Tuning Thiol Stability and Anticancer Activity in Benzimidazole‐Derived Au(I)–NHC Complexes Through Chloride‐to‐Thiolate Ligand Exchange

Gold(I) N ‐heterocyclic carbene (Au(I)–NHC) complexes are promising anticancer agents, but their therapeutic potential is often limited by rapid deactivation by thiol‐containing biomolecules such as glutathione (GSH) and cysteine (Cys). Here, we report a ligand engineering strategy to modulate the stability and biological activity of 1,3‐disubstituted benzimidazolium‐derived Au(I) complexes. A series of Au(I) chlorido complexes bearing diverse N ‐substituents was synthesized, and the chlorido ligand was replaced with thiolate ligands, including 2‐mercaptopyrimidine and thioglucose, to improve resistance to thiol‐mediated deactivation. The complexes were characterized by NMR, HRMS, Raman spectroscopy, X‐ray photoelectron spectroscopy (XPS), and single‐crystal X‐ray diffraction. Structural and computational studies revealed linear two‐coordinate Au(I) centers with strong AuC bonding and metal‐to‐ligand charge transfer character. The complexes showed potent cytotoxicity across multiple cancer cell lines, including HT1080, Huh‐7, MCF‐7, MDA‐MB‐231, A549, HCT116, and HeLa, with better selectivity than in noncancerous HEK293T cells. Several compounds outperformed auranofin. Mechanistic studies using inhibitors of apoptosis, necroptosis, autophagy, and ferroptosis suggested that the cytotoxicity does not involve canonical regulated cell death pathways, but it is consistent with a predominantly nonapoptotic, necrotic mode of cell death.