: JMNIB3; ISSN:1108-7161. (Journal of Musculoskeletal and Neuronal Interactions)
    In both sexes, a redn. in sex steroid prodn. with aging impairs the musculoskeletal system. The goal of our study was to test the ability of WH-9062, a novel non-steroidal small mol. inhibitor of the 17β-Hydroxysteroid Dehydrogenase type 2 enzyme, to maintain or improve bone strength without raising serum levels of testosterone or estradiol. Mature, female cynomolgus monkeys with sealed growth plates were allocated into six groups: Sham controls, OVX controls, OVX+Premarin (15 mg/kg/d), and three groups of OVX monkeys receiving WH-9062 at 1, 5 and 25 mg/kg/day. All treatments were administered by daily oral dosing for 23 wk. Changes in lipid profile caused by OVX were cor. with WH-9062 and included lowering total of cholesterol and non-HDL cholesterol, and maintenance of initial plasma levels of HDL cholesterol. Only the highest dose of WH-9062 lowered bone resorption relative to OVX controls. Elevated bone specific alk. phosphatase, osteocalcin, BMC and dynamic bone histomorphometry data resulted in desirable bone balance and bone strength. The obtained results support our theory that inhibition of 17β-HSD type 2 resulted in high local estrogen and/or testosterone levels leading to maintenance of bone formation and bone strength. Collectively, our data demonstrated that the treatment paradigm that utilizes tissue selectivity and receptor bioavailability in conversion of inactive hormones to active forms could be achieved and could result in desirable effects on target tissues such as bone and muscles.
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    Perspicace, E.; Cozzoli, L.; Gargano, E. M.; Hanke, N.; Carotti, A.; Hartmann, R. W.; Marchais-Oberwinkler, S. Eur. J. Med. Chem. 2014, 83, 317– 337 DOI: 10.1016/j.ejmech.2014.06.036
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    Vuorinen, A.; Engeli, R.; Meyer, A.; Bachmann, F.; Griesser, U. J.; Schuster, D.; Odermatt, A. J. Med. Chem. 2014, 57, 5995– 6007 DOI: 10.1021/jm5004914
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    Wetzel, M.; Marchais-Oberwinkler, S.; Perspicace, E.; Möller, G.; Adamski, J.; Hartmann, R. W. J. Med. Chem. 2011, 54, 7547– 7557 DOI: 10.1021/jm2008453
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    Xu, K.; Al-Soud, Y. A.; Wetzel, M.; Hartmann, R. W.; Marchais-Oberwinkler, S. Eur. J. Med. Chem. 2011, 46, 5978– 5990 DOI: 10.1016/j.ejmech.2011.10.010
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    Deluca, D.; Krazeisen, A.; Breitling, R.; Prehn, C.; Möller, G.; Adamski, J. J. Steroid Biochem. Mol. Biol. 2005, 93, 285– 292 DOI: 10.1016/j.jsbmb.2004.12.035
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    Inhibition of 17beta-hydroxysteroid dehydrogenases by phytoestrogens: Comparison with other steroid metabolizing enzymes
    Deluca, D.; Krazeisen, A.; Breitling, R.; Prehn, C.; Moeller, G.; Adamski, J.
    Journal of Steroid Biochemistry and Molecular Biology (2005), 93 (2-5), 285-292CODEN: JSBBEZ; ISSN:0960-0760. (Elsevier B.V.)
    A review of effects of phytoestrogens on human health have been reported for decades. These include not only beneficial action in cancer prevention but also endocrine disruption in males. Since then many mol. mechanisms underlying these effects have been identified. Targets of phytoestrogens comprise steroid receptors, steroid metabolising enzymes, elements of signal transduction and apoptosis pathways, and even the DNA processing machinery. Understanding the specific vs. pleiotropic effects of selected phytoestrogens will be crucial for their biomedical application. This review will conc. on the influence of phytoestrogens on 17beta-hydroxysteroid dehydrogenases from a comparative perspective with other steroid metabolizing enzymes.
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    Le Bail, J. C.; Laroche, T.; Marre-Fournier, F.; Habrioux, G. Cancer Lett. 1998, 133, 101– 106 DOI: 10.1016/S0304-3835(98)00211-0
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    Aromatase and 17β-hydroxysteroid dehydrogenase inhibition by flavonoids
    Le Bail, J. C.; Laroche, T.; Marre-Fournier, F.; Habrioux, G.
    Cancer Letters (Shannon, Ireland) (1998), 133 (1), 101-106CODEN: CALEDQ; ISSN:0304-3835. (Elsevier Science Ireland Ltd.)
    A method for estg. in the same assay both aromatase and 17β-hydroxysteroid dehydrogenase activities in human placental microsomes using radiolabeled [1,2,6,7-3H]4-androstene-3,17-dione was proposed. In this assay, estrone (E1) and estradiol (E2) produced were sepd. by HPLC and estd. using a radioactive flow detector. Using this method, the inhibitory effect of various flavonoids, including flavone, flavanone and isoflavone, on the human placental aromatase and 17β-hydroxysteroid dehydrogenase was studied. Flavonoids were shown to be potent inhibitors of both aromatase and 17β-hydroxysteroid dehydrogenase activities. We found that 7-hydroxyflavone and apigenin are the most effective aromatase and 17β-hydroxysteroid dehydrogenase inhibitors, resp. Expts. showed that a hydroxyl group in position 7 was essential for anti-17β-hydroxysteroid dehydrogenase activity. However, flavonoids with 7-methoxy or 8-hydroxyl groups on the A ring showed only anti-aromatase activity. Structure-activity relationships were discussed.
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    Schuster, D.; Nashev, L. G.; Kirchmair, J.; Laggner, C.; Wolber, G.; Langer, T.; Odermatt, A. J. Med. Chem. 2008, 51, 4188– 4199 DOI: 10.1021/jm800054h
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    Atanasov, 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. Biotechnol. Adv. 2015, 33, 1582– 614 DOI: 10.1016/j.biotechadv.2015.08.001
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    Discovery and resupply of pharmacologically active plant-derived natural products: A review
    Atanasov, 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, Hermann
    Biotechnology 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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    Newman, D. J.; Cragg, G. M. J. Nat. Prod. 2012, 75, 311– 335 DOI: 10.1021/np200906s
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    Natural Products As Sources of New Drugs over the 30 Years from 1981 to 2010
    Newman, David J.; Cragg, Gordon M.
    Journal of Natural Products (2012), 75 (3), 311-335CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)
    This review is an updated and expanded version of the three prior reviews that were published in this journal in 1997, 2003, and 2007. In the case of all approved therapeutic agents, the time frame has been extended to cover the 30 years from Jan. 1, 1981, to Dec. 31, 2010, for all diseases worldwide, and from 1950 (earliest so far identified) to Dec. 2010 for all approved antitumor drugs worldwide. We have continued to utilize our secondary subdivision of a "natural product mimic" or "NM" to join the original primary divisions and have added a new designation, "natural product botanical" or "NB", to cover those botanical "defined mixts." that have now been recognized as drug entities by the FDA and similar organizations. From the data presented, the utility of natural products as sources of novel structures, but not necessarily the final drug entity, is still alive and well. Thus, in the area of cancer, over the time frame from around the 1940s to date, of the 175 small mols., 131, or 74.8%, are other than "S" (synthetic), with 85, or 48.6%, actually being either natural products or directly derived therefrom. In other areas, the influence of natural product structures is quite marked, with, as expected from prior information, the anti-infective area being dependent on natural products and their structures. Although combinatorial chem. techniques have succeeded as methods of optimizing structures and have been used very successfully in the optimization of many recently approved agents, we are able to identify only one de novo combinatorial compd. approved as a drug in this 30-yr time frame. We wish to draw the attention of readers to the rapidly evolving recognition that a significant no. of natural product drugs/leads are actually produced by microbes and/or microbial interactions with the "host from whence it was isolated", and therefore we consider that this area of natural product research should be expanded significantly.
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    Eder, J.; Sedrani, R.; Wiesmann, C. Nat. Rev. Drug Discovery 2014, 13, 577– 587 DOI: 10.1038/nrd4336
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    Williamson, E. M.; Heinrich, M.; Jäger, A. K., Eds. Ethnopharmacology; John Wiley & Sons Ltd: Chichester, West Sussex, UK, 2015; pp 213– 226.
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    Sharma, C.; Kumari, T.; Arya, K. R. Int. J. Pharm. Res. Health Sci. 2014, 2, 185– 190
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    Blum, A.; Favia, A. D.; Maser, E. Mol. Cell. Endocrinol. 2009, 301, 132– 136 DOI: 10.1016/j.mce.2008.08.028
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    11β-Hydroxysteroid dehydrogenase type 1 inhibitors with oleanan and ursan scaffolds
    Blum, Andreas; Favia, Angelo D.; Maser, Edmund
    Molecular and Cellular Endocrinology (2009), 301 (1-2), 132-136CODEN: MCEND6; ISSN:0303-7207. (Elsevier Ireland Ltd.)
    The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) converts cortisone to the active glucocorticoid cortisol, thereby acting as a cellular switch to mediate glucocorticoid action in many tissues. Several studies have indicated that 11β-HSD1 plays a crucial role in the onset of type 2 diabetes and central obesity. As a consequence, selective inhibition of 11β-HSD1 in humans might become a new and promising approach for lowering blood glucose concns. and for counteracting the accumulation of visceral fat and its related metabolic abnormalities in type 2 diabetes. In this study, we present the synthesis and the biol. evaluation of ursan or oleanan type triterpenoids which may act as selective 11β-HSD1 inhibitors in liver as well as in peripheral tissues, like adipocytes and muscle cells. In order to rationalize the outcomes of the inhibition data, docking simulations of the ligands were performed on the exptl. detd. structure of 11β-HSD1. Furthermore, we discuss the structural determinants that confer enzymic specificity. From our investigation, valuable information has been obtained to design selective 11β-HSD1 blockers based on the oleanan and ursan scaffold.
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    Kratschmar, D. V.; Vuorinen, A.; Da Cunha, T.; Wolber, G.; Classen-Houben, D.; Doblhoff, O.; Schuster, D.; Odermatt, A. J. Steroid Biochem. Mol. Biol. 2011, 125, 129– 142 DOI: 10.1016/j.jsbmb.2010.12.019
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    Characterization of activity and binding mode of glycyrrhetinic acid derivatives inhibiting 11β-hydroxysteroid dehydrogenase type 2
    Kratschmar, Denise V.; Vuorinen, Anna; Da Cunha, Thierry; Wolber, Gerhard; Classen-Houben, Dirk; Doblhoff, Otto; Schuster, Daniela; Odermatt, Alex
    Journal of Steroid Biochemistry and Molecular Biology (2011), 125 (1-2), 129-142CODEN: JSBBEZ; ISSN:0960-0760. (Elsevier Ltd.)
    Modulation of intracellular glucocorticoid availability is considered as a promising strategy to treat glucocorticoid-dependent diseases. 18β-Glycyrrhetinic acid (GA), the biol. active triterpenoid metabolite of glycyrrhizin, which is contained in the roots and rhizomes of licorice (Glycyrrhiza spp.), represents a well-known but non-selective inhibitor of 11β-hydroxysteroid dehydrogenases (11β-HSDs). However, to assess the physiol. functions of the resp. enzymes and for potential therapeutic applications selective inhibitors are needed. In the present study, we applied bioassays and 3D-structure modeling to characterize nine 11β-HSD1 and fifteen 11β-HSD2 inhibiting GA derivs. Comparison of the GA derivs. in assays using cell lysates revealed that modifications at the 3-hydroxyl and/or the carboxyl led to highly selective and potent 11β-HSD2 inhibitors. The data generated significantly extends our knowledge on structure-activity relationship of GA derivs. as 11β-HSD inhibitors. Using recombinant enzymes we found also potent inhibition of mouse 11β-HSD2, despite significant species-specific differences. The selected GA derivs. potently inhibited 11β-HSD2 in intact SW-620 colon cancer cells, although the rank order of inhibitory potential differed from that obtained in cell lysates. The biol. activity of compds. was further demonstrated in glucocorticoid receptor (GR) transactivation assays in cells coexpressing GR and 11β-HSD1 or 11β-HSD2. 3D-structure modeling provides an explanation for the differences in the selectivity and activity of the GA derivs. investigated. The most potent and selective 11β-HSD2 inhibitors should prove useful as mechanistic tools for further anti-inflammatory and anti-cancer in vitro and in vivo studies. Article from the Special issue on Targeted Inhibitors.
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    Rollinger, J. M.; Kratschmar, D. V.; Schuster, D.; Pfisterer, P. H.; Gumy, C.; Aubry, E. M.; Brandstötter, S.; Stuppner, H.; Wolber, G.; Odermatt, A. Bioorg. Med. Chem. 2010, 18, 1507– 1515 DOI: 10.1016/j.bmc.2010.01.010
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    The lipoxygenase inhibitor, nordihydroguaiaretic acid, inhibits ovulation and reduces leukotriene and prostaglandin levels in the rat ovary
    Mikuni, Masato; Yoshida, Mami; Hellberg, Pir; Peterson, C. Anthony; Edwin, Samuel S.; Brannstrom, Mats; Peterson, C. Matthew
    Biology of Reproduction (1998), 58 (5), 1211-1216CODEN: BIREBV; ISSN:0006-3363. (Society for the Study of Reproduction)
    Eicosanoids, the active metabolites of arachidonic acid, are grouped into cyclooxygenase products (prostaglandins [PGs] and thromboxanes) and lipoxygenase products (leukotrienes [LTs] and lipoxins). Numerous studies suggest a role for the lipoxygenase system in ovulation. The aim of this study was to further characterize the effects of lipoxygenase inhibition and the interactions of the lipoxygenase and cyclooxygenase systems in the rat ovary during ovulation. The lipoxygenase inhibitor, nordihydroguaiaretic acid (NDGA), was administered in vivo and in the isolated perfused rat ovary to det. its effect on ovulation rate. The in vivo study confirmed the inhibitory effect of NDGA, and in the perfusion expts., NDGA caused a dose-dependent redn. in the ovulation rate. To further define the interaction between the lipoxygenase and cyclooxygenase systems, a second set of perfusions was performed with NDGA (10 μM) and the combination of NDGA (10 μM) plus a nonselective cyclooxygenase inhibitor, indomethacin (10 μM). NDGA significantly reduced the no. of ovulations compared to that in controls. The ovulation rate for the combination of NDGA+indomethacin was also significantly lower than in controls but not different from that in the NDGA-treated group. Steroidogenesis was decreased only in the NDGA+indomethacin perfusions. Ovarian tissue PGE2 and PGF2α levels in the NDGA-treated ovaries were significantly suppressed compared to those in controls. Almost a complete block of PGE2 and PGF2α was seen in the NDGA+indomethacin group. LTB4 levels in the 10-h-perfused ovarian tissues were significantly decreased by NDGA compared to those in control tissues. Furthermore, LTB4 (3 μg added twice) completely reversed the inhibitory effect of 0.1 μM NDGA on ovulation rate and partially reversed the effect of 10 μM NDGA in the perfusion model. These results demonstrate that the products of the lipoxygenase pathway, esp. LTB4, are important in the process of ovulation in this cyclically ovulating species. The interconnected lipoxygenase and cyclooxygenase pathways may optimize ovulation and facilitate steroidogenesis.
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    Benassayag, C.; Perrot-Applanat, M.; Ferre, F. J. Chromatogr. B: Anal. Technol. Biomed. Life Sci. 2002, 777, 233– 248 DOI: 10.1016/S1570-0232(02)00340-9
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    Phytoestrogens as modulators of steroid action in target cells
    Benassayag, C.; Perrot-Applanat, M.; Ferre, F.
    Journal of Chromatography, B: Analytical Technologies in the Biomedical and Life Sciences (2002), 777 (1-2), 233-248CODEN: JCBAAI; ISSN:1570-0232. (Elsevier Science B.V.)
    A review. Although numerous reports exist on the potential beneficial role of nutritional phytoestrogens in human health, their mol. mechanism in target cells is still not completely understood. Phytoestrogens promote estrogen and antiestrogen effects by interacting with numerous mols., carrier proteins, enzymes and membrane and nuclear receptors, directly or indirectly involved in the transfer of estrogen signals. The hypothesis that the ERβ subtype plays a key role in antiproliferative effect of phytoestrogens, esp. in breast cancer, is examd. here. This review focus on the effects of phytoestrogens in developmental processes such as those linked to reproductive function, tumorigenesis and angiogenesis.
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    Fujimoto, N.; Kohta, R.; Kitamura, S.; Honda, H. Life Sci. 2004, 74, 1417– 1425 DOI: 10.1016/j.lfs.2003.08.012
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    Ono, K.; Hasegawa, K.; Yoshiike, Y.; Takashima, A.; Yamada, M.; Naiki, H. J. Neurochem. 2002, 81, 434– 40 DOI: 10.1046/j.1471-4159.2002.00904.x
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    Nordihydroguaiaretic acid potently breaks down pre-formed Alzheimer's β-amyloid fibrils in vitro
    Ono, Kenjiro; Hasegawa, Kazuhiro; Yoshiike, Yuji; Takashima, Akihiko; Yamada, Masahito; Naiki, Hironobu
    Journal of Neurochemistry (2002), 81 (3), 434-440CODEN: JONRA9; ISSN:0022-3042. (Blackwell Science Ltd.)
    Inhibition of the accumulation of amyloid β-peptide (Aβ) and the formation of β-amyloid fibrils (fAβ) from Aβ, as well as the degrdn. of pre-formed fAβ in the CNS would be attractive therapeutic objectives for the treatment of Alzheimer's disease (AD). We previously reported that nordihydroguaiaretic acid (NDGA) inhibited fAβ formation from Aβ(1-40) and Aβ(1-42) dose-dependently in the range of 10-30 μM in vitro. Utilizing fluorescence spectroscopic anal. with thioflavin T and electron microscopic study, we show here that NDGA dose-dependently breaks down fAβ(1-40) and fAβ(1-42) within a few hours at pH 7.5 at 37. At 4 h, the fluorescence of fAβ(1-40) and fAβ(1-42) incubated with 50 μM NDGA was 5% and 10% of the initial fluorescence, resp. The activity of NDGA to break down these fAβs was obsd. even at a low concn. of 0.1 μM. At 1 h, many short, sheared fibrils were obsd. in the mixt. incubated with 50 μM NDGA, and at 4 h, the no. of fibrils reduced markedly, and small amorphous aggregates were obsd. We next compared the activity of NDGA to break down fAβ(1-40) and fAβ(1-42), with other mols. reported to inhibit fAβ formation from Aβ and/or to degrade pre-formed fAβ both in vivo and in vitro. At a concn. of 50 μM, the overall activity of the mols. examd. in this study was in the order of: NDGA » rifampicin = tetracycline > poly(vinylsulfonic acid, sodium salt) = 1,3-propane disulfonic acid, disodium salt > β-sheet breaker peptide (iAβ5). In cell culture expts., fAβ disrupted by NDGA were less toxic than intact fAβ, as demonstrated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Although the mechanisms by which NDGA inhibits fAβ formation from Aβ, as well as breaking down pre-formed fAβ in vitro, are still unclear, NDGA could be a key mol. for the development of therapeutics for AD.
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    Yamada, M.; Ono, K.; Hamaguchi, T.; Noguchi-Shinohara, M. Adv. Exp. Med. Biol. 2015, 863, 79– 94 DOI: 10.1007/978-3-319-18365-7_4
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    Gupta, S. C.; Patchva, S.; Koh, W.; Aggarwal, B. B. Clin. Exp. Pharmacol. Physiol. 2012, 39, 283– 299 DOI: 10.1111/j.1440-1681.2011.05648.x
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    Discovery of curcumin, a component of golden spice, and its miraculous biological activities
    Gupta, Subash C.; Patchva, Sridevi; Koh, Wonil; Aggarwal, Bharat B.
    Clinical and Experimental Pharmacology and Physiology (2012), 39 (3), 283-299CODEN: CEXPB9; ISSN:0305-1870. (Wiley-Blackwell)
    A review. 1. Curcumin is the active ingredient of the dietary spice turmeric and was consumed for medicinal purposes for thousands of years. Modern science has shown that curcumin modulates various signaling mols., including inflammatory mols., transcription factors, enzymes, protein kinases, protein reductases, carrier proteins, cell survival proteins, drug resistance proteins, adhesion mols., growth factors, receptors, cell cycle regulatory proteins, chemokines, DNA, RNA, and metal ions. 2. Because of this polyphenol's potential to modulate multiple signaling mols., it was reported to possess pleiotropic activities. First demonstrated to have antibacterial activity in 1949, curcumin has since been shown to have anti-inflammatory, anti-oxidant, pro-apoptotic, chemopreventive, chemotherapeutic, antiproliferative, wound healing, antinociceptive, antiparasitic, and antimalarial properties as well. Animal studies have suggested that curcumin may be active against a wide range of human diseases, including diabetes, obesity, neurol. and psychiatric disorders, and cancer, as well as chronic illnesses affecting the eyes, lungs, liver, kidneys, and gastrointestinal and cardiovascular systems. 3. Although many clin. trials evaluating the safety and efficacy of curcumin against human ailments have already been completed, others are still ongoing. Moreover, curcumin is used as a supplement in several countries, including India, Japan, the US, Thailand, China, Korea, Turkey, South Africa, Nepal, and Pakistan. Although inexpensive, apparently well tolerated and potentially active, curcumin was not approved for the treatment of any human disease. 4. In the present article, we discuss the discovery and key biol. activities of curcumin, with a particular emphasis on its activities at the mol. and cellular levels, as well as in animals and humans.
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    Manolova, Y.; Deneva, V.; Antonov, L.; Drakalska, E.; Momekova, D.; Lambov, N. Spectrochim. Acta, Part A 2014, 132, 815– 820 DOI: 10.1016/j.saa.2014.05.096
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    The effect of the water on the curcumin tautomerism: A quantitative approach
    Manolova, Yana; Deneva, Vera; Antonov, Liudmil; Drakalska, Elena; Momekova, Denitsa; Lambov, Nikolay
    Spectrochimica Acta, Part A: Molecular and Biomolecular Spectroscopy (2014), 132 (), 815-820CODEN: SAMCAS; ISSN:1386-1425. (Elsevier B.V.)
    The tautomerism of curcumin has been investigated in ethanol/water binary mixts. by using UV-Vis spectroscopy and advanced quantum-chem. calcns. The spectral changes were processed by using advanced chemometric procedure, based on resoln. of overlapping bands technique. As a result, molar fractions of the tautomers and their individual spectra have been estd. It has been shown that in ethanol the enol-keto tautomer only is presented. The addn. of water leads to appearance of a new spectral band, which was assigned to the diketo tautomeric form. The results show that in 90% water/10% ethanol the diketo form is dominating. The obsd. shift in the equil. is explained by the quantum chem. calcns., which show that water mols. stabilize diketo tautomer through formation of stable complexes. To our best knowledge we report for the first time quant. data for the tautomerism of curcumin and the effect of the water.
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    Eigner, D.; Scholz, D. J. Ethnopharmacol. 1999, 67, 1– 6 DOI: 10.1016/S0378-8741(98)00234-7
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    Ghosh, S.; Banerjee, S.; Sil, P. C. Food Chem. Toxicol. 2015, 83, 111– 24 DOI: 10.1016/j.fct.2015.05.022
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    The beneficial role of curcumin on inflammation, diabetes and neurodegenerative disease: A recent update
    Ghosh, 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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    Epstein, J.; Sanderson, I. R.; Macdonald, T. T. Br. J. Nutr. 2010, 103, 1545– 1557 DOI: 10.1017/S0007114509993667
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    Curcumin as a therapeutic agent: the evidence from in vitro, animal and human studies
    Epstein, Jenny; Sanderson, Ian R.; MacDonald, Thomas T.
    British Journal of Nutrition (2010), 103 (11), 1545-1557CODEN: BJNUAV; ISSN:0007-1145. (Cambridge University Press)
    A review. Curcumin is the active ingredient of turmeric. It is widely used as a kitchen spice and food colorant throughout India, Asia and the Western world. Curcumin is a major constituent of curry powder, to which it imparts its characteristic yellow color. For over 4000 years, curcumin has been used in traditional Asian and African medicine to treat a wide variety of ailments. There is a strong current public interest in naturally occurring plant-based remedies and dietary factors related to health and disease. Curcumin is non-toxic to human subjects at high doses. It is a complex mol. with multiple biol. targets and different cellular effects. Recently, its mol. mechanisms of action have been extensively investigated. It has anti-inflammatory, antioxidant and anti-cancer properties. Under some circumstances its effects can be contradictory, with uncertain implications for human treatment. While more studies are warranted to further understand these contradictions, curcumin holds promise as a disease-modifying and chemopreventive agent. We review the evidence for the therapeutic potential of curcumin from in vitro studies, animal models and human clin. trials.
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    Ko, E. Y.; Moon, A. J. Cancer Prev. 2015, 20, 223– 231 DOI: 10.15430/JCP.2015.20.4.223
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    Natural Products for Chemoprevention of Breast Cancer
    Ko Eun-Yi; Moon Aree
    Journal of cancer prevention (2015), 20 (4), 223-31 ISSN:2288-3649.
    Breast cancer is the primary cause of cancer death in women. Although current therapies have shown some promise against breast cancer, there is still no effective cure for the majority of patients in the advanced stages of breast cancer. Development of effective agents to slow, reduce, or reverse the incidence of breast cancer in high-risk women is necessary. Chemoprevention of breast cancer by natural products is advantageous, as these compounds have few side effects and low toxicity compared to synthetic compounds. In the present review, we summarize natural products which exert chemopreventive activities against breast cancer, such as curcumin, sauchinone, lycopene, denbinobin, genipin, capsaicin, and ursolic acid. This review examines the current knowledge about natural compounds and their mechanisms that underlie breast cancer chemopreventive activity both in vitro and in vivo. The present review may provide information on the use of these compounds for the prevention of breast cancer.
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    Anand, P.; Kunnumakkara, A. B.; Newman, R. A.; Aggarwal, B. B. Mol. Pharmaceutics 2007, 4, 807– 818 DOI: 10.1021/mp700113r
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    Bioavailability of Curcumin: Problems and Promises
    Anand, Preetha; Kunnumakkara, Ajaikumar B.; Newman, Robert A.; Aggarwal, Bharat B.
    Molecular Pharmaceutics (2007), 4 (6), 807-818CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
    A review. Curcumin, a polyphenolic compd. derived from dietary spice turmeric, possesses diverse pharmacol. effects including anti-inflammatory, antioxidant, antiproliferative and antiangiogenic activities. Phase I clin. trials have shown that curcumin is safe even at high doses (12 g/day) in humans but exhibit poor bioavailability. Major reasons contributing to the low plasma and tissue levels of curcumin appear to be due to poor absorption, rapid metab., and rapid systemic elimination. To improve the bioavailability of curcumin, numerous approaches have been undertaken. These approaches involve, first, the use of adjuvant like piperine that interferes with glucuronidation; second, the use of liposomal curcumin; third, curcumin nanoparticles; fourth, the use of curcumin phospholipid complex; and fifth, the use of structural analogs of curcumin (e.g., EF-24). The latter has been reported to have a rapid absorption with a peak plasma half-life. Despite the lower bioavailability, therapeutic efficacy of curcumin against various human diseases, including cancer, cardiovascular diseases, diabetes, arthritis, neurol. diseases and Crohn's disease, has been documented. Enhanced bioavailability of curcumin in the near future is likely to bring this promising natural product to the forefront of therapeutic agents for treatment of human disease.
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    Feeling 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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    New Substructure Filters for Removal of Pan Assay Interference Compounds (PAINS) from Screening Libraries and for Their Exclusion in Bioassays
    Baell, 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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    Bisson, J.; McAlpine, J. B.; Friesen, J. B.; Chen, S. N.; Graham, J.; Pauli, G. F. J. Med. Chem. 2016, 59, 1671– 90 DOI: 10.1021/acs.jmedchem.5b01009
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    Can 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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    Nelson, K. M.; Dahlin, J. L.; Bisson, J.; Graham, J.; Pauli, G. F.; Walters, M. A. J. Med. Chem. 2017, 60, 1620 DOI: 10.1021/acs.jmedchem.6b00975
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    The Essential Medicinal Chemistry of Curcumin
    Nelson, Kathryn M.; Dahlin, Jayme L.; Bisson, Jonathan; Graham, James; Pauli, Guido F.; Walters, Michael A.
    Journal of Medicinal Chemistry (2017), 60 (5), 1620-1637CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    A review. Curcumin is a constituent (3-5%) 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 compds.) and an IMPS (invalid metabolic panaceas) candidate. The likely false activity of curcumin in vitro and in vivo has resulted in >120 clin. trials of curcuminoids against several diseases. No double-blinded, placebo controlled clin. trial of curcumin has been successful. This Perspective reviews the essential medicinal chem. of curcumin and provides evidence that curcumin is an unstable, reactive, nonbioavailable compd. and, therefore, a highly improbable lead. Based on this in-depth evaluation, potential new directions for research on curcuminoids are discussed.
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    Antibacterial and Antimycobacterial Lignans and Flavonoids from Larrea tridentata
    Favela-Hernandez, J. M. J.; Garcia, A.; Garza-Gonzalez, E.; Rivas-Galindo, V. M.; Camacho-Corona, M. R.
    Phytotherapy Research (2012), 26 (12), 1957-1960CODEN: PHYREH; ISSN:0951-418X. (John Wiley & Sons Ltd.)
    Three lignans and four flavonoids were isolated and characterized from Larrea tridentata and compds. were tested against 16 bacterial species/strains. Results showed that: dihydroguaiaretic acid (1) had activity towards methicillin resistant (MR) Staphylococcus aureus (min. inhibitory concn. (MIC) 50 μg/mL) and multidrug-resistant (MDR) strains of Mycobacterium tuberculosis (MIC 12.5-50 μg/mL); 4-epi-larreatricin (2) was active against Enterobacter cloacae (MIC 12.5 μg/mL), as well as sensitive (MIC 50 μg/mL) and MDR strains of M. tuberculosis (MIC 25 μg/mL). 3'-Demethoxy-6-O-demethylisoguaiacin (3) displayed activity against sensitive and resistant S. aureus (MIC 25 μg/mL), Enterococcus faecalis (MIC 12.5 μg/mL), Escherichia coli (MIC 50 μg/mL), E. cloacae (MIC 12.5 μg/mL) and MDR strains of M. tuberculosis (MIC 12.5 μg/mL). 5,4'-Dihydroxy-3,7,8,3'-tetramethoxyflavone (4) and 5,4'-dihydroxy-3,7,8-trimethoxyflavone (5) were active against M. tuberculosis MDR strains having MIC values of 25 and 25-50 μg/mL, resp., while 5,4'-dihydroxy-7-methoxyflavone (6) was active against S. aureus (MIC 50 μg/mL) and E. faecalis (MIC 50 μg/mL). We concluded that lignan 3 is the main compd. responsible for the antibacterial activity of L. tridentata. Lignans 1 and 2 as well as flavonoid 6 contribute with some degree of antibacterial activity. On the other hand, compds. 1, 2, 3, 4 and 5 contributed to the antimycobacterial activity found in L. tridentata. Copyright © 2012 John Wiley & Sons, Ltd.
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    Yamauchi, S.; Masuda, T.; Sugahara, T.; Kawaguchi, Y.; Ohuchi, M.; Someya, T.; Akiyama, J.; Tominaga, S.; Yamawaki, M.; Kishida, T.; Akiyama, K.; Maruyama, M. Biosci., Biotechnol., Biochem. 2008, 72, 2981– 2986 DOI: 10.1271/bbb.80461
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    Choi, M. S.; Jeong, H. J.; Kang, T. H.; Shin, H. M.; Oh, S. T.; Choi, Y.; Jeon, S. Life Sci. 2015, 141, 81– 89 DOI: 10.1016/j.lfs.2015.09.003
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    Filleur, F.; Le Bail, J. C.; Duroux, J. L.; Simon, A.; Chulia, A. J. Planta Med. 2001, 67, 700– 704 DOI: 10.1055/s-2001-18349
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    Antiproliferative, anti-aromatase, anti-17β-HSD and antioxidant activities of lignans isolated from Myristica argentea
    Filleur, F.; Le Bail, J. C.; Duroux, J. L.; Simon, A.; Chulia, A. J.
    Planta Medica (2001), 67 (8), 700-704CODEN: PLMEAA; ISSN:0032-0943. (Georg Thieme Verlag)
    Four lignans were isolated from the petrol ext. of Myristica argentea mace (Myristicaceae) and their structures were elucidated by NMR and mass spectrometry. Although they have been previously described, NMR data are only available for threo-austrobailignan-5, which has been isolated only once, and is incomplete. Three of them, erythro-austrobailignan-6, meso-dihydroguaiaretic acid and nectandrin-B, exert an antiproliferative effect on MCF-7 cells as well as antioxidant activity on the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical, but not the threo-austrobailignan-5. Nectandrin-B also possesses anti-17β-hydroxysteroid dehydrogenase and anti-aromatase activities.
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    Li, S.; Li, W.; Wang, Y.; Asada, Y.; Koike, K. Bioorg. Med. Chem. Lett. 2010, 20, 5398– 401 DOI: 10.1016/j.bmcl.2010.07.110
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    Prenylflavonoids from Glycyrrhiza uralensis and their protein tyrosine phosphatase-1B inhibitory activities
    Li, Songpei; Li, Wei; Wang, Yinghua; Asada, Yoshihisa; Koike, Kazuo
    Bioorganic & Medicinal Chemistry Letters (2010), 20 (18), 5398-5401CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
    Two new 2-arylbenzofurans, glycybenzofuran (1) and cyclolicocoumarone (2), together with 10 known flavonoids including licocoumarone (3), glycyrrhisoflavone (4), glisoflavone (5), cycloglycyrrhisoflavone (6), isoliquiritigenin (7), licoflavone A (8), apigenin (9), isokaempferide (10), glycycoumarin (11), and isoglycycoumarin (12), were isolated from the roots of Glycyrrhiza uralensis and their structures were detd. by extensive spectroscopic analyses. Compds. 1 and 5 showed significant protein tyrosine phosphatase-1B (PTP1B) inhibitory activity in vitro with the IC50 values of 25.5 and 27.9 μM, resp. The structure-activity relationship indicated that the presence of prenyl group and ortho-hydroxy group is important for exhibiting the activity. Kinetic anal. indicated that compd. 1 inhibits PTP1B by a competitive mode, whereas compd. 5 by a mixed mode.
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    Peng, F.; Du, Q.; Peng, C.; Wang, N.; Tang, H.; Xie, X.; Shen, J.; Chen, J. Phytother. Res. 2015, 29, 969– 977 DOI: 10.1002/ptr.5348
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    A Review: The Pharmacology of Isoliquiritigenin
    Peng, Fu; Du, Qiaohui; Peng, Cheng; Wang, Neng; Tang, Hailin; Xie, Xiaoming; Shen, Jiangang; Chen, Jianping
    Phytotherapy Research (2015), 29 (7), 969-977CODEN: PHYREH; ISSN:0951-418X. (John Wiley & Sons Ltd.)
    A review. Isoliquiritigenin (ISL) is one of the bioactive ingredients isolated from the roots of plants belonging to licorice, including Glycyrrhiza uralensis, Mongolian glycyrrhiza, Glycyrrhiza glabra, and so forth. Liquiritigenin is available in common foods and alternative medicine, and its deriv.-ISL is applied into food additives and disease treatment like cancer therapy, antibiotic therapy, and so on. This review aims at providing a comprehensive summary of the pharmacol. activities of ISL. The information published between 1972 and 2014 from a no. of reliable sources including PubMed, ScienceDirect, Springer, and Wiley-Blackwell. The practical application of ISL on the various disease prevention and treatments may stem from its numerous pharmacol. properties such as antiinflammatory, anti-microbial, anti-oxidative, anticancer activities, immunoregulatory, hepatoprotective, and cardioprotective effects. However, further studies are needed to verify the target-organ toxicity or side effects investigation. Copyright © 2015 John Wiley & Sons, Ltd.
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    Ye, L.; Gho, W. M.; Chan, F. L.; Chen, S.; Leung, L. K. Int. J. Cancer 2009, 124, 1028– 36 DOI: 10.1002/ijc.24046
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    Dietary administration of the licorice flavonoid isoliquiritigenin deters the growth of MCF-7 cells overexpressing aromatase
    Ye, Lan; Gho, Wai M.; Chan, Franky L.; Chen, Shiuan; Leung, Lai K.
    International Journal of Cancer (2009), 124 (5), 1028-1036CODEN: IJCNAW; ISSN:0020-7136. (Wiley-Liss, Inc.)
    Licorice is the sweet-tasting rhizomes of a bean plant and is quite commonly used in Western countries for culinary purposes, while it is a medicinal herb in China. Many flavonoids have been isolated from licorice, and their pharmacol. properties may be applicable in preventive medicine. Overexposure to estrogen has been implicated in the etiol. of breast cancer, and cytochrome P 450 (CYP) 19 enzyme, or aromatase, catalyzes the rate-limiting reaction. Phytocompounds that are able to inhibit this enzyme may potentially suppress breast cancer development. In the present study the licorice flavonoid isoliquiritigenin (ILN) was shown to be an aromatase inhibitor in recombinant protein and MCF-7 cells stably transfected with CYP19 (MCF-7aro). ILN displayed a Ki value of around 3 μM, and it also blocked the MCF-7aro cell growth pertaining to the enzyme activity in vitro. Subsequently, the compd. administered in diet was given to ovariectomized athymic mice transplanted with MCF-7aro cells. This mouse model is widely accepted for studying postmenopausal breast cancer. The phytochem. significantly deterred the xenograft growth without affecting the body wt. Subsequently, the flavonoid's effect on CYP19 transcriptional control in vitro was also investigated. At the mRNA level, ILN could also suppress the expression in wild-type MCF-7 cells. Reporter gene assay and real-time PCR verified that the transactivity of CYP19 driven by promoters I.3 and II was suppressed in these cells. Deactivation of C/EBP could be the underlying mol. mechanism. Our study demonstrated that ILN was an inhibitor of aromatase and a potential chemopreventive agent against breast cancer.
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    Ateba, S. B.; Njamen, D.; Medjakovic, S.; Zehl, M.; Kaehlig, H.; Jungbauer, A.; Krenn, L. BMC Complementary Altern. Med. 2014, 14, 294 DOI: 10.1186/1472-6882-14-294
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    Lupinalbin A as the most potent estrogen receptor α- and aryl hydrocarbon receptor agonist in Eriosema laurentii de Wild. (Leguminosae)
    Ateba, Sylvin Benjamin; Njamen, Dieudonne; Medjakovic, Svjetlana; Zehl, Martin; Kaehlig, Hanspeter; Jungbauer, Alois; Krenn, Liselotte
    BMC Complementary and Alternative Medicine (2014), 14 (), 294/1-294/10, 10 pp.CODEN: BCAMCV; ISSN:1472-6882. (BioMed Central Ltd.)
    Background: Eriosema laurentii De Wild. (Leguminosae) is a plant used in Cameroon against infertility and gynecol. or menopausal complaints. In our previous report, a methanol ext. of its aerial parts was shown to exhibit estrogenic and aryl hydrocarbon receptor agonistic activities in vitro and to prevent menopausal symptoms in ovariectomized Wistar rats. Methods: In order to det. the major estrogen receptor α (ERα) agonists in the ext., an activity-guided fractionation was performed using the ERα yeast screen. To check whether the ERα active fractions/compds. also accounted for the aryl hydrocarbon receptor (AhR) agonistic activity of the crude methanol ext., they were further tested on the AhR yeast screen. Results: This study led to the identification of 2'-hydroxygenistein, lupinalbin A and genistein as major estrogenic principles of the ext. 2'-hydroxygenistein and lupinalbin A were, for the first time, also shown to possess an AhR agonistic activity, whereas genistein was not active in this assay. In addn., it was possible to deduce structure-activity relationships. Conclusions: These results suggest that the identified compds. are the major active principles responsible for the estrogenic and AhR agonistic activities of the crude methanol ext. of the aerial parts of Eriosema laurentii.
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    Rosmarinic acid
    Petersen, Maike; Simmonds, Monique S. J.
    Phytochemistry (Elsevier) (2003), 62 (2), 121-125CODEN: PYTCAS; ISSN:0031-9422. (Elsevier Science Ltd.)
    A review. Rosmarinic acid is an ester of caffeic acid and 3,4-dihydroxyphenyllactic acid. It is commonly found in species of the Boraginaceae and the subfamily Nepetoideae of the Lamiaceae. However, it is also found in species of other higher plant families and in some fern and hornwort species. Rosmarinic acid has a no. of interesting biol. activities, e.g. antiviral, antibacterial, antiinflammatory and antioxidant. The presence of rosmarinic acid in medicinal plants, herbs and spices has beneficial and health promoting effects. In plants, rosmarinic acid is supposed to act as a preformed constitutively accumulated defense compd. The biosynthesis of rosmarinic acid starts with the amino acids L-phenylalanine and L-tyrosine. All eight enzymes involved in the biosynthesis are known and characterized and cDNAs of several of the involved genes have been isolated. Plant cell cultures, e.g. from Coleus blumei or Salvia officinalis, accumulate rosmarinic acid in amts. much higher than in the plant itself (up to 36% of the cell dry wt.). For this reason a biotechnol. prodn. of rosmarinic acid with plant cell cultures has been proposed.
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    Comfrey: A Clinical Overview
    Staiger, Christiane
    Phytotherapy Research (2012), 26 (10), 1441-1448CODEN: PHYREH; ISSN:0951-418X. (John Wiley & Sons Ltd.)
    A review. Comfrey has a centuries-old tradition as a medicinal plant. Today, multiple randomized controlled trials have demonstrated the efficacy and safety of comfrey prepns. for the topical treatment of pain, inflammation and swelling of muscles and joints in degenerative arthritis, acute myalgia in the back, sprains, contusions and strains after sports injuries and accidents, also in children aged 3 or 4 and over. This paper provides information on clin. trials and non-interventional studies published on comfrey to date and further literature, substantiating the fact that topical comfrey prepns. are a valuable therapy option for the treatment of painful muscle and joint complaints. Copyright © 2012 John Wiley & Sons, Ltd.
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    Blazevic, I.; Radonic, A.; Mastelic, J.; Zekic, M.; Skocibusic, M.; Maravic, A. Chem. Biodiversity 2010, 7, 2023– 2034 DOI: 10.1002/cbdv.200900234
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    Synthesis and spectroscopic characterisation of a combinatorial library based on the fungal natural product 3-chloro-4-hydroxyphenylacetamide
    Davis, Rohan A.; Pierens, Gregory K.; Parsons, Peter G.
    Magnetic Resonance in Chemistry (2007), 45 (5), 442-445CODEN: MRCHEG; ISSN:0749-1581. (John Wiley & Sons Ltd.)
    Parallel soln.-phase chem. has yielded a series of secondary amide analogs of the fungal natural product 3-chloro-4-hydroxyphenylacetamide. 3-Chloro-4-hydroxyphenylacetic acid was coupled to a variety of primary amines using 1-ethyl-3-(3'-dimethylaminopropyl)-carbodiimide hydrochloride. The desired products were obtained in good yield and high purity following rapid silica purifn. All analogs were spectroscopically characterized using NMR, UV, IR and MS data. One compd. displayed moderate cytotoxicity against the human melanoma and prostate cell lines, MM96L and DU145.
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    Goldberg, F. W.; Dossetter, A. G.; Scott, J. S.; Robb, G. R.; Boyd, S.; Groombridge, S. D.; Kemmitt, P. D.; Sjögren, T.; Gutierrez, P. M.; deSchoolmeester, J.; Swales, J. G.; Turnbull, A. V.; Wild, M. J. J. Med. Chem. 2014, 57, 970– 986 DOI: 10.1021/jm4016729
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    17β-Hydroxysteroid dehydrogenases involved in local oestrogen synthesis have prognostic significance in breast cancer
    Gunnarsson, C.; Hellqvist, E.; Stal, O.
    British Journal of Cancer (2005), 92 (3), 547-552CODEN: BJCAAI; ISSN:0007-0920. (Nature Publishing Group)
    The 17β-hydroxysteroid dehydrogenase (17HSD) enzymes are involved in the local regulation of sex steroids. The 17HSD type 1 enzyme catalyzes the interconversion of the weak estrone (E1) to the more potent estradiol (E2), whereas 17HSD type 2 catalyzes the oxidn. of E2 to E1. The aim of this study was to correlate the expression of these enzymes in the tumor with the recurrence-free survival of tamoxifen-treated breast cancer patients. We used real-time reverse transcriptase PCR to investigate the mRNA expression of 17HSD types 1 and 2 in tumor samples from 230 postmenopausal patients. For the patients with estrogen receptor (ER)-pos. breast cancer, we found a statistically significant pos. correlation between recurrence-free survival and expression of 17HSD type 2 (P=0.026). We examd. the ratio of 17HSD types 2 and 1, and ER-pos. patients with low ratios showed a significantly higher rate of recurrence than those with higher ratios (P=0.0047). ER pos. patients with high expression levels of 17HSD type 1 had a significantly higher risk for late relapse (P=0.0051). The expression of 17HSD types 1 and 2 in breast cancer differs from the expression of these enzymes in normal mammary gland, and this study indicates that the expression has prognostic significance in breast cancer.
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    Kitawaki, J.; Koshiba, H.; Ishihara, H.; Kusuki, I.; Tsukamoto, K.; Honjo, H. J. Clin. Endocrinol. Metab. 2000, 85, 3292– 6 DOI: 10.1210/jcem.85.9.6829
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    Progesterone induction of 17β-hydroxysteroid dehydrogenase type 2 during the secretory phase occurs in the endometrium of estrogen-dependent benign diseases but not in normal endometrium
    Kitawaki, Jo; Koshiba, Hisato; Ishihara, Hiroaki; Kusuki, Izumi; Tsukamoto, Katsumi; Honjo, Hideo
    Journal of Clinical Endocrinology and Metabolism (2000), 85 (9), 3292-3296CODEN: JCEMAZ; ISSN:0021-972X. (Endocrine Society)
    In the human endometrium, inactivation of 17β-estradiol to estrone is catalyzed by 17β-hydroxysteroid dehydrogenase type 2 (17βHSD2). Previous studies have shown that the 17βHSD2 activity in the endometrium is elevated during the secretory phase, as compared with the level during the proliferative phase, and that the elevation is in response to progesterone via the progesterone receptors. Recently, it has been demonstrated that aromatase cytochrome P 450, the enzyme responsible for estrogen biosynthesis, is not present in the endometrium obtained from normal menstruating women with cervical cancer in situ showing no other gynecol. disease (defined as "disease free"), but present in the endometrium obtained from patients with endometriosis, adenomyosis, and/or leiomyomas (defined as "diseased"). However, the previous 17βHSD studies have been performed without distinguishing between disease-free and diseased endometria. The authors, therefore, analyzed 17βHSD2 distinguishing between disease-free and diseased endometria. During the proliferative phase, the abundance of mRNA and activity of 17βHSD2 were comparable in both disease-free and diseased endometrium. However, during the secretory phase, while the abundance of mRNA and activity of 17βHSD2 increased 4- to 6-fold in diseased endometrium, the 17βHSD2 remained unchanged in the disease-free endometrium. Kinetic studies showed that the Km was identical among the four groups of endometria, suggesting that the elevation of 17βHSD2 simply resulted from increased mRNA transcription. Organ culture of proliferative endometria in the presence of progestins resulted in the stimulation of 17βHSD2 in diseased endometria via the progesterone receptors, whereas disease-free endometrium was not stimulated by progestins. These results suggest that the previous paradigm that 17βHSD2 activity in the endometrium is elevated during the secretory phase is confined to diseased endometrium but not to disease-free endometrium and that the estrogen metab. is altered in the endometria of the patients with estrogen-dependent benign diseases.
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    Davis, R. A.; Carroll, A. R.; Andrews, K. T.; Boyle, G. M.; Tran, T. L.; Healy, P. C.; Kalaitzis, J. A.; Shivas, R. G. Org. Biomol. Chem. 2010, 8, 1785– 1790 DOI: 10.1039/b924169h
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    Choomuenwai, V.; Andrews, K. T.; Davis, R. A. Bioorg. Med. Chem. 2012, 20, 7167– 7174 DOI: 10.1016/j.bmc.2012.09.052
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    Synthesis and antimalarial evaluation of a screening library based on a tetrahydroanthraquinone natural product scaffold
    Choomuenwai, Vanida; Andrews, Katherine T.; Davis, Rohan A.
    Bioorganic & Medicinal Chemistry (2012), 20 (24), 7167-7174CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)
    As part of a research program aimed at discovering new antimalarial leads from Australian macrofungi a unique fungi-derived prefractionated library was screened against a chloroquine-sensitive Plasmodium falciparum line (3D7) using a radiometric growth inhibition assay. A library fraction derived from a Cortinarius species displayed promising antimalarial activity. UV-guided fractionation on the CH2Cl2/MeOH ext. from this fungus resulted in the isolation of four known compds.: (1S,3R)-austrocortirubin (1), (1S,3S)-austrocortirubin (2), 1-deoxyaustrocortirubin (3), and austrocortinin (4). Compd. 2 was used as a natural product scaffold in the parallel soln.-phase synthesis of a small library of N-substituted tetrahydroanthraquinones (5-15). All compds. (1-15) were tested in vitro against P. falciparum 3D7 parasites and (1S,3S)-austrocortirubin (2), the major fungal constituent, was shown to be the most active compd. with an IC50 of 1.9 μM. This compd. displayed moderate cytotoxicity against neonatal foreskin fibroblast (NFF) cells with an IC50 of 15.6 μM.
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    Levrier, C.; Balastrier, M.; Beattie, K. D.; Carroll, A. R.; Martin, F.; Choomuenwai, V.; Davis, R. A. Phytochemistry 2013, 86, 121– 126 DOI: 10.1016/j.phytochem.2012.09.019
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    Barnes, E. C.; Said, N. A. B. M.; Williams, E. D.; Hooper, J. N. A.; Davis, R. A. Tetrahedron 2010, 66, 283– 287 DOI: 10.1016/j.tet.2009.10.109
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    Liberio, M. S.; Sooraj, D.; Williams, E. D.; Feng, Y.; Davis, R. A. Tetrahedron Lett. 2011, 52, 6729– 6731 DOI: 10.1016/j.tetlet.2011.09.151
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    Barnes, E. C.; Choomuenwai, V.; Andrews, K. T.; Quinn, R. J.; Davis, R. A. Org. Biomol. Chem. 2012, 10, 4015– 4023 DOI: 10.1039/c2ob00029f
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    Design and synthesis of screening libraries based on the muurolane natural product scaffold
    Barnes, Emma C.; Choomuenwai, Vanida; Andrews, Katherine T.; Quinn, Ronald J.; Davis, Rohan A.
    Organic & Biomolecular Chemistry (2012), 10 (20), 4015-4023CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)
    The plant-derived natural product 14-hydroxy-6,12-muuroloadien-15-oic acid (1) was identified as a unique scaffold that could be chem. elaborated to generate novel lead- or drug-like screening libraries. Prior to synthesis a virtual library was generated and prioritized based on drug-like physicochem. parameters such as log P, log D5.5, hydrogen bond donors/acceptors, and mol. wt. The natural product scaffold (1) was isolated from the endemic Australian plant Eremophila mitchelli and then utilized in the parallel soln.-phase generation of two series of analogs. The first library consisted of six semisynthetic amide derivs., while the second contained six carbamate analogs. These libraries have been evaluated for antimalarial activity using a chloroquine-sensitive Plasmodium falciparum line (3D7) and several compds. displayed low to moderate activity with IC50 values ranging from 14 to 33 μM.
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    Atanasov, A. G.; Wang, J. N.; Gu, S. P.; Bu, J.; Kramer, M. P.; Baumgartner, L.; Fakhrudin, N.; Ladurner, A.; Malainer, C.; Vuorinen, A.; Noha, S. M.; Schwaiger, S.; Rollinger, J. M.; Schuster, D.; Stuppner, H.; Dirsch, V. M.; Heiss, E. H. Biochim. Biophys. Acta, Gen. Subj. 2013, 1830, 4813– 9 DOI: 10.1016/j.bbagen.2013.06.021
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    Honokiol: A non-adipogenic PPARγ agonist from nature
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  • Abstract

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    Figure 1

    Figure 1. Enzymatic reactions catalyzed by 17β-HSD2 and reverse reactions catalyzed by other HSD enzymes.

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    Figure 2

    Figure 2. Pharmacophore models for 17β-HSD2 inhibitors. (A) Chemical features of models 1 and 2 describing the types, locations, and tolerance spheres of inhibitory chemical functionalities. Pharmacophore features are colored as follows: red, hydrogen-bond acceptor; green, hydrogen-bond donor; yellow, hydrophobic; and blue, aromatic ring. Optional features are depicted in scattered style. (B) Full versions of models 1 and 2 with gray exclusion volumes as steric restraints for inhibitor size (forbidden areas). A 3D video view of model 1 is available as Supporting Information.

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    Figure 3

    Figure 3. Structures of natural products identified in this study that inhibit 17β-HSD2.

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    Figure 4

    Figure 4. Semisynthetic fungal natural products that inhibit 17β-HSD2.

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    Figure 5

    Figure 5. Illustration of the SAR of semisynthetic natural product derivatives (Table 3). (A) The core structure with compounds S12 (gray), S15 (red), and S11 (blue) with a pharmacophore model illustrating the interaction pattern. (B) The moderately active compounds 14 (yellow) and 15 (gray) with the additional hydrophobic feature. (C) The most active compounds 13 (orange), N-benzyl-2-(3-chloro-4-hydroxyphenyl)acetamide (16, green), N-(2-(1H-indol-3-yl)ethyl)-2-(3-chloro-4-hydroxyphenyl) (17, purple), and 18 (gray) with the additional aromatic ring feature.

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    Figure 6

    Figure 6. SAR of the flavonoids inhibiting 17β-HSD2. (A) The three most active compounds, 9 (2′-hydroxygenistein, blue), kaempferol (30, red), and quercetin (31, green), share a combined hydrogen bond acceptor/donor at position C-4′, a hydrophobic (aromatic) ring (ring B), two neighboring hydrogen bond acceptors on rings A and C, and the aromatic ring A. (B) The moderately active inhibitors 5 (magenta), naringenin (23, gray), genistein (32, black), and biochanin A (33, yellow) fit into the SAR-pharmacophore illustrating the importance of the hydrogen bond acceptor features on the B and C rings, respectively. (C) For comparison, the general flavonoid model not distinguishing active from inactive compounds is shown with all 17 flavonoids from Table 4.

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    Figure 7

    Figure 7. Alignment of the 17β-HSD2 inhibitor model 1 from Vuorinen et al. (19) and the SAR model (features highlighted by grid) for highly active flavonoids. The pharmacophore features are color-coded: hydrogen bond acceptor, red; hydrogen bond donor, green; hydrophobic, yellow; aromatic ring, blue. The alignment centers are indicated with orange spheres.

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    4. 4
      Mustonen, M. V.; Isomaa, V. V.; Vaskivuo, T.; Tapanainen, J.; Poutanen, M. H.; Stenback, F.; Vihko, R. K.; Vihko, P. T. J. Clin. Endocrinol. Metab. 1998, 83, 1319– 1324 DOI: 10.1210/jcem.83.4.4709
      4
      Human 17β-hydroxysteroid dehydrogenase type 2 messenger ribonucleic acid expression and localization in term placenta and in endometrium during the menstrual cycle
      Mustonen, Mika V. J.; Isomaa, Veli V.; Vaskivuo, Tommi; Tapanainen, Juha; Poutanen, Matti H.; Stenback, Frej; Vihko, Reijo K.; Vihko, Pirkko T.
      Journal of Clinical Endocrinology and Metabolism (1998), 83 (4), 1319-1324CODEN: JCEMAZ; ISSN:0021-972X. (Endocrine Society)
      According to the current hypothesis, 17β-hydroxysteroid dehydrogenases (17HSDs) regulate the extent of estrogen influence in the endometrium by converting estradiol (E2) locally into a biol. less active sex steroid, estrone (E1), and vice versa. Recently, we have shown that both 17HSD type 1 and type 2 are expressed in the human endometrium, and in the present work, using in situ hybridization, we show that 17HSD type 2 is localized in the glandular epithelial cells as previously shown for the type 1 enzyme, but in contrast to type 1, the expression of type 2 is highest at the end of the cycle. Hence, we hypothesize that the differential expression of the two 17HSD enzymes, with opposite activities in same cell types, could modulate intracellular E2 concns. during the end of the luteal phase of the menstrual cycle. We further analyzed the expression of 17HSD type 1 and type 2 mRNAs in term human placenta. Expression of 17HSD type 1 mRNA was detected in the syncytiotrophoblasts, and signals for type 2 mRNA were found inside the villi, corresponding to cytotrophoblasts. The expression of 17HSD type 2 in the placenta may serve to maintain the presence of inactive sex steroids and attenuate the formation of biol. potent androgens and estrogens.
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    5. 5
      Takeyama, J.; Sasano, H.; Suzuki, T.; Iinuma, K.; Nagura, H.; Andersson, S. J. Clin. Endocrinol. Metab. 1998, 83, 3710– 3715 DOI: 10.1210/jcem.83.10.5212
      5
      17β-Hydroxysteroid dehydrogenase types 1 and 2 in human placenta: an immunohistochemical study with correlation to placental development
      Takeyama, Junji; Sasano, Hironobu; Suzuki, Takashi; Iinuma, Kazuie; Nagura, Hiroshi; Andersson, Stefan
      Journal of Clinical Endocrinology and Metabolism (1998), 83 (10), 3710-3715CODEN: JCEMAZ; ISSN:0021-972X. (Endocrine Society)
      In estrogen metab., the enzymic properties of the 17β-hydroxysteroid dehydrogenase (17βHSD) isoenzymes play very important roles in steroid hormone metab. in various tissues, including the placenta. 17βHSD type 1 catalyzes primarily the redn. of estrone (E1) to estradiol (E2), whereas 17βHSD type 2 catalyzes primarily the oxidn. of E2 to E1. In this study, we examd. immunohistochem. localization of 17βHSD types 1 and 2 in human placenta (31 cases) ranging from 4-40 wk gestation. The immunoreactivity of 17βHSD type 1 was exclusively detected in syncytiotrophoblast from 4 wk gestation to term placenta. Immunoreactivity of 17βHSD type 2 first appeared in endothelial cells of intravillous vessels at 12 wk gestation, and the no. of 17βHSD type 2-pos. endothelial cells markedly increased up to 19 wk, then reached a plateau. We quant. evaluated the 17βHSD type 2-pos. endothelial cells in chorionic villi and detd. the ratio of 17βHSD type 2-pos. endothelial cells using immunohistochem. of CD34, an endothelial antigen, in serial mirror tissue sections and subsequent image anal. using CAS 200. CD34 was detected from 4 wk gestation, and its pos. areas continued to increase toward term. The 17βHSD type 2-pos. area per CD34-pos. area markedly increased from 13 wk gestation and reached a plateau at 19 wk gestation, in which almost all endothelial cells were pos. for 17βHSD type 2. 17βHSD type 2, therefore, is considered to prevent the passage of excessive estrogens into the fetal circulation at endothelial cells of the intravillous fetal capillaries by catalyzing the inactivation of E2 to E1.
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    6. 6
      Puranen, T. J.; Kurkela, R. M.; Lakkakorpi, J. T.; Poutanen, M. H.; Itaranta, P. V.; Melis, J. P.; Ghosh, D.; Vihko, R. K.; Vihko, P. T. Endocrinology 1999, 140, 3334– 3341 DOI: 10.1210/endo.140.7.6861
      There is no corresponding record for this reference.
    7. 7
      Wu, L.; Einstein, M.; Geissler, W. M.; Chan, H. K.; Elliston, K. O.; Andersson, S. J. Biol. Chem. 1993, 268, 12964– 12969
      There is no corresponding record for this reference.
    8. 8
      Lukacik, P.; Kavanagh, K. L.; Oppermann, U. Mol. Cell. Endocrinol. 2006, 248, 61– 71 DOI: 10.1016/j.mce.2005.12.007
      8
      Structure and function of human 17β-hydroxysteroid dehydrogenases
      Lukacik, Petra; Kavanagh, Kathryn L.; Oppermann, Udo
      Molecular and Cellular Endocrinology (2006), 248 (1-2), 61-71CODEN: MCEND6; ISSN:0303-7207. (Elsevier Ltd.)
      A review. 17β-Hydroxysteroid dehydrogenases (17β-HSDs) catalyze the NAD(P)(H)-dependent oxidoredn. at C17 oxo/β-hydroxyl groups of androgen and estrogen hormones. This reversible reaction constitutes an important pre-receptor control mechanism for nuclear receptor ligands, since the conversion "switches" between the 17β-OH receptor ligands and their inactive 17-oxo metabolites. At present, 14 mammalian 17β-HSDs have been described, of which at least 11 exist within the human genome, encoded by different genes. The enzymes differ in their expression pattern, nucleotide cofactor preference, steroid substrate specificity, and subcellular localization, and thus constitute a complex system ensuring cell-specific adaptation and regulation of sex steroid hormone levels. Broad and overlapping substrate specificities with enzymes involved in lipid metab. suggest interactions of several 17β-HSDs with other metabolic pathways. Several 17β-HSDs constitute promising drug targets, of particular importance in cancer, metabolic diseases, neurodegeneration, and possibly immunity.
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    9. 9
      Dufort, I.; Rheault, P.; Huang, X. F.; Soucy, P.; Luu-The, V. Endocrinology 1999, 140, 568– 574 DOI: 10.1210/endo.140.2.6531
      There is no corresponding record for this reference.
    10. 10
      Geissler, W. M.; Davis, D. L.; Wu, L.; Bradshaw, K. D.; Patel, S.; Mendonca, B. B.; Elliston, K. O.; Wilson, J. D.; Russell, D. W.; Andersson, S. Nat. Genet. 1994, 7, 34– 39 DOI: 10.1038/ng0594-34
      10
      Male pseudohermaphroditism caused by mutations of testicular 17β-hydroxysteroid dehydrogenase 3
      Geissler, Wayne M.; Davis, Daphne L.; Wu, Ling; Bradshaw, Karen D.; Patel, Sushma; Mendonca, Berenice B.; Elliston, Keith O.; Wilson, Jean D.; Russell, David W.; Andersson, Stefan
      Nature Genetics (1994), 7 (1), 34-39CODEN: NGENEC; ISSN:1061-4036.
      Defects in the conversion of androstenedione to testosterone in the fetal testes by the enzyme 17β-hydroxysteroid dehydrogenase (17β-HSD) give rise to genetic males with female external genitalia. The authors have used expression cloning to isolate cDNAs encoding a microsomal 17β-HSD type 3 isoenzyme that shares 23% sequence identity with other 17β-HSD enzymes, uses NADPH as a cofactor, and is expressed predominantly in the testes. The 17βHSD3 gene on chromosome 9q22 contains 11 exons. Four substitution and two splice junction mutations were identified in the 17βHSD3 genes of five unrelated male pseudohermaphrodites. The substitution mutations severely compromised the activity of the 17β-HSD type 3 isoenzyme.
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    11. 11
      Ghosh, D.; Vihko, P. Chem.-Biol. Interact. 2001, 130–132, 637– 650 DOI: 10.1016/S0009-2797(00)00255-6
      11
      Molecular mechanisms of estrogen recognition and 17-keto reduction by human 17β-hydroxysteroid dehydrogenase 1
      Ghosh, D.; Vihko, P.
      Chemico-Biological Interactions (2001), 130-132 (1-3), 637-650CODEN: CBINA8; ISSN:0009-2797. (Elsevier Science Ireland Ltd.)
      A review with 34 refs. The redn. of inactive estrone (E1) to the active estrogen 17β-estradiol (E2) is catalyzed by type 1 17β-hydroxysteroid dehydrogenase (17HSD1). Crystallog. studies, modeling and activity measurement of mutants and chimeric enzymes have led to the understanding of its mechanism of action and the mol. basis for the estrogenic specificity. An electrophilic attack on the C17-keto oxygen by the Tyr 155 hydroxyl is proposed for initiation of the transition state. The active site is a hydrophobic pocket with catalytic residues at one end and the recognition machinery on the other. Tyr 155, Lys 159 and Ser 142 are essential for the activity. The presence of certain other amino acids near the substrate recognition end of the active site including His 152 and Pro 187 is crit. to the shape complementarity of estrogenic ligands. His 221 and Glu 282 form hydrogen bonds with 3-hydroxyl of the arom. A-ring of the ligand. This mechanism of recognition of E1 by 17HSD1 is similar to that of E2 by estrogen receptor α. In a ternary complex with NADP+ and equilin, an equine estrogen with C7=C8 double bond, the orientation of C17=O of equilin relative to the C4-hydride is more acute than the near normal approach of the hydride for the substrate. In the apo-enzyme structure, a substrate-entry loop (residues 186-201) is in an open conformation. The loop is closed in this complex and Phe 192 and Met 193 make contacts with the ligand. Residues of the entry loop could be partially responsible for the estrogenic specificity.
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    12. 12
      Soubhye, J.; Alard, I. C.; van Antwerpen, P.; Dufrasne, F. Future Med. Chem. 2015, 7, 1431– 1456 DOI: 10.4155/fmc.15.74
      12
      Type 2 17-β hydroxysteroid dehydrogenase as a novel target for the treatment of osteoporosis
      Soubhye, Jalal; Alard, Ibaa Chikh; van Antwerpen, Pierre; Dufrasne, Francois
      Future Medicinal Chemistry (2015), 7 (11), 1431-1456CODEN: FMCUA7; ISSN:1756-8919. (Future Science Ltd.)
      Low estradiol level in postmenopausal women is implicated in osteoporosis, which occurs because of the high bone resorption rate. Estrogen formation is controlled by 17-β hydroxysteroid dehydrogenase 17-β HSD enzymes, where 17-β HSD type 1 contributes in the formation of estradiol, while type 2 catalyzes its catabolism. Inhibiting 17-β HSD2 can help in increasing estradiol concn. Several promising 17-β HSD2 inhibitors that can act at low nanomolar range have been identified. However, there are some specific challenges assocd. with the application of these compds. Our review provides an up-to-date summary of the current status and recent progress in the prodn. of 17-β HSD2 inhibitors as well as the future challenges in their clin. application.
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    13. 13
      Compston, J. E. Physiol. Rev. 2001, 81, 419– 447
      There is no corresponding record for this reference.
    14. 14
      Riggs, B. L.; Khosla, S.; Melton, L. J. J. Bone Miner. Res. 1998, 13, 763– 773 DOI: 10.1359/jbmr.1998.13.5.763
      14
      A unitary model for involutional osteoporosis: estrogen deficiency causes both type I and type II osteoporosis in postmenopausal women and contributes to bone loss in aging men
      Riggs B L; Khosla S; Melton L J 3rd
      Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research (1998), 13 (5), 763-73 ISSN:0884-0431.
      We propose here a new unitary model for the pathophysiology of involutional osteoporosis that identifies estrogen (E) deficiency as the cause of both the early, accelerated and the late, slow phases of bone loss in postmenopausal women and as a contributing cause of the continuous phase of bone loss in aging men. The accelerated phase in women is most apparent during the first decade after menopause, involves disproportionate loss of cancellous bone, and is mediated mainly by loss of the direct restraining effects of E on bone cell function. The ensuing slow phase continues throughout life in women, involves proportionate losses of cancellous and cortical bone, and is associated with progressive secondary hyperparathyroidism. This phase is mediated mainly by loss of E action on extraskeletal calcium homeostasis which results in net calcium wasting and increases in the level of dietary calcium intake required to maintain bone balance. Because elderly men have low circulating levels of both bioavailable E and bioavailable testosterone (T) and because recent data suggest that E is at least as important as T in determining bone mass in aging men, E deficiency may also contribute substantially to the continuous bone loss of aging men. In both genders, E deficiency increases bone resorption and may also impair a compensatory increase in bone formation. For the most part, this unitary model is well supported by observational and experimental data and provides plausible explanations to traditional objections to a unitary hypothesis.
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    15. 15
      Chin, K.-Y.; Ima-Nirwana, S. Int. J. Endocrinol. 2012, 2012, 208719 DOI: 10.1155/2012/208719
      15
      Sex steroids and bone health status in men
      Chin Kok-Yong; Ima-Nirwana Soelaiman
      International journal of endocrinology (2012), 2012 (), 208719 ISSN:.
      Male osteoporosis is a health problem which deserves more attention as nearly 30% of osteoporotic fractures happen in men aged 50 years and above. Although men do not experience an accelerated bone loss phase and testosterone deficiency is not a universal characteristic for aged men, osteoporosis due to age-related testosterone deficiency does have a negative impact on bone health status of men. Observations from epidemiological studies indicate that elderly men with higher testosterone can preserve their BMD better and thus are less prone to fracture. Observations on men with estrogen resistance or aromatase deficiency indicate that estrogen is equally important in the maintenance of bone health status. This had been validated in several epidemiological studies which found that the relationships between estrogen and bone health indices are significant and sometimes stronger than testosterone. Studies on the relationship between quantitative ultrasound and bone remodeling markers suggest that testosterone and estrogen may have differential effects on bone, but further evidence was needed. In conclusion, both testosterone and estrogen are important in the maintenance of bone health in men.
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    16. 16
      Michael, H.; Härkönen, P. L.; Väänänen, H. K.; Hentunen, T. A. J. Bone Miner. Res. 2005, 20, 2224– 2232 DOI: 10.1359/JBMR.050803
      16
      Estrogen and testosterone use different cellular pathways to inhibit osteoclastogenesis and bone resorption
      Michael, Husheem; Harkonen, Pirkko L.; Vaananen, H. Kalervo; Hentunen, Teuvo A.
      Journal of Bone and Mineral Research (2005), 20 (12), 2224-2232CODEN: JBMREJ; ISSN:0884-0431. (American Society for Bone and Mineral Research)
      Using human peripheral blood CD14+ osteoclast precursors, we show that testosterone directly inhibits osteoclast formation and bone resorption at physiol. concns. Instead, estrogen has no direct effects, whereas its action seems to be mediated through osteoblasts by producing osteoprotegerin. Both estrogen and testosterone acts through their cognate receptors. Introduction: Estrogen (E2) deficiency is assocd. with both the development of postmenopausal and senile form of osteoporosis in elderly women. Testosterone (Te) deficiency, on the other hand, may cause osteoporosis in men. In both sexes, osteoporosis is assocd. with disturbed bone turnover, including increased bone resorption caused by enhanced osteoclast formation and increased osteoclast activity. However, the mechanisms by which E2 or Te act on bone are not fully understood, and one of the central questions is whether these hormones act directly on osteoclast precursors or whether their action is mediated through osteoblastic cells. Materials and Methods: We cultured human peripheral blood CD14+ osteoclast precursors in the presence of RANKL, macrophage-colony stimulating factor (M-CSF), TNF-α, and dexamethasone to induce them to differentiate into osteoclasts. To study the possible osteoblast-mediated effects, osteoclast precursors were also co-cultured either with human MG-63 or SaOS-2 osteoblast-derived osteosarcoma cells. These cultures were treated with 10-8-10-12 M of E2 or Te for 7 days. Results: E2 did not have any direct effect on osteoclast formation, whereas testosterone inhibited osteoclast formation and bone resorption in a dose-dependent manner. In co-cultures, where MG-63 or SaOS-2 cells were present, E2 and Te inhibited osteoclast formation in a dose-dependent manner. At the same time, E2 and Te treatment in MG-63 or SaOS-2 cell-contg. cultures stimulated significantly the formation of osteoprotegerin (OPG) compared with untreated cultures measured by ELISA assay from the culture medium. The effects of E2 and Te on osteoclast formation and bone resorption were completely antagonized by an E2 receptor (ER) antagonist, ICI 182,780, and an androgen receptor (AR) antagonist, flutamide, suggesting ER- and AR-mediated mechanisms, resp., in these cultures. Conclusions: Te is likely to have direct and indirect inhibitory effects on human osteoclast formation and bone resorption, whereas the effect of E2 on osteoclast precursors and osteoclasts seems to be mediated by osteoblastic cells. Inhibitory effect of E2 is assocd. with the stimulated secretion of OPG by osteoblast-derived osteosarcoma cells. Mechanism of action of E2 and Te is mediated by ER and AR, resp.
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    17. 17
      Bagi, C. M.; Wood, J.; Wilkie, D.; Dixon, B. J. Musculoskelet. Neuronal. Interact. 2008, 8, 267– 280
      17
      Effect of 17β-hydroxysteroid dehydrogenase type 2 inhibitor on bone strength in ovariectomized cynomolgus monkeys
      Bagi, C. M.; Wood, J.; Wilkie, D.; Dixon, B.
      Journal of Musculoskeletal & Neuronal Interactions (2008), 8 (3), 267-280CODEN: JMNIB3; ISSN:1108-7161. (Journal of Musculoskeletal and Neuronal Interactions)
      In both sexes, a redn. in sex steroid prodn. with aging impairs the musculoskeletal system. The goal of our study was to test the ability of WH-9062, a novel non-steroidal small mol. inhibitor of the 17β-Hydroxysteroid Dehydrogenase type 2 enzyme, to maintain or improve bone strength without raising serum levels of testosterone or estradiol. Mature, female cynomolgus monkeys with sealed growth plates were allocated into six groups: Sham controls, OVX controls, OVX+Premarin (15 mg/kg/d), and three groups of OVX monkeys receiving WH-9062 at 1, 5 and 25 mg/kg/day. All treatments were administered by daily oral dosing for 23 wk. Changes in lipid profile caused by OVX were cor. with WH-9062 and included lowering total of cholesterol and non-HDL cholesterol, and maintenance of initial plasma levels of HDL cholesterol. Only the highest dose of WH-9062 lowered bone resorption relative to OVX controls. Elevated bone specific alk. phosphatase, osteocalcin, BMC and dynamic bone histomorphometry data resulted in desirable bone balance and bone strength. The obtained results support our theory that inhibition of 17β-HSD type 2 resulted in high local estrogen and/or testosterone levels leading to maintenance of bone formation and bone strength. Collectively, our data demonstrated that the treatment paradigm that utilizes tissue selectivity and receptor bioavailability in conversion of inactive hormones to active forms could be achieved and could result in desirable effects on target tissues such as bone and muscles.
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    18. 18
      Perspicace, E.; Cozzoli, L.; Gargano, E. M.; Hanke, N.; Carotti, A.; Hartmann, R. W.; Marchais-Oberwinkler, S. Eur. J. Med. Chem. 2014, 83, 317– 337 DOI: 10.1016/j.ejmech.2014.06.036
      There is no corresponding record for this reference.
    19. 19
      Vuorinen, A.; Engeli, R.; Meyer, A.; Bachmann, F.; Griesser, U. J.; Schuster, D.; Odermatt, A. J. Med. Chem. 2014, 57, 5995– 6007 DOI: 10.1021/jm5004914
      There is no corresponding record for this reference.
    20. 20
      Wetzel, M.; Marchais-Oberwinkler, S.; Perspicace, E.; Möller, G.; Adamski, J.; Hartmann, R. W. J. Med. Chem. 2011, 54, 7547– 7557 DOI: 10.1021/jm2008453
      There is no corresponding record for this reference.
    21. 21
      Xu, K.; Al-Soud, Y. A.; Wetzel, M.; Hartmann, R. W.; Marchais-Oberwinkler, S. Eur. J. Med. Chem. 2011, 46, 5978– 5990 DOI: 10.1016/j.ejmech.2011.10.010
      There is no corresponding record for this reference.
    22. 22
      Deluca, D.; Krazeisen, A.; Breitling, R.; Prehn, C.; Möller, G.; Adamski, J. J. Steroid Biochem. Mol. Biol. 2005, 93, 285– 292 DOI: 10.1016/j.jsbmb.2004.12.035
      22
      Inhibition of 17beta-hydroxysteroid dehydrogenases by phytoestrogens: Comparison with other steroid metabolizing enzymes
      Deluca, D.; Krazeisen, A.; Breitling, R.; Prehn, C.; Moeller, G.; Adamski, J.
      Journal of Steroid Biochemistry and Molecular Biology (2005), 93 (2-5), 285-292CODEN: JSBBEZ; ISSN:0960-0760. (Elsevier B.V.)
      A review of effects of phytoestrogens on human health have been reported for decades. These include not only beneficial action in cancer prevention but also endocrine disruption in males. Since then many mol. mechanisms underlying these effects have been identified. Targets of phytoestrogens comprise steroid receptors, steroid metabolising enzymes, elements of signal transduction and apoptosis pathways, and even the DNA processing machinery. Understanding the specific vs. pleiotropic effects of selected phytoestrogens will be crucial for their biomedical application. This review will conc. on the influence of phytoestrogens on 17beta-hydroxysteroid dehydrogenases from a comparative perspective with other steroid metabolizing enzymes.
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    23. 23
      Le Bail, J. C.; Laroche, T.; Marre-Fournier, F.; Habrioux, G. Cancer Lett. 1998, 133, 101– 106 DOI: 10.1016/S0304-3835(98)00211-0
      23
      Aromatase and 17β-hydroxysteroid dehydrogenase inhibition by flavonoids
      Le Bail, J. C.; Laroche, T.; Marre-Fournier, F.; Habrioux, G.
      Cancer Letters (Shannon, Ireland) (1998), 133 (1), 101-106CODEN: CALEDQ; ISSN:0304-3835. (Elsevier Science Ireland Ltd.)
      A method for estg. in the same assay both aromatase and 17β-hydroxysteroid dehydrogenase activities in human placental microsomes using radiolabeled [1,2,6,7-3H]4-androstene-3,17-dione was proposed. In this assay, estrone (E1) and estradiol (E2) produced were sepd. by HPLC and estd. using a radioactive flow detector. Using this method, the inhibitory effect of various flavonoids, including flavone, flavanone and isoflavone, on the human placental aromatase and 17β-hydroxysteroid dehydrogenase was studied. Flavonoids were shown to be potent inhibitors of both aromatase and 17β-hydroxysteroid dehydrogenase activities. We found that 7-hydroxyflavone and apigenin are the most effective aromatase and 17β-hydroxysteroid dehydrogenase inhibitors, resp. Expts. showed that a hydroxyl group in position 7 was essential for anti-17β-hydroxysteroid dehydrogenase activity. However, flavonoids with 7-methoxy or 8-hydroxyl groups on the A ring showed only anti-aromatase activity. Structure-activity relationships were discussed.
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    24. 24
      Schuster, D.; Nashev, L. G.; Kirchmair, J.; Laggner, C.; Wolber, G.; Langer, T.; Odermatt, A. J. Med. Chem. 2008, 51, 4188– 4199 DOI: 10.1021/jm800054h
      There is no corresponding record for this reference.
    25. 25
      Atanasov, 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. Biotechnol. Adv. 2015, 33, 1582– 614 DOI: 10.1016/j.biotechadv.2015.08.001
      25
      Discovery and resupply of pharmacologically active plant-derived natural products: A review
      Atanasov, 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, Hermann
      Biotechnology 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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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhvFGjsbjJ&md5=e1f2296576f1f80b984d99adbf83a20d
    26. 26
      Newman, D. J.; Cragg, G. M. J. Nat. Prod. 2012, 75, 311– 335 DOI: 10.1021/np200906s
      26
      Natural Products As Sources of New Drugs over the 30 Years from 1981 to 2010
      Newman, David J.; Cragg, Gordon M.
      Journal of Natural Products (2012), 75 (3), 311-335CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)
      This review is an updated and expanded version of the three prior reviews that were published in this journal in 1997, 2003, and 2007. In the case of all approved therapeutic agents, the time frame has been extended to cover the 30 years from Jan. 1, 1981, to Dec. 31, 2010, for all diseases worldwide, and from 1950 (earliest so far identified) to Dec. 2010 for all approved antitumor drugs worldwide. We have continued to utilize our secondary subdivision of a "natural product mimic" or "NM" to join the original primary divisions and have added a new designation, "natural product botanical" or "NB", to cover those botanical "defined mixts." that have now been recognized as drug entities by the FDA and similar organizations. From the data presented, the utility of natural products as sources of novel structures, but not necessarily the final drug entity, is still alive and well. Thus, in the area of cancer, over the time frame from around the 1940s to date, of the 175 small mols., 131, or 74.8%, are other than "S" (synthetic), with 85, or 48.6%, actually being either natural products or directly derived therefrom. In other areas, the influence of natural product structures is quite marked, with, as expected from prior information, the anti-infective area being dependent on natural products and their structures. Although combinatorial chem. techniques have succeeded as methods of optimizing structures and have been used very successfully in the optimization of many recently approved agents, we are able to identify only one de novo combinatorial compd. approved as a drug in this 30-yr time frame. We wish to draw the attention of readers to the rapidly evolving recognition that a significant no. of natural product drugs/leads are actually produced by microbes and/or microbial interactions with the "host from whence it was isolated", and therefore we consider that this area of natural product research should be expanded significantly.
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    27. 27
      Eder, J.; Sedrani, R.; Wiesmann, C. Nat. Rev. Drug Discovery 2014, 13, 577– 587 DOI: 10.1038/nrd4336
      There is no corresponding record for this reference.
    28. 28
      Williamson, E. M.; Heinrich, M.; Jäger, A. K., Eds. Ethnopharmacology; John Wiley & Sons Ltd: Chichester, West Sussex, UK, 2015; pp 213– 226.
      There is no corresponding record for this reference.
    29. 29
      Sharma, C.; Kumari, T.; Arya, K. R. Int. J. Pharm. Res. Health Sci. 2014, 2, 185– 190
      There is no corresponding record for this reference.
    30. 30
      Blum, A.; Favia, A. D.; Maser, E. Mol. Cell. Endocrinol. 2009, 301, 132– 136 DOI: 10.1016/j.mce.2008.08.028
      30
      11β-Hydroxysteroid dehydrogenase type 1 inhibitors with oleanan and ursan scaffolds
      Blum, Andreas; Favia, Angelo D.; Maser, Edmund
      Molecular and Cellular Endocrinology (2009), 301 (1-2), 132-136CODEN: MCEND6; ISSN:0303-7207. (Elsevier Ireland Ltd.)
      The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) converts cortisone to the active glucocorticoid cortisol, thereby acting as a cellular switch to mediate glucocorticoid action in many tissues. Several studies have indicated that 11β-HSD1 plays a crucial role in the onset of type 2 diabetes and central obesity. As a consequence, selective inhibition of 11β-HSD1 in humans might become a new and promising approach for lowering blood glucose concns. and for counteracting the accumulation of visceral fat and its related metabolic abnormalities in type 2 diabetes. In this study, we present the synthesis and the biol. evaluation of ursan or oleanan type triterpenoids which may act as selective 11β-HSD1 inhibitors in liver as well as in peripheral tissues, like adipocytes and muscle cells. In order to rationalize the outcomes of the inhibition data, docking simulations of the ligands were performed on the exptl. detd. structure of 11β-HSD1. Furthermore, we discuss the structural determinants that confer enzymic specificity. From our investigation, valuable information has been obtained to design selective 11β-HSD1 blockers based on the oleanan and ursan scaffold.
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    31. 31
      Kratschmar, D. V.; Vuorinen, A.; Da Cunha, T.; Wolber, G.; Classen-Houben, D.; Doblhoff, O.; Schuster, D.; Odermatt, A. J. Steroid Biochem. Mol. Biol. 2011, 125, 129– 142 DOI: 10.1016/j.jsbmb.2010.12.019
      31
      Characterization of activity and binding mode of glycyrrhetinic acid derivatives inhibiting 11β-hydroxysteroid dehydrogenase type 2
      Kratschmar, Denise V.; Vuorinen, Anna; Da Cunha, Thierry; Wolber, Gerhard; Classen-Houben, Dirk; Doblhoff, Otto; Schuster, Daniela; Odermatt, Alex
      Journal of Steroid Biochemistry and Molecular Biology (2011), 125 (1-2), 129-142CODEN: JSBBEZ; ISSN:0960-0760. (Elsevier Ltd.)
      Modulation of intracellular glucocorticoid availability is considered as a promising strategy to treat glucocorticoid-dependent diseases. 18β-Glycyrrhetinic acid (GA), the biol. active triterpenoid metabolite of glycyrrhizin, which is contained in the roots and rhizomes of licorice (Glycyrrhiza spp.), represents a well-known but non-selective inhibitor of 11β-hydroxysteroid dehydrogenases (11β-HSDs). However, to assess the physiol. functions of the resp. enzymes and for potential therapeutic applications selective inhibitors are needed. In the present study, we applied bioassays and 3D-structure modeling to characterize nine 11β-HSD1 and fifteen 11β-HSD2 inhibiting GA derivs. Comparison of the GA derivs. in assays using cell lysates revealed that modifications at the 3-hydroxyl and/or the carboxyl led to highly selective and potent 11β-HSD2 inhibitors. The data generated significantly extends our knowledge on structure-activity relationship of GA derivs. as 11β-HSD inhibitors. Using recombinant enzymes we found also potent inhibition of mouse 11β-HSD2, despite significant species-specific differences. The selected GA derivs. potently inhibited 11β-HSD2 in intact SW-620 colon cancer cells, although the rank order of inhibitory potential differed from that obtained in cell lysates. The biol. activity of compds. was further demonstrated in glucocorticoid receptor (GR) transactivation assays in cells coexpressing GR and 11β-HSD1 or 11β-HSD2. 3D-structure modeling provides an explanation for the differences in the selectivity and activity of the GA derivs. investigated. The most potent and selective 11β-HSD2 inhibitors should prove useful as mechanistic tools for further anti-inflammatory and anti-cancer in vitro and in vivo studies. Article from the Special issue on Targeted Inhibitors.
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    32. 32
      Rollinger, J. M.; Kratschmar, D. V.; Schuster, D.; Pfisterer, P. H.; Gumy, C.; Aubry, E. M.; Brandstötter, S.; Stuppner, H.; Wolber, G.; Odermatt, A. Bioorg. Med. Chem. 2010, 18, 1507– 1515 DOI: 10.1016/j.bmc.2010.01.010
      There is no corresponding record for this reference.
    33. 33
      Vuorinen, A.; Seibert, J.; Papageorgiou, V. P.; Rollinger, J. M.; Odermatt, A.; Schuster, D.; Assimopoulou, A. N. Planta Med. 2015, 81, 525– 532 DOI: 10.1055/s-0035-1545720
      There is no corresponding record for this reference.
    34. 34
      Lambert, J. D.; Zhao, D.; Meyers, R. O.; Kuester, R. K.; Timmermann, B. N.; Dorr, R. T. Toxicon 2002, 40, 1701– 1708 DOI: 10.1016/S0041-0101(02)00203-9
      There is no corresponding record for this reference.
    35. 35
      Mikuni, M.; Yoshida, M.; Hellberg, P.; Peterson, C. A.; Edwin, S. S.; Brännström, M.; Peterson, C. M. Biol. Reprod. 1998, 58, 1211– 1216 DOI: 10.1095/biolreprod58.5.1211
      35
      The lipoxygenase inhibitor, nordihydroguaiaretic acid, inhibits ovulation and reduces leukotriene and prostaglandin levels in the rat ovary
      Mikuni, Masato; Yoshida, Mami; Hellberg, Pir; Peterson, C. Anthony; Edwin, Samuel S.; Brannstrom, Mats; Peterson, C. Matthew
      Biology of Reproduction (1998), 58 (5), 1211-1216CODEN: BIREBV; ISSN:0006-3363. (Society for the Study of Reproduction)
      Eicosanoids, the active metabolites of arachidonic acid, are grouped into cyclooxygenase products (prostaglandins [PGs] and thromboxanes) and lipoxygenase products (leukotrienes [LTs] and lipoxins). Numerous studies suggest a role for the lipoxygenase system in ovulation. The aim of this study was to further characterize the effects of lipoxygenase inhibition and the interactions of the lipoxygenase and cyclooxygenase systems in the rat ovary during ovulation. The lipoxygenase inhibitor, nordihydroguaiaretic acid (NDGA), was administered in vivo and in the isolated perfused rat ovary to det. its effect on ovulation rate. The in vivo study confirmed the inhibitory effect of NDGA, and in the perfusion expts., NDGA caused a dose-dependent redn. in the ovulation rate. To further define the interaction between the lipoxygenase and cyclooxygenase systems, a second set of perfusions was performed with NDGA (10 μM) and the combination of NDGA (10 μM) plus a nonselective cyclooxygenase inhibitor, indomethacin (10 μM). NDGA significantly reduced the no. of ovulations compared to that in controls. The ovulation rate for the combination of NDGA+indomethacin was also significantly lower than in controls but not different from that in the NDGA-treated group. Steroidogenesis was decreased only in the NDGA+indomethacin perfusions. Ovarian tissue PGE2 and PGF2α levels in the NDGA-treated ovaries were significantly suppressed compared to those in controls. Almost a complete block of PGE2 and PGF2α was seen in the NDGA+indomethacin group. LTB4 levels in the 10-h-perfused ovarian tissues were significantly decreased by NDGA compared to those in control tissues. Furthermore, LTB4 (3 μg added twice) completely reversed the inhibitory effect of 0.1 μM NDGA on ovulation rate and partially reversed the effect of 10 μM NDGA in the perfusion model. These results demonstrate that the products of the lipoxygenase pathway, esp. LTB4, are important in the process of ovulation in this cyclically ovulating species. The interconnected lipoxygenase and cyclooxygenase pathways may optimize ovulation and facilitate steroidogenesis.
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    36. 36
      Benassayag, C.; Perrot-Applanat, M.; Ferre, F. J. Chromatogr. B: Anal. Technol. Biomed. Life Sci. 2002, 777, 233– 248 DOI: 10.1016/S1570-0232(02)00340-9
      36
      Phytoestrogens as modulators of steroid action in target cells
      Benassayag, C.; Perrot-Applanat, M.; Ferre, F.
      Journal of Chromatography, B: Analytical Technologies in the Biomedical and Life Sciences (2002), 777 (1-2), 233-248CODEN: JCBAAI; ISSN:1570-0232. (Elsevier Science B.V.)
      A review. Although numerous reports exist on the potential beneficial role of nutritional phytoestrogens in human health, their mol. mechanism in target cells is still not completely understood. Phytoestrogens promote estrogen and antiestrogen effects by interacting with numerous mols., carrier proteins, enzymes and membrane and nuclear receptors, directly or indirectly involved in the transfer of estrogen signals. The hypothesis that the ERβ subtype plays a key role in antiproliferative effect of phytoestrogens, esp. in breast cancer, is examd. here. This review focus on the effects of phytoestrogens in developmental processes such as those linked to reproductive function, tumorigenesis and angiogenesis.
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    37. 37
      Fujimoto, N.; Kohta, R.; Kitamura, S.; Honda, H. Life Sci. 2004, 74, 1417– 1425 DOI: 10.1016/j.lfs.2003.08.012
      There is no corresponding record for this reference.
    38. 38
      Ono, K.; Hasegawa, K.; Yoshiike, Y.; Takashima, A.; Yamada, M.; Naiki, H. J. Neurochem. 2002, 81, 434– 40 DOI: 10.1046/j.1471-4159.2002.00904.x
      38
      Nordihydroguaiaretic acid potently breaks down pre-formed Alzheimer's β-amyloid fibrils in vitro
      Ono, Kenjiro; Hasegawa, Kazuhiro; Yoshiike, Yuji; Takashima, Akihiko; Yamada, Masahito; Naiki, Hironobu
      Journal of Neurochemistry (2002), 81 (3), 434-440CODEN: JONRA9; ISSN:0022-3042. (Blackwell Science Ltd.)
      Inhibition of the accumulation of amyloid β-peptide (Aβ) and the formation of β-amyloid fibrils (fAβ) from Aβ, as well as the degrdn. of pre-formed fAβ in the CNS would be attractive therapeutic objectives for the treatment of Alzheimer's disease (AD). We previously reported that nordihydroguaiaretic acid (NDGA) inhibited fAβ formation from Aβ(1-40) and Aβ(1-42) dose-dependently in the range of 10-30 μM in vitro. Utilizing fluorescence spectroscopic anal. with thioflavin T and electron microscopic study, we show here that NDGA dose-dependently breaks down fAβ(1-40) and fAβ(1-42) within a few hours at pH 7.5 at 37. At 4 h, the fluorescence of fAβ(1-40) and fAβ(1-42) incubated with 50 μM NDGA was 5% and 10% of the initial fluorescence, resp. The activity of NDGA to break down these fAβs was obsd. even at a low concn. of 0.1 μM. At 1 h, many short, sheared fibrils were obsd. in the mixt. incubated with 50 μM NDGA, and at 4 h, the no. of fibrils reduced markedly, and small amorphous aggregates were obsd. We next compared the activity of NDGA to break down fAβ(1-40) and fAβ(1-42), with other mols. reported to inhibit fAβ formation from Aβ and/or to degrade pre-formed fAβ both in vivo and in vitro. At a concn. of 50 μM, the overall activity of the mols. examd. in this study was in the order of: NDGA » rifampicin = tetracycline > poly(vinylsulfonic acid, sodium salt) = 1,3-propane disulfonic acid, disodium salt > β-sheet breaker peptide (iAβ5). In cell culture expts., fAβ disrupted by NDGA were less toxic than intact fAβ, as demonstrated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Although the mechanisms by which NDGA inhibits fAβ formation from Aβ, as well as breaking down pre-formed fAβ in vitro, are still unclear, NDGA could be a key mol. for the development of therapeutics for AD.
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    39. 39
      Yamada, M.; Ono, K.; Hamaguchi, T.; Noguchi-Shinohara, M. Adv. Exp. Med. Biol. 2015, 863, 79– 94 DOI: 10.1007/978-3-319-18365-7_4
      There is no corresponding record for this reference.
    40. 40
      Gupta, S. C.; Patchva, S.; Koh, W.; Aggarwal, B. B. Clin. Exp. Pharmacol. Physiol. 2012, 39, 283– 299 DOI: 10.1111/j.1440-1681.2011.05648.x
      40
      Discovery of curcumin, a component of golden spice, and its miraculous biological activities
      Gupta, Subash C.; Patchva, Sridevi; Koh, Wonil; Aggarwal, Bharat B.
      Clinical and Experimental Pharmacology and Physiology (2012), 39 (3), 283-299CODEN: CEXPB9; ISSN:0305-1870. (Wiley-Blackwell)
      A review. 1. Curcumin is the active ingredient of the dietary spice turmeric and was consumed for medicinal purposes for thousands of years. Modern science has shown that curcumin modulates various signaling mols., including inflammatory mols., transcription factors, enzymes, protein kinases, protein reductases, carrier proteins, cell survival proteins, drug resistance proteins, adhesion mols., growth factors, receptors, cell cycle regulatory proteins, chemokines, DNA, RNA, and metal ions. 2. Because of this polyphenol's potential to modulate multiple signaling mols., it was reported to possess pleiotropic activities. First demonstrated to have antibacterial activity in 1949, curcumin has since been shown to have anti-inflammatory, anti-oxidant, pro-apoptotic, chemopreventive, chemotherapeutic, antiproliferative, wound healing, antinociceptive, antiparasitic, and antimalarial properties as well. Animal studies have suggested that curcumin may be active against a wide range of human diseases, including diabetes, obesity, neurol. and psychiatric disorders, and cancer, as well as chronic illnesses affecting the eyes, lungs, liver, kidneys, and gastrointestinal and cardiovascular systems. 3. Although many clin. trials evaluating the safety and efficacy of curcumin against human ailments have already been completed, others are still ongoing. Moreover, curcumin is used as a supplement in several countries, including India, Japan, the US, Thailand, China, Korea, Turkey, South Africa, Nepal, and Pakistan. Although inexpensive, apparently well tolerated and potentially active, curcumin was not approved for the treatment of any human disease. 4. In the present article, we discuss the discovery and key biol. activities of curcumin, with a particular emphasis on its activities at the mol. and cellular levels, as well as in animals and humans.
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    41. 41
      Manolova, Y.; Deneva, V.; Antonov, L.; Drakalska, E.; Momekova, D.; Lambov, N. Spectrochim. Acta, Part A 2014, 132, 815– 820 DOI: 10.1016/j.saa.2014.05.096
      41
      The effect of the water on the curcumin tautomerism: A quantitative approach
      Manolova, Yana; Deneva, Vera; Antonov, Liudmil; Drakalska, Elena; Momekova, Denitsa; Lambov, Nikolay
      Spectrochimica Acta, Part A: Molecular and Biomolecular Spectroscopy (2014), 132 (), 815-820CODEN: SAMCAS; ISSN:1386-1425. (Elsevier B.V.)
      The tautomerism of curcumin has been investigated in ethanol/water binary mixts. by using UV-Vis spectroscopy and advanced quantum-chem. calcns. The spectral changes were processed by using advanced chemometric procedure, based on resoln. of overlapping bands technique. As a result, molar fractions of the tautomers and their individual spectra have been estd. It has been shown that in ethanol the enol-keto tautomer only is presented. The addn. of water leads to appearance of a new spectral band, which was assigned to the diketo tautomeric form. The results show that in 90% water/10% ethanol the diketo form is dominating. The obsd. shift in the equil. is explained by the quantum chem. calcns., which show that water mols. stabilize diketo tautomer through formation of stable complexes. To our best knowledge we report for the first time quant. data for the tautomerism of curcumin and the effect of the water.
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    42. 42
      Eigner, D.; Scholz, D. J. Ethnopharmacol. 1999, 67, 1– 6 DOI: 10.1016/S0378-8741(98)00234-7
      There is no corresponding record for this reference.
    43. 43
      Ghosh, S.; Banerjee, S.; Sil, P. C. Food Chem. Toxicol. 2015, 83, 111– 24 DOI: 10.1016/j.fct.2015.05.022
      43
      The beneficial role of curcumin on inflammation, diabetes and neurodegenerative disease: A recent update
      Ghosh, 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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    44. 44
      Epstein, J.; Sanderson, I. R.; Macdonald, T. T. Br. J. Nutr. 2010, 103, 1545– 1557 DOI: 10.1017/S0007114509993667
      44
      Curcumin as a therapeutic agent: the evidence from in vitro, animal and human studies
      Epstein, Jenny; Sanderson, Ian R.; MacDonald, Thomas T.
      British Journal of Nutrition (2010), 103 (11), 1545-1557CODEN: BJNUAV; ISSN:0007-1145. (Cambridge University Press)
      A review. Curcumin is the active ingredient of turmeric. It is widely used as a kitchen spice and food colorant throughout India, Asia and the Western world. Curcumin is a major constituent of curry powder, to which it imparts its characteristic yellow color. For over 4000 years, curcumin has been used in traditional Asian and African medicine to treat a wide variety of ailments. There is a strong current public interest in naturally occurring plant-based remedies and dietary factors related to health and disease. Curcumin is non-toxic to human subjects at high doses. It is a complex mol. with multiple biol. targets and different cellular effects. Recently, its mol. mechanisms of action have been extensively investigated. It has anti-inflammatory, antioxidant and anti-cancer properties. Under some circumstances its effects can be contradictory, with uncertain implications for human treatment. While more studies are warranted to further understand these contradictions, curcumin holds promise as a disease-modifying and chemopreventive agent. We review the evidence for the therapeutic potential of curcumin from in vitro studies, animal models and human clin. trials.
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    45. 45
      Ko, E. Y.; Moon, A. J. Cancer Prev. 2015, 20, 223– 231 DOI: 10.15430/JCP.2015.20.4.223
      45
      Natural Products for Chemoprevention of Breast Cancer
      Ko Eun-Yi; Moon Aree
      Journal of cancer prevention (2015), 20 (4), 223-31 ISSN:2288-3649.
      Breast cancer is the primary cause of cancer death in women. Although current therapies have shown some promise against breast cancer, there is still no effective cure for the majority of patients in the advanced stages of breast cancer. Development of effective agents to slow, reduce, or reverse the incidence of breast cancer in high-risk women is necessary. Chemoprevention of breast cancer by natural products is advantageous, as these compounds have few side effects and low toxicity compared to synthetic compounds. In the present review, we summarize natural products which exert chemopreventive activities against breast cancer, such as curcumin, sauchinone, lycopene, denbinobin, genipin, capsaicin, and ursolic acid. This review examines the current knowledge about natural compounds and their mechanisms that underlie breast cancer chemopreventive activity both in vitro and in vivo. The present review may provide information on the use of these compounds for the prevention of breast cancer.
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    46. 46
      Anand, P.; Kunnumakkara, A. B.; Newman, R. A.; Aggarwal, B. B. Mol. Pharmaceutics 2007, 4, 807– 818 DOI: 10.1021/mp700113r
      46
      Bioavailability of Curcumin: Problems and Promises
      Anand, Preetha; Kunnumakkara, Ajaikumar B.; Newman, Robert A.; Aggarwal, Bharat B.
      Molecular Pharmaceutics (2007), 4 (6), 807-818CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
      A review. Curcumin, a polyphenolic compd. derived from dietary spice turmeric, possesses diverse pharmacol. effects including anti-inflammatory, antioxidant, antiproliferative and antiangiogenic activities. Phase I clin. trials have shown that curcumin is safe even at high doses (12 g/day) in humans but exhibit poor bioavailability. Major reasons contributing to the low plasma and tissue levels of curcumin appear to be due to poor absorption, rapid metab., and rapid systemic elimination. To improve the bioavailability of curcumin, numerous approaches have been undertaken. These approaches involve, first, the use of adjuvant like piperine that interferes with glucuronidation; second, the use of liposomal curcumin; third, curcumin nanoparticles; fourth, the use of curcumin phospholipid complex; and fifth, the use of structural analogs of curcumin (e.g., EF-24). The latter has been reported to have a rapid absorption with a peak plasma half-life. Despite the lower bioavailability, therapeutic efficacy of curcumin against various human diseases, including cancer, cardiovascular diseases, diabetes, arthritis, neurol. diseases and Crohn's disease, has been documented. Enhanced bioavailability of curcumin in the near future is likely to bring this promising natural product to the forefront of therapeutic agents for treatment of human disease.
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    47. 47
      Baell, J. B. J. Nat. Prod. 2016, 79, 616– 28 DOI: 10.1021/acs.jnatprod.5b00947
      47
      Feeling 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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    48. 48
      Baell, J. B.; Holloway, G. A. J. Med. Chem. 2010, 53, 2719– 40 DOI: 10.1021/jm901137j
      48
      New Substructure Filters for Removal of Pan Assay Interference Compounds (PAINS) from Screening Libraries and for Their Exclusion in Bioassays
      Baell, 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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    49. 49
      Bisson, J.; McAlpine, J. B.; Friesen, J. B.; Chen, S. N.; Graham, J.; Pauli, G. F. J. Med. Chem. 2016, 59, 1671– 90 DOI: 10.1021/acs.jmedchem.5b01009
      49
      Can 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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    50. 50
      Nelson, K. M.; Dahlin, J. L.; Bisson, J.; Graham, J.; Pauli, G. F.; Walters, M. A. J. Med. Chem. 2017, 60, 1620 DOI: 10.1021/acs.jmedchem.6b00975
      50
      The Essential Medicinal Chemistry of Curcumin
      Nelson, Kathryn M.; Dahlin, Jayme L.; Bisson, Jonathan; Graham, James; Pauli, Guido F.; Walters, Michael A.
      Journal of Medicinal Chemistry (2017), 60 (5), 1620-1637CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      A review. Curcumin is a constituent (3-5%) 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 compds.) and an IMPS (invalid metabolic panaceas) candidate. The likely false activity of curcumin in vitro and in vivo has resulted in >120 clin. trials of curcuminoids against several diseases. No double-blinded, placebo controlled clin. trial of curcumin has been successful. This Perspective reviews the essential medicinal chem. of curcumin and provides evidence that curcumin is an unstable, reactive, nonbioavailable compd. and, therefore, a highly improbable lead. Based on this in-depth evaluation, potential new directions for research on curcuminoids are discussed.
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    51. 51
      Ma, C. J.; Sung, S. H.; Kim, Y. C. Planta Med. 2004, 70, 79– 80 DOI: 10.1055/s-2004-815463
      There is no corresponding record for this reference.
    52. 52
      Kwon, H. S.; Kim, M. J.; Jeong, H. J.; Yang, M. S.; Park, K. H.; Jeong, T. S.; Lee, W. S. Bioorg. Med. Chem. Lett. 2008, 18, 194– 198 DOI: 10.1016/j.bmcl.2007.10.098
      There is no corresponding record for this reference.
    53. 53
      Favela-Hernandez, J. M.; Garcia, A.; Garza-Gonzalez, E.; Rivas-Galindo, V. M.; Camacho-Corona, M. R. Phytother. Res. 2012, 26, 1957– 1960 DOI: 10.1002/ptr.4660
      53
      Antibacterial and Antimycobacterial Lignans and Flavonoids from Larrea tridentata
      Favela-Hernandez, J. M. J.; Garcia, A.; Garza-Gonzalez, E.; Rivas-Galindo, V. M.; Camacho-Corona, M. R.
      Phytotherapy Research (2012), 26 (12), 1957-1960CODEN: PHYREH; ISSN:0951-418X. (John Wiley & Sons Ltd.)
      Three lignans and four flavonoids were isolated and characterized from Larrea tridentata and compds. were tested against 16 bacterial species/strains. Results showed that: dihydroguaiaretic acid (1) had activity towards methicillin resistant (MR) Staphylococcus aureus (min. inhibitory concn. (MIC) 50 μg/mL) and multidrug-resistant (MDR) strains of Mycobacterium tuberculosis (MIC 12.5-50 μg/mL); 4-epi-larreatricin (2) was active against Enterobacter cloacae (MIC 12.5 μg/mL), as well as sensitive (MIC 50 μg/mL) and MDR strains of M. tuberculosis (MIC 25 μg/mL). 3'-Demethoxy-6-O-demethylisoguaiacin (3) displayed activity against sensitive and resistant S. aureus (MIC 25 μg/mL), Enterococcus faecalis (MIC 12.5 μg/mL), Escherichia coli (MIC 50 μg/mL), E. cloacae (MIC 12.5 μg/mL) and MDR strains of M. tuberculosis (MIC 12.5 μg/mL). 5,4'-Dihydroxy-3,7,8,3'-tetramethoxyflavone (4) and 5,4'-dihydroxy-3,7,8-trimethoxyflavone (5) were active against M. tuberculosis MDR strains having MIC values of 25 and 25-50 μg/mL, resp., while 5,4'-dihydroxy-7-methoxyflavone (6) was active against S. aureus (MIC 50 μg/mL) and E. faecalis (MIC 50 μg/mL). We concluded that lignan 3 is the main compd. responsible for the antibacterial activity of L. tridentata. Lignans 1 and 2 as well as flavonoid 6 contribute with some degree of antibacterial activity. On the other hand, compds. 1, 2, 3, 4 and 5 contributed to the antimycobacterial activity found in L. tridentata. Copyright © 2012 John Wiley & Sons, Ltd.
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    54. 54
      Yamauchi, S.; Masuda, T.; Sugahara, T.; Kawaguchi, Y.; Ohuchi, M.; Someya, T.; Akiyama, J.; Tominaga, S.; Yamawaki, M.; Kishida, T.; Akiyama, K.; Maruyama, M. Biosci., Biotechnol., Biochem. 2008, 72, 2981– 2986 DOI: 10.1271/bbb.80461
      There is no corresponding record for this reference.
    55. 55
      Choi, M. S.; Jeong, H. J.; Kang, T. H.; Shin, H. M.; Oh, S. T.; Choi, Y.; Jeon, S. Life Sci. 2015, 141, 81– 89 DOI: 10.1016/j.lfs.2015.09.003
      There is no corresponding record for this reference.
    56. 56
      Filleur, F.; Le Bail, J. C.; Duroux, J. L.; Simon, A.; Chulia, A. J. Planta Med. 2001, 67, 700– 704 DOI: 10.1055/s-2001-18349
      56
      Antiproliferative, anti-aromatase, anti-17β-HSD and antioxidant activities of lignans isolated from Myristica argentea
      Filleur, F.; Le Bail, J. C.; Duroux, J. L.; Simon, A.; Chulia, A. J.
      Planta Medica (2001), 67 (8), 700-704CODEN: PLMEAA; ISSN:0032-0943. (Georg Thieme Verlag)
      Four lignans were isolated from the petrol ext. of Myristica argentea mace (Myristicaceae) and their structures were elucidated by NMR and mass spectrometry. Although they have been previously described, NMR data are only available for threo-austrobailignan-5, which has been isolated only once, and is incomplete. Three of them, erythro-austrobailignan-6, meso-dihydroguaiaretic acid and nectandrin-B, exert an antiproliferative effect on MCF-7 cells as well as antioxidant activity on the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical, but not the threo-austrobailignan-5. Nectandrin-B also possesses anti-17β-hydroxysteroid dehydrogenase and anti-aromatase activities.
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    57. 57
      Li, S.; Li, W.; Wang, Y.; Asada, Y.; Koike, K. Bioorg. Med. Chem. Lett. 2010, 20, 5398– 401 DOI: 10.1016/j.bmcl.2010.07.110
      57
      Prenylflavonoids from Glycyrrhiza uralensis and their protein tyrosine phosphatase-1B inhibitory activities
      Li, Songpei; Li, Wei; Wang, Yinghua; Asada, Yoshihisa; Koike, Kazuo
      Bioorganic & Medicinal Chemistry Letters (2010), 20 (18), 5398-5401CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
      Two new 2-arylbenzofurans, glycybenzofuran (1) and cyclolicocoumarone (2), together with 10 known flavonoids including licocoumarone (3), glycyrrhisoflavone (4), glisoflavone (5), cycloglycyrrhisoflavone (6), isoliquiritigenin (7), licoflavone A (8), apigenin (9), isokaempferide (10), glycycoumarin (11), and isoglycycoumarin (12), were isolated from the roots of Glycyrrhiza uralensis and their structures were detd. by extensive spectroscopic analyses. Compds. 1 and 5 showed significant protein tyrosine phosphatase-1B (PTP1B) inhibitory activity in vitro with the IC50 values of 25.5 and 27.9 μM, resp. The structure-activity relationship indicated that the presence of prenyl group and ortho-hydroxy group is important for exhibiting the activity. Kinetic anal. indicated that compd. 1 inhibits PTP1B by a competitive mode, whereas compd. 5 by a mixed mode.
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    58. 58
      Peng, F.; Du, Q.; Peng, C.; Wang, N.; Tang, H.; Xie, X.; Shen, J.; Chen, J. Phytother. Res. 2015, 29, 969– 977 DOI: 10.1002/ptr.5348
      58
      A Review: The Pharmacology of Isoliquiritigenin
      Peng, Fu; Du, Qiaohui; Peng, Cheng; Wang, Neng; Tang, Hailin; Xie, Xiaoming; Shen, Jiangang; Chen, Jianping
      Phytotherapy Research (2015), 29 (7), 969-977CODEN: PHYREH; ISSN:0951-418X. (John Wiley & Sons Ltd.)
      A review. Isoliquiritigenin (ISL) is one of the bioactive ingredients isolated from the roots of plants belonging to licorice, including Glycyrrhiza uralensis, Mongolian glycyrrhiza, Glycyrrhiza glabra, and so forth. Liquiritigenin is available in common foods and alternative medicine, and its deriv.-ISL is applied into food additives and disease treatment like cancer therapy, antibiotic therapy, and so on. This review aims at providing a comprehensive summary of the pharmacol. activities of ISL. The information published between 1972 and 2014 from a no. of reliable sources including PubMed, ScienceDirect, Springer, and Wiley-Blackwell. The practical application of ISL on the various disease prevention and treatments may stem from its numerous pharmacol. properties such as antiinflammatory, anti-microbial, anti-oxidative, anticancer activities, immunoregulatory, hepatoprotective, and cardioprotective effects. However, further studies are needed to verify the target-organ toxicity or side effects investigation. Copyright © 2015 John Wiley & Sons, Ltd.
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    59. 59
      Ye, L.; Gho, W. M.; Chan, F. L.; Chen, S.; Leung, L. K. Int. J. Cancer 2009, 124, 1028– 36 DOI: 10.1002/ijc.24046
      59
      Dietary administration of the licorice flavonoid isoliquiritigenin deters the growth of MCF-7 cells overexpressing aromatase
      Ye, Lan; Gho, Wai M.; Chan, Franky L.; Chen, Shiuan; Leung, Lai K.
      International Journal of Cancer (2009), 124 (5), 1028-1036CODEN: IJCNAW; ISSN:0020-7136. (Wiley-Liss, Inc.)
      Licorice is the sweet-tasting rhizomes of a bean plant and is quite commonly used in Western countries for culinary purposes, while it is a medicinal herb in China. Many flavonoids have been isolated from licorice, and their pharmacol. properties may be applicable in preventive medicine. Overexposure to estrogen has been implicated in the etiol. of breast cancer, and cytochrome P 450 (CYP) 19 enzyme, or aromatase, catalyzes the rate-limiting reaction. Phytocompounds that are able to inhibit this enzyme may potentially suppress breast cancer development. In the present study the licorice flavonoid isoliquiritigenin (ILN) was shown to be an aromatase inhibitor in recombinant protein and MCF-7 cells stably transfected with CYP19 (MCF-7aro). ILN displayed a Ki value of around 3 μM, and it also blocked the MCF-7aro cell growth pertaining to the enzyme activity in vitro. Subsequently, the compd. administered in diet was given to ovariectomized athymic mice transplanted with MCF-7aro cells. This mouse model is widely accepted for studying postmenopausal breast cancer. The phytochem. significantly deterred the xenograft growth without affecting the body wt. Subsequently, the flavonoid's effect on CYP19 transcriptional control in vitro was also investigated. At the mRNA level, ILN could also suppress the expression in wild-type MCF-7 cells. Reporter gene assay and real-time PCR verified that the transactivity of CYP19 driven by promoters I.3 and II was suppressed in these cells. Deactivation of C/EBP could be the underlying mol. mechanism. Our study demonstrated that ILN was an inhibitor of aromatase and a potential chemopreventive agent against breast cancer.
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    60. 60
      Choi, S. Y.; Ha, T. Y.; Ahn, J. Y.; Kim, S. R.; Kang, K. S.; Hwang, I. K.; Kim, S. Planta Med. 2008, 74, 25– 32 DOI: 10.1055/s-2007-993760
      There is no corresponding record for this reference.
    61. 61
      Ateba, S. B.; Njamen, D.; Medjakovic, S.; Hobiger, S.; Mbanya, J. C.; Jungbauer, A.; Krenn, L. J. Ethnopharmacol. 2013, 150, 298– 307 DOI: 10.1016/j.jep.2013.08.050
      There is no corresponding record for this reference.
    62. 62
      Waltenberger, B.; Rollinger, J. M.; Griesser, U. J.; Stuppner, H.; Gelbrich, T. Acta Crystallogr., Sect. C: Cryst. Struct. Commun. 2011, 67, o409– 12 DOI: 10.1107/S0108270111035761
      There is no corresponding record for this reference.
    63. 63
      Ateba, S. B.; Njamen, D.; Medjakovic, S.; Zehl, M.; Kaehlig, H.; Jungbauer, A.; Krenn, L. BMC Complementary Altern. Med. 2014, 14, 294 DOI: 10.1186/1472-6882-14-294
      63
      Lupinalbin A as the most potent estrogen receptor α- and aryl hydrocarbon receptor agonist in Eriosema laurentii de Wild. (Leguminosae)
      Ateba, Sylvin Benjamin; Njamen, Dieudonne; Medjakovic, Svjetlana; Zehl, Martin; Kaehlig, Hanspeter; Jungbauer, Alois; Krenn, Liselotte
      BMC Complementary and Alternative Medicine (2014), 14 (), 294/1-294/10, 10 pp.CODEN: BCAMCV; ISSN:1472-6882. (BioMed Central Ltd.)
      Background: Eriosema laurentii De Wild. (Leguminosae) is a plant used in Cameroon against infertility and gynecol. or menopausal complaints. In our previous report, a methanol ext. of its aerial parts was shown to exhibit estrogenic and aryl hydrocarbon receptor agonistic activities in vitro and to prevent menopausal symptoms in ovariectomized Wistar rats. Methods: In order to det. the major estrogen receptor α (ERα) agonists in the ext., an activity-guided fractionation was performed using the ERα yeast screen. To check whether the ERα active fractions/compds. also accounted for the aryl hydrocarbon receptor (AhR) agonistic activity of the crude methanol ext., they were further tested on the AhR yeast screen. Results: This study led to the identification of 2'-hydroxygenistein, lupinalbin A and genistein as major estrogenic principles of the ext. 2'-hydroxygenistein and lupinalbin A were, for the first time, also shown to possess an AhR agonistic activity, whereas genistein was not active in this assay. In addn., it was possible to deduce structure-activity relationships. Conclusions: These results suggest that the identified compds. are the major active principles responsible for the estrogenic and AhR agonistic activities of the crude methanol ext. of the aerial parts of Eriosema laurentii.
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    64. 64
      Petersen, M.; Simmonds, M. S. Phytochemistry 2003, 62, 121– 125 DOI: 10.1016/S0031-9422(02)00513-7
      64
      Rosmarinic acid
      Petersen, Maike; Simmonds, Monique S. J.
      Phytochemistry (Elsevier) (2003), 62 (2), 121-125CODEN: PYTCAS; ISSN:0031-9422. (Elsevier Science Ltd.)
      A review. Rosmarinic acid is an ester of caffeic acid and 3,4-dihydroxyphenyllactic acid. It is commonly found in species of the Boraginaceae and the subfamily Nepetoideae of the Lamiaceae. However, it is also found in species of other higher plant families and in some fern and hornwort species. Rosmarinic acid has a no. of interesting biol. activities, e.g. antiviral, antibacterial, antiinflammatory and antioxidant. The presence of rosmarinic acid in medicinal plants, herbs and spices has beneficial and health promoting effects. In plants, rosmarinic acid is supposed to act as a preformed constitutively accumulated defense compd. The biosynthesis of rosmarinic acid starts with the amino acids L-phenylalanine and L-tyrosine. All eight enzymes involved in the biosynthesis are known and characterized and cDNAs of several of the involved genes have been isolated. Plant cell cultures, e.g. from Coleus blumei or Salvia officinalis, accumulate rosmarinic acid in amts. much higher than in the plant itself (up to 36% of the cell dry wt.). For this reason a biotechnol. prodn. of rosmarinic acid with plant cell cultures has been proposed.
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    65. 65
      Boonyarikpunchai, W.; Sukrong, S.; Towiwat, P. Pharmacol., Biochem. Behav. 2014, 124, 67– 73 DOI: 10.1016/j.pbb.2014.05.004
      There is no corresponding record for this reference.
    66. 66
      Staiger, C. Phytother. Res. 2012, 26, 1441– 1448 DOI: 10.1002/ptr.4612
      66
      Comfrey: A Clinical Overview
      Staiger, Christiane
      Phytotherapy Research (2012), 26 (10), 1441-1448CODEN: PHYREH; ISSN:0951-418X. (John Wiley & Sons Ltd.)
      A review. Comfrey has a centuries-old tradition as a medicinal plant. Today, multiple randomized controlled trials have demonstrated the efficacy and safety of comfrey prepns. for the topical treatment of pain, inflammation and swelling of muscles and joints in degenerative arthritis, acute myalgia in the back, sprains, contusions and strains after sports injuries and accidents, also in children aged 3 or 4 and over. This paper provides information on clin. trials and non-interventional studies published on comfrey to date and further literature, substantiating the fact that topical comfrey prepns. are a valuable therapy option for the treatment of painful muscle and joint complaints. Copyright © 2012 John Wiley & Sons, Ltd.
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    67. 67
      Tai, A.; Sawano, T.; Ito, H. Biosci., Biotechnol., Biochem. 2012, 76, 314– 318 DOI: 10.1271/bbb.110700
      There is no corresponding record for this reference.
    68. 68
      Blazevic, I.; Radonic, A.; Mastelic, J.; Zekic, M.; Skocibusic, M.; Maravic, A. Chem. Biodiversity 2010, 7, 2023– 2034 DOI: 10.1002/cbdv.200900234
      There is no corresponding record for this reference.
    69. 69
      Davis, R. A.; Pierens, G. K.; Parsons, P. G. Magn. Reson. Chem. 2007, 45, 442– 445 DOI: 10.1002/mrc.1984
      69
      Synthesis and spectroscopic characterisation of a combinatorial library based on the fungal natural product 3-chloro-4-hydroxyphenylacetamide
      Davis, Rohan A.; Pierens, Gregory K.; Parsons, Peter G.
      Magnetic Resonance in Chemistry (2007), 45 (5), 442-445CODEN: MRCHEG; ISSN:0749-1581. (John Wiley & Sons Ltd.)
      Parallel soln.-phase chem. has yielded a series of secondary amide analogs of the fungal natural product 3-chloro-4-hydroxyphenylacetamide. 3-Chloro-4-hydroxyphenylacetic acid was coupled to a variety of primary amines using 1-ethyl-3-(3'-dimethylaminopropyl)-carbodiimide hydrochloride. The desired products were obtained in good yield and high purity following rapid silica purifn. All analogs were spectroscopically characterized using NMR, UV, IR and MS data. One compd. displayed moderate cytotoxicity against the human melanoma and prostate cell lines, MM96L and DU145.
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    70. 70
      Goldberg, F. W.; Dossetter, A. G.; Scott, J. S.; Robb, G. R.; Boyd, S.; Groombridge, S. D.; Kemmitt, P. D.; Sjögren, T.; Gutierrez, P. M.; deSchoolmeester, J.; Swales, J. G.; Turnbull, A. V.; Wild, M. J. J. Med. Chem. 2014, 57, 970– 986 DOI: 10.1021/jm4016729
      There is no corresponding record for this reference.
    71. 71
      Mazumdar, M.; Fournier, D.; Zhu, D. W.; Cadot, C.; Poirier, D.; Lin, S. X. Biochem. J. 2009, 424, 357– 366 DOI: 10.1042/BJ20091020
      There is no corresponding record for this reference.
    72. 72
      Gunnarsson, C.; Hellqvist, E.; Stal, O. Br. J. Cancer 2005, 92, 547– 52 DOI: 10.1038/sj.bjc.6602375
      72
      17β-Hydroxysteroid dehydrogenases involved in local oestrogen synthesis have prognostic significance in breast cancer
      Gunnarsson, C.; Hellqvist, E.; Stal, O.
      British Journal of Cancer (2005), 92 (3), 547-552CODEN: BJCAAI; ISSN:0007-0920. (Nature Publishing Group)
      The 17β-hydroxysteroid dehydrogenase (17HSD) enzymes are involved in the local regulation of sex steroids. The 17HSD type 1 enzyme catalyzes the interconversion of the weak estrone (E1) to the more potent estradiol (E2), whereas 17HSD type 2 catalyzes the oxidn. of E2 to E1. The aim of this study was to correlate the expression of these enzymes in the tumor with the recurrence-free survival of tamoxifen-treated breast cancer patients. We used real-time reverse transcriptase PCR to investigate the mRNA expression of 17HSD types 1 and 2 in tumor samples from 230 postmenopausal patients. For the patients with estrogen receptor (ER)-pos. breast cancer, we found a statistically significant pos. correlation between recurrence-free survival and expression of 17HSD type 2 (P=0.026). We examd. the ratio of 17HSD types 2 and 1, and ER-pos. patients with low ratios showed a significantly higher rate of recurrence than those with higher ratios (P=0.0047). ER pos. patients with high expression levels of 17HSD type 1 had a significantly higher risk for late relapse (P=0.0051). The expression of 17HSD types 1 and 2 in breast cancer differs from the expression of these enzymes in normal mammary gland, and this study indicates that the expression has prognostic significance in breast cancer.
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    73. 73
      Gunnarsson, C.; Olsson, B. M.; Stal, O. Southeast Sweden Breast Cancer Group Cancer Res. 2001, 61, 8448– 51
      There is no corresponding record for this reference.
    74. 74
      Kitawaki, J.; Koshiba, H.; Ishihara, H.; Kusuki, I.; Tsukamoto, K.; Honjo, H. J. Clin. Endocrinol. Metab. 2000, 85, 3292– 6 DOI: 10.1210/jcem.85.9.6829
      74
      Progesterone induction of 17β-hydroxysteroid dehydrogenase type 2 during the secretory phase occurs in the endometrium of estrogen-dependent benign diseases but not in normal endometrium
      Kitawaki, Jo; Koshiba, Hisato; Ishihara, Hiroaki; Kusuki, Izumi; Tsukamoto, Katsumi; Honjo, Hideo
      Journal of Clinical Endocrinology and Metabolism (2000), 85 (9), 3292-3296CODEN: JCEMAZ; ISSN:0021-972X. (Endocrine Society)
      In the human endometrium, inactivation of 17β-estradiol to estrone is catalyzed by 17β-hydroxysteroid dehydrogenase type 2 (17βHSD2). Previous studies have shown that the 17βHSD2 activity in the endometrium is elevated during the secretory phase, as compared with the level during the proliferative phase, and that the elevation is in response to progesterone via the progesterone receptors. Recently, it has been demonstrated that aromatase cytochrome P 450, the enzyme responsible for estrogen biosynthesis, is not present in the endometrium obtained from normal menstruating women with cervical cancer in situ showing no other gynecol. disease (defined as "disease free"), but present in the endometrium obtained from patients with endometriosis, adenomyosis, and/or leiomyomas (defined as "diseased"). However, the previous 17βHSD studies have been performed without distinguishing between disease-free and diseased endometria. The authors, therefore, analyzed 17βHSD2 distinguishing between disease-free and diseased endometria. During the proliferative phase, the abundance of mRNA and activity of 17βHSD2 were comparable in both disease-free and diseased endometrium. However, during the secretory phase, while the abundance of mRNA and activity of 17βHSD2 increased 4- to 6-fold in diseased endometrium, the 17βHSD2 remained unchanged in the disease-free endometrium. Kinetic studies showed that the Km was identical among the four groups of endometria, suggesting that the elevation of 17βHSD2 simply resulted from increased mRNA transcription. Organ culture of proliferative endometria in the presence of progestins resulted in the stimulation of 17βHSD2 in diseased endometria via the progesterone receptors, whereas disease-free endometrium was not stimulated by progestins. These results suggest that the previous paradigm that 17βHSD2 activity in the endometrium is elevated during the secretory phase is confined to diseased endometrium but not to disease-free endometrium and that the estrogen metab. is altered in the endometria of the patients with estrogen-dependent benign diseases.
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    75. 75
      Davis, R. A.; Carroll, A. R.; Andrews, K. T.; Boyle, G. M.; Tran, T. L.; Healy, P. C.; Kalaitzis, J. A.; Shivas, R. G. Org. Biomol. Chem. 2010, 8, 1785– 1790 DOI: 10.1039/b924169h
      There is no corresponding record for this reference.
    76. 76
      Choomuenwai, V.; Andrews, K. T.; Davis, R. A. Bioorg. Med. Chem. 2012, 20, 7167– 7174 DOI: 10.1016/j.bmc.2012.09.052
      76
      Synthesis and antimalarial evaluation of a screening library based on a tetrahydroanthraquinone natural product scaffold
      Choomuenwai, Vanida; Andrews, Katherine T.; Davis, Rohan A.
      Bioorganic & Medicinal Chemistry (2012), 20 (24), 7167-7174CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)
      As part of a research program aimed at discovering new antimalarial leads from Australian macrofungi a unique fungi-derived prefractionated library was screened against a chloroquine-sensitive Plasmodium falciparum line (3D7) using a radiometric growth inhibition assay. A library fraction derived from a Cortinarius species displayed promising antimalarial activity. UV-guided fractionation on the CH2Cl2/MeOH ext. from this fungus resulted in the isolation of four known compds.: (1S,3R)-austrocortirubin (1), (1S,3S)-austrocortirubin (2), 1-deoxyaustrocortirubin (3), and austrocortinin (4). Compd. 2 was used as a natural product scaffold in the parallel soln.-phase synthesis of a small library of N-substituted tetrahydroanthraquinones (5-15). All compds. (1-15) were tested in vitro against P. falciparum 3D7 parasites and (1S,3S)-austrocortirubin (2), the major fungal constituent, was shown to be the most active compd. with an IC50 of 1.9 μM. This compd. displayed moderate cytotoxicity against neonatal foreskin fibroblast (NFF) cells with an IC50 of 15.6 μM.
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    77. 77
      Levrier, C.; Balastrier, M.; Beattie, K. D.; Carroll, A. R.; Martin, F.; Choomuenwai, V.; Davis, R. A. Phytochemistry 2013, 86, 121– 126 DOI: 10.1016/j.phytochem.2012.09.019
      There is no corresponding record for this reference.
    78. 78
      Barnes, E. C.; Said, N. A. B. M.; Williams, E. D.; Hooper, J. N. A.; Davis, R. A. Tetrahedron 2010, 66, 283– 287 DOI: 10.1016/j.tet.2009.10.109
      There is no corresponding record for this reference.
    79. 79
      Liberio, M. S.; Sooraj, D.; Williams, E. D.; Feng, Y.; Davis, R. A. Tetrahedron Lett. 2011, 52, 6729– 6731 DOI: 10.1016/j.tetlet.2011.09.151
      There is no corresponding record for this reference.
    80. 80
      Barnes, E. C.; Choomuenwai, V.; Andrews, K. T.; Quinn, R. J.; Davis, R. A. Org. Biomol. Chem. 2012, 10, 4015– 4023 DOI: 10.1039/c2ob00029f
      80
      Design and synthesis of screening libraries based on the muurolane natural product scaffold
      Barnes, Emma C.; Choomuenwai, Vanida; Andrews, Katherine T.; Quinn, Ronald J.; Davis, Rohan A.
      Organic & Biomolecular Chemistry (2012), 10 (20), 4015-4023CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)
      The plant-derived natural product 14-hydroxy-6,12-muuroloadien-15-oic acid (1) was identified as a unique scaffold that could be chem. elaborated to generate novel lead- or drug-like screening libraries. Prior to synthesis a virtual library was generated and prioritized based on drug-like physicochem. parameters such as log P, log D5.5, hydrogen bond donors/acceptors, and mol. wt. The natural product scaffold (1) was isolated from the endemic Australian plant Eremophila mitchelli and then utilized in the parallel soln.-phase generation of two series of analogs. The first library consisted of six semisynthetic amide derivs., while the second contained six carbamate analogs. These libraries have been evaluated for antimalarial activity using a chloroquine-sensitive Plasmodium falciparum line (3D7) and several compds. displayed low to moderate activity with IC50 values ranging from 14 to 33 μM.
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    81. 81
      Atanasov, A. G.; Wang, J. N.; Gu, S. P.; Bu, J.; Kramer, M. P.; Baumgartner, L.; Fakhrudin, N.; Ladurner, A.; Malainer, C.; Vuorinen, A.; Noha, S. M.; Schwaiger, S.; Rollinger, J. M.; Schuster, D.; Stuppner, H.; Dirsch, V. M.; Heiss, E. H. Biochim. Biophys. Acta, Gen. Subj. 2013, 1830, 4813– 9 DOI: 10.1016/j.bbagen.2013.06.021
      81
      Honokiol: A non-adipogenic PPARγ agonist from nature
      Atanasov, Atanas G.; Wang, Jian N.; Gu, Shi P.; Bu, Jing; Kramer, Matthias P.; Baumgartner, Lisa; Fakhrudin, Nanang; Ladurner, Angela; Malainer, Clemens; Vuorinen, Anna; Noha, Stefan M.; Schwaiger, Stefan; Rollinger, Judith M.; Schuster, Daniela; Stuppner, Hermann; Dirsch, Verena M.; Heiss, Elke H.
      Biochimica et Biophysica Acta, General Subjects (2013), 1830 (10), 4813-4819CODEN: BBGSB3; ISSN:0304-4165. (Elsevier B.V.)
      Peroxisome proliferator-activated receptor gamma (PPARγ) agonists are clin. used to counteract hyperglycemia. However, so far experienced unwanted side effects, such as wt. gain, promote the search for new PPARγ activators. We used a combination of in silico, in vitro, cell-based, and in vivo models to identify and validate natural products as promising leads for partial novel PPARγ agonists. The natural product honokiol from the traditional Chinese herbal drug Magnolia bark was in silico predicted to bind into the PPARγ ligand binding pocket as dimer. Honokiol indeed directly bound to purified PPARγ ligand-binding domain (LBD) and acted as partial agonist in a PPARγ-mediated luciferase reporter assay. Honokiol was then directly compared to the clin. used full agonist pioglitazone with regard to stimulation of glucose uptake in adipocytes as well as adipogenic differentiation in 3T3-L1 pre-adipocytes and mouse embryonic fibroblasts. While honokiol stimulated basal glucose uptake to a similar extent as pioglitazone, it did not induce adipogenesis in contrast to pioglitazone. In diabetic KKAy mice oral application of honokiol prevented hyperglycemia and suppressed wt. gain. We identified honokiol as a partial non-adipogenic PPARγ agonist in vitro which prevented hyperglycemia and wt. gain in vivo. This obsd. activity profile suggests honokiol as promising new pharmaceutical lead or dietary supplement to combat metabolic disease, and provides a mol. explanation for the use of Magnolia in traditional medicine.
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    82. 82
      Bauer, J.; Waltenberger, B.; Noha, S. M.; Schuster, D.; Rollinger, J. M.; Boustie, J.; Chollet, M.; Stuppner, H.; Werz, O. ChemMedChem 2012, 7, 2077– 2081 DOI: 10.1002/cmdc.201200345
      82
      Discovery of Depsides and Depsidones from Lichen as Potent Inhibitors of Microsomal Prostaglandin E2 Synthase-1 Using Pharmacophore Models
      Bauer, Julia; Waltenberger, Birgit; Noha, Stefan M.; Schuster, Daniela; Rollinger, Judith M.; Boustie, Joel; Chollet, Marylene; Stuppner, Hermann; Werz, Oliver
      ChemMedChem (2012), 7 (12), 2077-2081CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Depsides and depsidones were isolated from lichen and tested for inhibitory action on microsomal prostaglandin E2 synthase-1 using pharmacophore models.
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    83. 83
      Fakhrudin, N.; Ladurner, A.; Atanasov, A. G.; Heiss, E. H.; Baumgartner, L.; Markt, P.; Schuster, D.; Ellmerer, E. P.; Wolber, G.; Rollinger, J. M.; Stuppner, H.; Dirsch, V. M. Mol. Pharmacol. 2010, 77, 559– 566 DOI: 10.1124/mol.109.062141
      There is no corresponding record for this reference.
    84. 84
      Oettl, S. K.; Gerstmeier, J.; Khan, S. Y.; Wiechmann, K.; Bauer, J.; Atanasov, A. G.; Malainer, C.; Awad, E. M.; Uhrin, P.; Heiss, E. H.; Waltenberger, B.; Remias, D.; Breuss, J. M.; Boustie, J.; Dirsch, V. M.; Stuppner, H.; Werz, O.; Rollinger, J. M. PLoS One 2013, 8, e76929 DOI: 10.1371/journal.pone.0076929
      84
      Imbricaric acid and perlatolic acid: multi-targeting anti-inflammatory depsides from Cetrelia monachorum
      Oettl, Sarah K.; Gerstmeier, Jana; Khan, Shafaat Y.; Wiechmann, Katja; Bauer, Julia; Atanasov, Atanas G.; Malainer, Clemens; Awad, Ezzat M.; Uhrin, Pavel; Heiss, Elke H.; Waltenberger, Birgit; Remias, Daniel; Breuss, Johannes M.; Boustie, Joel; Dirsch, Verena M.; Stuppner, Hermann; Werz, Oliver; Rollinger, Judith M.
      PLoS One (2013), 8 (10), e76929CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
      In vitro screening of 17 Alpine lichen species for their inhibitory activity against 5-lipoxygenase, microsomal prostaglandin E2 synthase-1 and nuclear factor kappa B revealed Cetrelia monachorum (Zahlbr.) W.L. Culb. & C.F. Culb. As conceivable source for novel anti-inflammatory compds. Phytochem. investigation of the ethanolic crude ext. resulted in the isolation and identification of 11 constituents, belonging to depsides and derivs. of orsellinic acid, olivetolic acid and olivetol. The two depsides imbricaric acid (4) and perlatolic acid (5) approved dual inhibitory activities on microsomal prostaglandin E2 synthase-1 (IC50 = 1.9 and 0.4 μM, resp.) and on 5-lipoxygenase tested in a cell-based assay (IC50 = 5.3 and 1.8 μM, resp.) and on purified enzyme (IC50 = 3.5 and 0.4 μM, resp.). Addnl., these two main constituents quantified in the ext. with 15.22% (4) and 9.10% (5) showed significant inhibition of tumor necrosis factor alpha-induced nuclear factor kappa B activation in luciferase reporter cells with IC50 values of 2.0 and 7.0 μM, resp. In a murine in vivo model of inflammation, 5 impaired the inflammatory, thioglycollate-induced recruitment of leukocytes to the peritoneum. The potent inhibitory effects on the three identified targets attest 4 and 5 a pronounced multi-target anti-inflammatory profile which warrants further investigation on their pharmacokinetics and in vivo efficacy.
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    85. 85
      Barnes, E. C.; Kavanagh, A. M.; Ramu, S.; Blaskovich, M. A.; Cooper, M. A.; Davis, R. A. Phytochemistry 2013, 93, 162– 166 DOI: 10.1016/j.phytochem.2013.02.021
      85
      Antibacterial serrulatane diterpenes from the Australian native plant Eremophila microtheca
      Barnes, Emma C.; Kavanagh, Angela M.; Ramu, Soumya; Blaskovich, Mark A.; Cooper, Matthew A.; Davis, Rohan A.
      Phytochemistry (Elsevier) (2013), 93 (), 162-169CODEN: PYTCAS; ISSN:0031-9422. (Elsevier Ltd.)
      Chem. investigations of the aerial parts of the Australian plant Eremophila microtheca resulted in the isolation of three serrulatane diterpenoids, 3-acetoxy-7,8-dihydroxyserrulat-14-en-19-oic acid (I), 3,7,8-trihydroxyserrulat-14-en-19-oic acid (II) and 3,19-diacetoxy-8-hydroxyserrulat-14-ene (III) as well as the previously reported compds. verbascoside (4) and jaceosidin (5). Acetylation and methylation of the major serrulatane diterpenoid 2 afforded 3,8-diacetoxy-7-hydroxyserrulat-14-en-19-oic acid (6) and 3,7,8-trihydroxyserrulat-14-en-19-oic acid Me ester (7), resp. The antibacterial activity of 1-7 was assessed against a panel of Gram-pos. and Gram-neg. bacterial isolates. All of the serrulatane compds. exhibited moderate activity against Streptococcus pyogenes (ATCC 12344) with min. inhibitory concns. (MICs) ranging from 64-128 μg/mL. Serrulatane 1 demonstrated activity against all Gram-pos. bacterial strains (MICs 64-128 μg/mL) except for Enterococcus faecalis and Enterococcus faecium. This is the first report of natural products from E. microtheca.
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    86. 86
      Baron, P. S.; Neve, J. E.; Camp, D.; Suraweera, L.; Lam, A.; Lai, J.; Jovanovic, L.; Nelson, C.; Davis, R. A. Magn. Reson. Chem. 2013, 51, 358– 363 DOI: 10.1002/mrc.3958
      86
      Design, synthesis and spectroscopic characterization of a focused library based on the polyandrocarpamine natural product scaffold
      Baron, Paul S.; Neve, Juliette E.; Camp, David; Suraweera, Lekha; Lam, Ann; Lai, John; Jovanovic, Lidija; Nelson, Colleen; Davis, Rohan A.
      Magnetic Resonance in Chemistry (2013), 51 (6), 358-363CODEN: MRCHEG; ISSN:0749-1581. (John Wiley & Sons Ltd.)
      A focused library based on the marine natural products polyandrocarpamines A and B has been designed and synthesized using parallel soln.-phase chem. In silico physicochem. property calcns. were performed on synthetic candidates in order to optimize the library for drug discovery and chem. biol. A library of ten 2-aminoimidazolone products was prepd. by coupling glycocyamidine and a variety of aldehydes using a one-step aldol condensation reaction under microwave conditions. All analogs were characterized by NMR, UV, IR and MS. The library was evaluated for cytotoxicity towards the prostate cancer cell lines, LNCaP, PC-3 and 22Rv1. Copyright 2013 John Wiley & Sons, Ltd.
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    87. 87
      Davis, R. A.; Barnes, E. C.; Longden, J.; Avery, V. M.; Healy, P. C. Bioorg. Med. Chem. 2009, 17, 1387– 1392 DOI: 10.1016/j.bmc.2008.12.030
      There is no corresponding record for this reference.
    88. 88
      Healy, P. C.; Hocking, A.; Tran-Dinh, N.; Pitt, J. I.; Shivas, R. G.; Mitchell, J. K.; Kotiw, M.; Davis, R. A. Phytochemistry 2004, 65, 2373– 2378 DOI: 10.1016/j.phytochem.2004.07.019
      There is no corresponding record for this reference.
    89. 89
      Waltenberger, B.; Atanasov, A. G.; Heiss, E. H.; Bernhard, D.; Rollinger, J. M.; Breuss, J. M.; Schuster, D.; Bauer, R.; Kopp, B.; Franz, C.; Bochkov, V.; Mihovilovic, M. D.; Dirsch, V. M.; Stuppner, H. Monatsh. Chem. 2016, 147, 479– 491 DOI: 10.1007/s00706-015-1653-y
      89
      Drugs from nature targeting inflammation (DNTI): a successful Austrian interdisciplinary network project
      Waltenberger, Birgit; Atanasov, Atanas G.; Heiss, Elke H.; Bernhard, David; Rollinger, Judith M.; Breuss, Johannes M.; Schuster, Daniela; Bauer, Rudolf; Kopp, Brigitte; Franz, Chlodwig; Bochkov, Valery; Mihovilovic, Marko D.; Dirsch, Verena M.; Stuppner, Hermann
      Monatshefte fuer Chemie (2016), 147 (3), 479-491CODEN: MOCMB7; ISSN:0026-9247. (Springer-Verlag GmbH)
      Abstr.: Inflammation is part of numerous pathol. conditions, which are lacking satisfying treatment and effective concepts of prevention. A national research network project, DNTI, involving scientists from six Austrian universities as well as several external partners aimed to identify and characterize natural products capable of combating inflammatory processes specifically in the cardiovascular system. The combined use of computational techniques with traditional knowledge, high-tech chem. anal. and synthesis, and a broad range of in vitro, cell-based, and in vivo pharmacol. models led to the identification of a series of promising anti-inflammatory drug lead candidates. Mechanistic studies contributed to a better understanding of their mechanism of action and delivered new knowledge on the mol. level of inflammatory processes. Herein, the used approaches and selected highlights of the results of this interdisciplinary project are presented. Graphical abstr.: [Figure not available: see fulltext.].
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    90. 90
      Wolber, G.; Langer, T. J. Chem. Inf. Model. 2005, 45, 160– 169 DOI: 10.1021/ci049885e
      90
      LigandScout: 3-D pharmacophores derived from protein-bound ligands and their use as virtual screening filters
      Wolber Gerhard; Langer Thierry
      Journal of chemical information and modeling (2005), 45 (1), 160-9 ISSN:1549-9596.
      From the historically grown archive of protein-ligand complexes in the Protein Data Bank small organic ligands are extracted and interpreted in terms of their chemical characteristics and features. Subsequently, pharmacophores representing ligand-receptor interaction are derived from each of these small molecules and its surrounding amino acids. Based on a defined set of only six types of chemical features and volume constraints, three-dimensional pharmacophore models are constructed, which are sufficiently selective to identify the described binding mode and are thus a useful tool for in-silico screening of large compound databases. The algorithms for ligand extraction and interpretation as well as the pharmacophore creation technique from the automatically interpreted data are presented and applied to a rhinovirus capsid complex as application example.
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