Impact of Chelation on Reactivity and Cytotoxicity of Hemilabile Biphenyl Gold(III) N-Heterocyclic Carbene Complexes.

Although great progresses have been accomplished in the field of antineoplastic treatments, the need for chemotherapy agents with new mechanisms of action remains essential. Metal complexes presenting hemilabile ligands could combine structural toxicity upon full coordination of the ligand and reactive toxicity upon ligand partial decoordination and direct coordination of the metal center to biological targets. To investigate the relevance of hemilability in the case of Au(III) complexes, we synthesized eight open biphenyl gold(III) N-heterocyclic carbene complexes coined BGC of general formula [(C^C)Au(NHC^het)Cl] where het is a pyridine-type entity and C^C is 4,4'-diterbutylbiphenyl. Chloride abstraction afforded the chelated cationic complexes [(C^C)Au(NHC^N)]PF(6) in which the pyridine arm coordinates the gold ion. Quantitative irreversible conversion of the cationic forms to the neutral ones in the presence of chloride ions was demonstrated through extensive speciation studies by (1)H NMR spectroscopy on both forms in different media including DMSO/cell culture medium mixture. The BGC complexes exhibited antiproliferative activity in the low micromolar range with equivalent activities for each open neutral/chelated cationic pair. Time lapse fluorescence videomicroscopy studies demonstrated the activation of effector caspases 3/7, suggesting the induction of apoptosis. Preliminary mechanistic studies suggest that apoptotic cell death may arise partially from mitochondrial membrane depolarization.