Au(I) complexes bearing allyldiphenylphosphine and thiolate ligands: Synthesis, structural characterization, and biological evaluation

Abstract

This study presents the synthesis of gold(I) thiolate complexes, [Au(SR)(PPh₂allyl)], PPh₂allyl refers to allyldiphenylphosphine, and SR represents the deprotonated forms of various thiols, including pyridine-2-thiol (HSpy, 1a), pyrimidine-2-thiol (HSpyN, 1b), benzothiazole-2-thiol (HSbt, 1c), and benzimidazole-2-thiol (Sbi, 1d). The complexes were prepared via nucleophilic substitution reactions between chlorogold complex [AuCl(PPh₂allyl)], A, and in situ generated thiolate salts under inert conditions. Characterization was performed using NMR spectroscopy and HR ESI-Mass, while single-crystal X-ray diffraction provided structural confirmation for A and 1b. The anticancer activity of these gold complexes was assessed in three human cancer cell lines: lung (A549), ovarian (SKOV3), and breast (MCF-7), alongside a non-cancerous breast cell line (MCF-10 A). The results revealed promising antitumor effects, with 1a and 1b demonstrating superior selectivity and potency compared to standard treatments such as cisplatin and auranofin. These compounds demonstrated a good selectivity index. Further investigations indicated that 1b induces 77.0 % apoptosis in a dose-dependent manner, suggesting its potential as a therapeutic agent. Additionally, 1b's effects on cell cycle progression were observed, with higher concentrations promoting S phase entry, which may influence cell viability. Although genotoxicity was noted, the primary mechanism of action for 1b appears to be the induction of apoptosis rather than direct DNA interaction. Correlating cytotoxicity data with molecular docking results revealed a trend where compounds with stronger binding affinities to DNA and thioredoxin reductase (TrxR), particularly 1b and 1d, exhibited lower IC₅₀ values. Mechanistic insights were refined by acknowledging the dynamic reactivity of these complexes with TrxR's selenocysteine, suggesting that docking results represent initial binding prior to potential ligand exchange. Although some genotoxicity was observed, the primary mechanism appears to be TrxR-mediated apoptosis rather than direct DNA targeting, consistent with broader literature emphasizing protein interactions over nucleic acid effects. These findings underscore the therapeutic potential of these gold complexes in targeting cancer cells, highlighting their promise as selective anticancer agents.