Abstract / Summary
Abstract Imidazole- and benzimidazole-based Au(I) N-heterocyclic carbene (NHC) complexes show great potency as anticancer agents. However, other NHC scaffolds are only sparsely explored. Four gold(I) NHC complexes featuring thiazolium-based ligands (NHCthia) with varying N-substituents were synthesized and evaluated for their biological activity. The complexes containing aromatic N-substituents demonstrate higher stability, higher TrxR inhibition, and activity against breast (MDA-MB-231 and MCF-7) and ovarian (A2780) cancer cell lines, compared to the tested alkyl N-substituted complexes. Specifically, mesityl-substituted complex 1 exhibits high activity with IC50 values in the nanomolar range, exceeding the potency of auranofin in MDA-MB-231 cells. Mechanistic studies in leukemia cells (Nalm-6) revealed that complex 1 induces ROS formation, activates BAX and BAK, and causes mitochondrial membrane potential loss, initiating intrinsic apoptosis. Notably, the ligand precursor L1 shows no significant cytotoxicity, confirming that the gold(I) moiety drives the activity. Additionally, complex 1 can overcome resistance to etoposide and prednisolone without affecting healthy leukocytes, making Au(I) bis-NHCthia complexes a compelling class of antiproliferative agents.