Gold(III) heteroleptic complexes with SNS-thiosemicarbazonate ligands as cytotoxic agents: Experimental and computational insights into the mechanism of action

New gold(III) heteroleptic complexes of general formula [AuX(dmtsc)], with (dmtsc)(2-) = (dieth-ylaminothiocarbonyl)benzimidoyl-morpholinyl-thiosemicarbazonate and X = xant(-) (ethyl xanthate) or damp- (dimethyl-1-phenylmethanamine), were synthesized and compared to the chlorido precursor [AuCl(dmtsc)]. The characterization of the new complexes included FTIR, elemental analysis, molar conductivity, UV-Vis, H-1 and C-13 NMR spectroscopies and ESI(+)-MS. In addition, the xanthate derivative was analyzed by single-crystal X-ray diffraction. In vitro assays against three tumor cell lines (B16-F10, HCT-8 and MDA-MB-231) showed that the gold(III) complexes display remarkable antiproliferative effects on human breast adenocarcinoma cell line with influence of the co-ligands. The cytotoxicity on VERO cells was also investigated revealing that the organome-tallic complex [Au(damp)(dmtsc)] was the most selective compound for MDA-MB-231, although not the most active. Attempting to comprehend their behavior in biological medium, studies involving the interactions with possible biological targets were performed by experimental methods and theoretical docking simulations. Their results indicated that HSA might be a probable carrier of the compounds in the biological medium, whereas DNA is not supposed to be their main target. On the other hand, all compounds totally inhibited thioredoxin reductase enzyme (TrxR) at the concentration of 50 mu M and formed significant molecular interactions, suggesting that it might be one of the molecular targets of these gold(III) complexes.

Automated summary

This study synthesized new gold(III) heteroleptic complexes and characterized them. In vitro experiments showed that these complexes have significant antiproliferative effects on breast adenocarcinoma cells, and their activity is influenced by the co-ligands. Further investigation revealed that these complexes may interact with human serum albumin (HSA) and inhibit thioredoxin reductase (TrxR) enzyme.