European Journal of Medicinal Chemistry 2015-01-01

Regioselective chemical and rapid enzymatic synthesis of a novel redox – Antiproliferative molecular hybrid.

Elena Geromichalou, Nisar Sayyad, Eleni Kyriakou, Alexandra V Chatzikonstantinou, Efstathia Giannopoulou, Norbert Vrbjar, Haralabos P Kalofonos, Haralambos Stamatis, Andreas G Tzakos

Index: Eur. J. Med. Chem. 96 , 47-57, (2015)

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Abstract

Recent science evidenced the interlinkage of oxidative stress and cancer. Due to the inherent complexity of cancer and its accompanying effect of oxidative stress, novel molecules, containing combinatorial functionalities should be targeted. Herein, we synthesized gemcitabine-5'-O-lipoate derived from a regioselective coupling of the chemotherapeutic drug gemcitabine (GEM), a first-line agent for cancer therapy and α-lipoic acid (LA), a potent antioxidant. gemcitabine-5'-O-lipoate was obtained in 4 chemical steps. To avoid the tedious and laborious chemical steps we also utilized biocatalysis using immobilized Candida antarctica lipase B (CALB), and the optimum conditions for the regioselective and one-pot synthesis of gemcitabine-5'-O-lipoate were established by exploiting different solvents (organic solvents and ionic liquids) and enzyme immobilization (acrylic resin and carbon nanotubes). Cytotoxic activity of co-administrating GEM and LA was proven to be synergistic against non-small cell lung cancer cells whereas antagonistic for bladder cancer cells. In contrast, the gemcitabine-5'-O-lipoate hybrid was found to be superior to the parent compounds against both non-small cell lung cancer and bladder cancer cells as also was found to preserve the redox activity of the parent compound LA. The regioselective biotransformation mediated synthesis of the anticancer-antioxidant hybrid illustrates the capacity of biocatalysis to act as an asset in molecular hybridization techniques.Copyright © 2015 Elsevier Masson SAS. All rights reserved.