Curcumin Derivatives as Metal-Chelating Agents With Potential Multifunctional Activity for Pharmaceutical Applications

J Inorg Biochem. 2014 Oct;139:38-48. doi: 10.1016/j.jinorgbio.2014.06.002. Epub 2014 Jun 11.

Abstract

Curcuminoids represent new perspectives for the development of novel therapeutics for Alzheimer's disease (AD), one probable mechanism of action is related to their metal complexing ability. In this work we examined the metal complexing ability of substituted curcuminoids to propose new chelating molecules with biological properties comparable with curcumin but with improved stability as new potential AD therapeutic agents. The K2T derivatives originate from the insertion of a -CH2COOC(CH3)3 group on the central atom of the diketonic moiety of curcumin. They retain the diketo-ketoenol tautomerism which is solvent dependent. In aqueous solution the prevalent form is the diketo one but the addition of metal ion (Ga(3+), Cu(2+)) causes the dissociation of the enolic proton creating chelate complexes and shifting the tautomeric equilibrium towards the keto-enol form. The formation of metal complexes is followed by both NMR and UV-vis spectroscopy. The density functional theory (DFT) calculations on K2T21 complexes with Ga(3+) and Cu(2+) are performed and compared with those on curcumin complexes. [Ga(K2T21)2(H2O)2](+) was found more stable than curcumin one. Good agreement is detected between calculated and experimental (1)H and (13)C NMR data. The calculated OH bond dissociation energy (BDE) and the OH proton dissociation enthalpy (PDE), allowed to predict the radical scavenging ability of the metal ion complexed with K2T21, while the calculated electronic affinity (EA) and ionization potential (IP) represent yardsticks of antioxidant properties. Eventually theoretical calculations suggest that the proton-transfer-associated superoxide-scavenging activity is enhanced after binding metal ions, and that Ga(3+) complexes display possible superoxide dismutase (SOD)-like activity.

Keywords: Alzheimer's disease; Cu(2+) complexes; Curcumin derivatives; DFT calculation; Ga(3+) complexes; NMR spectroscopy.

MeSH terms

  • Chelating Agents / chemistry*
  • Copper / chemistry
  • Curcumin / analogs & derivatives*
  • Curcumin / chemistry*
  • Free Radical Scavengers / chemistry
  • Gallium / chemistry
  • Hydrogen-Ion Concentration
  • Models, Molecular
  • Molecular Conformation
  • Superoxides / chemistry
  • Thermodynamics

Substances

  • Chelating Agents
  • Free Radical Scavengers
  • Superoxides
  • Copper
  • Gallium
  • Curcumin