Biocompatible silver(I) complexes with heterocyclic thioamide ligands for selective killing of cancer cells and high antimicrobial activity - A combined in vitro and in silico study

Abstract

A series of heteroleptic Ag(I) complexes bearing 4,6-dimethyl-2-pyrimidinethiol (dmp2SH), i.e., [AgCl(dmp2SH)(PPh₃)₂] (1), [Ag(dmp2SH)(PPh₃)₂]NO₃ (2), [Ag(dmp2SΗ)(xantphos)]NO₃ (3), [Ag(μ-dmp2S)(PPh₃)]₂ (4), [Ag(dmp2S)(xantphos)] (5), [Ag(μ-dmp2S)(DPEphos)]₂ (6) (xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene and DPEPhos = bis[(2-diphenylphosphino)phenyl]ether) were synthesized. The complexes display systematic variation of particular structural characteristics which were proved to have a significant impact on their in vitro cytotoxicity and antimicrobial properties. A moderate-to-high potential for bacteria growth inhibition was observed for all complexes, with 2, 3 and 5 being particularly effective against Gram-(+) bacteria (IC₅₀ = 1.6-4.5 μM). The three complexes exhibit high in vitro cytotoxicity against HeLa and MCF-7 cancer cells (IC₅₀ = 0.32-3.00 μΜ), suggesting the importance of coordination unsaturation and cationic charge for effective bioactivity. A very low cytotoxicity against HDFa normal cells was observed, revealing a high degree of selectivity (selectivity index ~10) and, hence, biocompatibility. Fluorescence microscopy using 2 showed effective targeting on the membrane of the HeLa cancer cells, subsequently inducing cell death. Binding of the complexes to serum albumin proteins is reasonably strong for potential uptake and subsequent release to target sites. A moderate in vitro antioxidant capacity for free radicals scavenging was observed and a low potential to destroy the double-strand structure of calf-thymus DNA by intercalation, suggesting likely implication of these properties in the bioactivity mechanisms of these complexes. Further insight into possible mechanisms of bioactivity was obtained by molecular modeling calculations, by exploring their ability to act as potential inhibitors of DNA-gyrase, human estrogen receptor alpha, human cyclin-dependent kinase 6, and human papillomavirus E6 oncoprotein.

Keywords: Antimicrobial activity; Crystal structures; Cytotoxicity; Heterocyclic thioamides; Selectivity; Silver(I) complexes.