Topical Perspectives
Metal chelating ability and antioxidant properties of Curcumin-metal complexes – A DFT approach

https://doi.org/10.1016/j.jmgm.2017.10.022 Get rights and content

Highlights

Abstract

Curcumin, a well-documented phytochemical compound used to treat various diseases because of its more tolerability in the human body and has no side effects. The present study describes the metal chelating ability of Curcumin for Mn2+, Fe2+ and Zn2+ metal ions and their antioxidant properties using density functional theory in both gas and DMSO solvent phases. Results reveal that the carbonyl group at diketo moiety is destabilized due to the metal ion coordination. The interaction energies reveal that CurEN-Zn2+ are the most stable rather than the CurEN-Mn2+ and CurEN-Fe2+ complexes. The AIM analysis confirms that the interaction between the metal ions and Curcumin are to be electrostatic dominant. The HOMO-LUMO orbital analysis shows that the charge transfer interaction is dominant for CurEN-Mn2+ and CurEN-Fe2+ complexes. The DMSO solvent interactions decrease the stability of the CurEN-M2+ cation complexes. The antioxidant mechanism is more reactive for metal complexes than the isolated Curcumin. Since Curcumin possess both metal chelating and antioxidant properties, it can be used in chelation therapy for the cure of Alzheimer’s disease.

Introduction

The metal ions are essentially needed to perform a sequence of significant biological functioning in the brain, such as nerve transmission, oxygen transport, synthesis and metabolism of neurotransmitters [1]. Over the past few decades [2], [3], [4], [5], [6], [7], [8], there is a considerable attention has been paid to the role of transition metal ions such as Mn2+, Fe2+, Cu2+ and Zn2+ in the brain and their involvement in the neurodegenerative disorders. Since the abnormal accumulation of these transition metal ions in the brain plays a crucial role in the pathological process such as protein aggregation and oxidative stress in the neurodegenerative disorders, which are characterized by the progressive loss of neuron structure and function which ultimately leads to neuronal death [9], [10], [11]. The apparent association of such transition metal ions in both protein aggregation process and oxidative stress, therefore, renders chelation therapy as an appropriate treatment for removing the metal ions such as Mn2+, Fe2+, Cu2+ and Zn2+ which are responsible for inducing the neurodegenerative disorders [12], [13].

Curcumin (1,7-bis [4-hydroxy-3-methoxyphenyl] −1,6-heptadiene-3,5-dione) which is an important natural phytochemical compound and the principle coloring agent present in the rhizomes of Curcuma longa (Zingiberaceae). It has attracted considerable attention due to its wide range of biological and pharmacological activities, including antioxidant, antitumor, anti-inflammatory, antibacterial, antifungal, antiviral and anticoagulant activities and so on [14], [15], [16], [17], [18], [19], [20], [21], [22]. Curcumin can exist in two tautomeric forms: β-diketone (CurK) and β-keto-Enol (CurE), the latter one is the most stable [23], [24], [25], [26], [27], [28]. Barik et al. [29] reported that the antioxidant activity of CurE is higher than the CurK tautomer. The CurE has three possible metal chelating sites: the keto-enolic moieties and the two phenol groups as the potential reactive centers. Of these potential reactive centers, the keto-enolic moiety is most likely to form metal chelates [28], [29], [30], [31], [32], [33], [34], [35] and can scavenge the active free radicals which may be produced by the metal ions [36], [37]. The CurE can form metal chelates of type 1:1 and 1:2 with the metal ions such as Mn2+, Fe2+, Cu2+, and Zn2+ [38], [39], [40], [41]. The ability of Curcumin to bind redox-active transition metal ions and to form tight and active complexes could be a possible pathway for the protection of the brain from neurodegenerative disorders. The anti-inflammatory property of Curcumin could also contribute to the reduced amount of swelling observed within neuronal cells [42]. Because of these unique properties of Curcumin, it has been recognized as the natural drug to treat the neurodegenerative disorders.

Priya et al. [43] synthesized the isolated Curcumin and their metal complexes in order to study the reactive centers of Curcumin and the possible antioxidant activity of the metal complexes of Curcumin. Their study reveals that the Curcumin can act simultaneously as a metal chelator and antioxidant and, in consequence, an efficient brain protector. Barzegar [26] experimentally investigated the role of electron transfer and hydrogen atom transfer (HAT) in the free radical reaction and reported that, the HAT mechanism is weakly solvent dependent, and the electron transfer mechanism is mostly to be concerned in polar solvents like an aqueous solution. So in the present study, we use DMSO solvent and studied the metal interaction with Curcumin minimum energy conformers. Gorgannezhad et al. [44] studied the complexation behavior of the CurE-Mn(II) complex through model-based analysis and also investigated their antiradical activity of isolated Curcumin and CurE-Mn(II) complex. Their study reveals that both Curcumin and CurE-Mn(II) complex have strong antioxidant activities which it is comparatively stronger for Curcumin than its complex. Shen et al. [42] theoretically studied the Cu(II)-chelating properties of Curcumin and found that the Curcumin could efficiently sequester Cu(II) and Cu(II) − Curcumin complexes were more active than the parent Curcumin in scavenging radicals by donating a proton or an electron and therefore Curcumin can act as a multipotent agent to combat neurodegenerative disorder such as Alzheimer disease with the activities of scavenging redox active species, blocking Aβ aggregation and chelating metal ions. Sun et al. [45] studied the antioxidant properties of the Curcumin tautomers and reported that keto-enolic form is a more stable than the β-diketone form due to the intramolecular hydrogen bond formed in the enol with the extended conjugation in the enol chain. Based on the phenol Osingle bondH bond dissociation enthalpy, Curcumin in its most stable form can be suggested to be a relatively good antioxidant. Shen et al. [46] theoretically studied the physicochemical properties of Curcumin and provided direct evidence that the enolic proton of Curcumin is the most easily dissociable proton which has important implications for the proton-transfer/dissociation-associated radical-scavenging mechanisms of Curcumin. Rajesh et al. [47] investigated the interaction between Cu (II) complexes in 1:1 and 1:2 ratios of metal, ligand and CT-DNA using UV–vis, circular dichroism, fluorescence spectra, cyclic voltammetry and gel electrophoresis and reported that two Cu (II) complexes strongly interact with CT-DNA, by groove binding mode. Zhao et al. [39] have demonstrated that Curcumin can form a Metal-Ligand (ML) type complex with Zn2+ and Cu2+ and the ability to scavenge free radical is stronger for Cu2+ -Curcumin complex than that of Zn2+-Curcumin complex. Barik et al. [48] made a comparative study on CurE-Cu(II) complexes of ML type 1:1 and 1:2. This study demonstrated that the 1:1 metal complex of Curcumin would be able to undergo and sustain the distortion from square planar geometry to the distorted tetrahedral one during its reaction with superoxide radical which allows for the compound to remain intact and undergoes many redox cycles and hence as an efficient antioxidant than 1:2 complex, since the 1:2 complex is planar but rigid and hence cannot undergo the distortions and therefore is a less powerful antioxidant.

As above, there is much literature are available about the CurE-M2+ complexes, their antioxidant and free radical scavenging properties [26], [45], [48], [49], [50], [51]. But the electronic and geometrical properties of CurE-M2+ are still needed to be investigated clearly at molecular level in order to get a detailed picture on the metal ion selectivity, nature of the interaction between the coordinating ligand atoms and the metal ions and the effect of metal complexation on the antioxidant property of the Curcumin. According to this prospect, we have investigated the chelating properties and metal ion selectivity of Curcumin with the redox active metal ions such as Mn2+, Fe2+, and Zn2+ in detail using density functional theory (DFT) and studied their antioxidant property of the metal complexes in both gas and DMSO solvent phases. This study will clarify the structural properties of CurE-M2+ and may be helpful in selecting the appropriate chelating agent as well as a free radical scavenging agent for the chelation therapy of neurodegenerative disorders such as Alzheimer.

Section snippets

Computational details

Density functional theory method was applied to study the 1:1 mononuclear CurEN-M2+ chelate complexes. The equilibrium geometries of the isolated and CurEN-M2+ complexes were determined by optimizing the complexes using M06 functional [52] and hybrid Hartree – Fock DFT method known as B3LYP which includes Becke’s three (B3) parameter exchange functional along with Lee, Yang, Parr’s (LYP) gradient corrected correlation functional [53], [54], [55] using mixed basis set TZVP + LANL2DZ (TZVP for

Results and discussion

The enol tautomer of Curcumin can exist in three possible conformations such as Cis-up (CurE1), Cis-down (CurE2), and Trans (CurE3) due to rotation of one of the aromatic rings as shown in Fig. 1a–c respectively. The Cis-up and Cis-down indicate that the two phenol rings toward up and down the Curcumin backbone and Trans indicate that the two phenol groups are on opposite flank [36], [70]. According to the experimental findings, the enolic proton is readily dissociated in solution [41] and the

Conclusions

We have investigated the metal chelating and antioxidant properties of CurEN-M2+ chelates for the conformers of Curcumin at B3LYP/TZVP+LANL2DZ and M06/TZVP+LANL2DZ levels of theory in both gas and DMSO solvent phases and the following results have emerged from the detailed calculations.

  • As the ionic radii and the number of unpaired electrons in the d-orbit increases, the metal-ligand coordination distance is also found to be increased.

  • Coordination geometry for the CurEN-M2+ chelates in the

Funding

The authors (C. Pitchumani Violet Mary & S.Vijayakumar) thank the Department of Science and Technology – Science and Engineering Research Board (DST-SERB) India for awarding the research project under the OYS Scheme (Grant.no. SR/FTP/PS-115/2011 dated 19/09/2013).

References (79)

  • A. Barzegar

    The role of electron-transfer and H-atom donation on the superb antioxidant activity and free radical reaction of curcumin

    Food Chem.

    (2012)
  • A. Barik et al.

    Evaluation of a new copper(II)-curcumin complex as superoxide dismutase mimic and its free radical reactions

    Free Radic. Biol. Med.

    (2005)
  • S. Daniel et al.

    Through metal binding, curcumin protects against lead- and cadmium-induced lipid peroxidation in rat brain homogenates and against lead-induced tissue damage in rat brain

    J. Inorg. Biochem.

    (2004)
  • M. Borsari et al.

    Curcuminoids as potential new iron-chelating agents: spectroscopic, polarographic and potentiometric study on their Fe(III) complexing ability

    Inorganica Chim. Acta.

    (2002)
  • O. Vajragupta et al.

    Manganese complexes of curcumin and its derivatives: evaluation for the radical scavenging ability and neuroprotective activity

    Free Radic. Biol. Med.

    (2003)
  • K.I. Priyadarsini et al.

    Role of phenolic O-H and methylene hydrogen on the free radical reactions and antioxidant activity of curcumin

    Free Radic. Biol. Med.

    (2003)
  • Y. Jiao et al.

    Iron chelation in the biological activity of curcumin

    Free Radic. Biol. Med.

    (2006)
  • X.-Z. Zhao et al.

    Interaction of curcumin with Zn(II) and Cu(II) ions based on experiment and theoretical calculation

    J. Mol. Struct.

    (2010)
  • L. Shen et al.

    A theoretical study on Cu(II)-chelating properties of curcumin and its implications for curcumin as a multipotent agent to combat Alzheimer’s disease

    J. Mol. Struct. THEOCHEM.

    (2005)
  • L. Gorgannezhad et al.

    Complex of manganese (II) with curcumin: spectroscopic characterization, DFT study, model-based analysis and antiradical activity

    J. Mol. Struct.

    (2016)
  • L. Shen et al.

    Theoretical study on physicochemical properties of curcumin

    Spectrochim. Acta. A. Mol. Biomol. Spectrosc.

    (2007)
  • J. Rajesh et al.

    Analytical methods to determine the comparative DNA binding studies of curcumin-Cu(II) complexes

    Spectrochim. Acta – Part A Mol. Biomol. Spectrosc.

    (2012)
  • A. Barik et al.

    Comparative study of copper(II)-curcumin complexes as superoxide dismutase mimics and free radical scavengers

    Eur. J. Med. Chem.

    (2007)
  • S.F. Boys et al.

    The calculation of small molecular interactions by the differences of separate total energies. Some procedures with reduced errors

    Mol. Phys.

    (1970)
  • C. Pitchumani Violet Mary et al.

    Interaction studies of human prion protein (HuPrP109-111: methionine-lysine-histidine) tripeptide model with transition metal cations

    J. Mol. Graph. Model.

    (2016)
  • R.F.W. Bader

    Atoms in Molecules, A Quantum Theory

    (1990)
  • J.R. Cheeseman et al.

    The mechanics of hydrogen bond formation in conjugated systems

    Chem. Phys. Lett.

    (1988)
  • U. Koch et al.

    Characterization of CHO hydrogen bonds on the basis of the charge density

    J. Phys. Chem.

    (1995)
  • S. Kaviani et al.

    A DFT study on the complex formation between desferrithiocin and metal ions (Mg2+, Al3+ Ca2+, Mn2+, Fe3+, Co2+, Ni2+, Cu2+, Zn2+)

    Comput. Biol. Chem.

    (2017)
  • S. Kaviani et al.

    Solvent and spin state effects on molecular structure, IR spectra, binding energies and quantum chemical reactivity indices of deferiprone?ferric complex: DFT study

    Polyhedron

    (2016)
  • L. Yang et al.

    Structural variation in copper(I) complexes with pyridylmethylamide ligands: structural analysis with a new four-coordinate geometry index tau4

    Dalton Trans.

    (2007)
  • E. House et al.

    Aluminium, iron, zinc and copper influence the in vitro formation of amyloid fibrils of Aβ_ {42} in a manner which may have consequences for metal chelation therapy in Alzheimer’s disease

    J. Alzheimer’s Dis.

    (2004)
  • C.J. Maynard et al.

    Metals and amyloid-beta in Alzheimer’s disease

    Int. J. Exp. Pathol.

    (2005)
  • E.C. Hirsch et al.

    Iron and aluminum increase in the substantia nigra of patients with Parkinson’s disease: an X-ray microanalysis

    J. Neurochem.

    (1991)
  • D.T. Dexter et al.

    Alterations in the Levels of Iron, Ferritin and Other Trace Metals in Parkinson’S Disease and Other Neurodegenerative Diseases Affecting the Basal Ganglia

    Brain

    (1991)
  • B. Faucheux et al.

    Neuromelanin associated redox-active iron is increased in the substantia nigra of patients with Parkinson’s disease

    J. Neurochem.

    (2003)
  • K.S.J. Rao et al.

    Trace elements in Alzheimer’s disease brain: a new hypothesis

    Alz. Rep.

    (1999)
  • G. Filiz et al.

    The role of metals in modulating metalloprotease activity in the AD brain

    Eur. Biophys. J.

    (2008)
  • A. Gaeta et al.

    The crucial role of metal ions in neurodegeneration: the basis for a promising therapeutic strategy

    Br. J. Pharmacol.

    (2005)
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