Gold(I) complexes with aryl-thiosemicarbazones: Molecular modeling, synthesis, cytotoxicity and TrxR inhibition

Thiosemicarbazones and their metal complexes are of considerable interest because of their chemical and biological properties. Gold(I) compounds form a family of potential anticancer agents that are currently undergoing intense preclinical investigations. Novel gold(I) complexes were obtained through the reaction of aryl-thiosemicarbazone ligands with KAuCl4 and Au(PPh3)Cl. The complexes were characterized by elemental analyses, Raman, IR and NMR spectroscopies, electrospray ionization mass spectrometry, TG/DTA, cyclic voltammetry and with the aid of molecular modeling. The cytotoxicity of the complexes was assessed against tumor cell lines (B16-F10 and CT26.WT) and non-tumor cell line (BHK-21). Most of the tested complexes showed satisfactory cytotoxic activity, some of them being even more cytotoxic in tumor cells than cisplatin with a high selectivity index in the tested cells. The gold complexes with phosphine derivatives showed a better biological response and higher selectivity indices than their respective non-phosphine gold complexes. A preliminary drug-receptor docking study suggests the interaction of thiosemicarbazone ligands with Y116 and E30, which are part of the catalytic N-terminal motif of thioredoxin reductase (TrxR). All compounds were evaluated for their ability to inhibit the activity of the TrxR enzyme. The non-substituted phosphine gold complexes turned out to be effective inhibitors of TrxR when compared to the phosphine analogues. Both complexes, in most of the cases, were more efficient TrxR inhibitors than the free ligands. (C) 2017 Elsevier Ltd. All rights reserved.