engleski

Radical scavenging and COX-2 inhibition by colon metabolites of polyphenols: A theoretical approach

Colon polyphenolic metabolites can reduce activity of enzymes involved in human carcinogenesis [1], for instance by inhibition of COX-2 [2]. Recent studies have shown the importance of selective inhibition of COX-2 for the anti-inflammatory and anticancer therapy [3], indicating COX-2 as a valid molecular target for cancer prevention and treatment [4]. Theoretical investigations of active site of COX-2 affirmed some natural phenolic antioxidants as potential inhibitors of this enzyme [5]. Radical scavenging mechanisms of selected polyphenolic metabolites were studied in water and pentyl ethanoate as a solvent, by DFT method using Gaussian 09 package [6]. Geometry optimizations and frequency calculations were carried out using the M06- 2X/6-311++G(d, p) level of theory, in conjunction with the SMD continuum solvation model. Inhibitory potency against COX- 2 by colon polyphenolic metabolites and their mono- and di-anionic forms, were theoretically studied. Free energy of binding and inhibition constant for these ligands at the most favourable binding positions were estimated. Hydrogen atom transfer and sequential proton loss electron transfer mechanisms were found to be thermodynamically probable and competitive processes in both media. The Gibbs free energy change for reaction of inactivation of radicals indicate selected metabolites as potent scavengers. Docking analysis with structural forms of selected metabolites indicates dianionic ligands as potent inhibitors of COX- 2. Obtained results indicate that, because polyphenolic metabolites are produced in high mM concentrations and are usually better absorbed than their precursor molecules, they may contribute to health benefits associated with regular intake of polyphenol-rich diet. Acknowledgments: We gratefully acknowledge the financial support to this work from The Foundation of the Croatian Academy of Sciences and Arts, under the project No. 10-102/244-1- 2016.- “Investigations of the antioxidant mechanisms of polyphenols and their metabolites.” [1] C. Miene, A. Weise, M. Glei, Nutr. Cancer, 2011, 63, 653. [2] P.C. Karlsson, U. Huss, A. Jenner, B. Halliwell, L. Bohlin, J.J. Rafter, J. Nutr., 2005, 135, 2343. [3] G. Dannhardt, W. Kiefer, Eur. J. Med. Chem., 2001, 36, 109. [4] R.A. Gupta, R.N. DuBois, Nat. Rev. Cancer, 2001, 1, 11. [5] M. Amaravani, N.K. Prasad, V. Ramakrishna, Springerplus, 2012, 1, 58. [6] M.J. Frisch, G.W. Trucks, H.B. Schlegel et al., GAUSSIAN 09, Wallingford, CT, 2009.

radical scavenging ; COX-2 ; polyphenolic metabolites ; DFT ; HAT ; ET-PT ; SPLET

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