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

TL;DR

Researchers studied gold(III) complexes with special ligands and found they can kill cancer cells by causing cell death through mitochondrial damage.

Contribution

The study introduces hemilabile biphenyl gold(III) complexes with antiproliferative activity linked to their neutral form and mitochondrial effects.

Findings

BGC complexes show antiproliferative activity in the low micromolar range against human cells.

Neutral open forms of the complexes are responsible for observed biological activity.

Complexes induce mitochondrial membrane depolarization, potentially leading to apoptosis.

Abstract

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)]PF6 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 1H 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.

An array of eight pairs of biphenyl gold(III) complexes comprising NHC–pyridine ligands having a hemilabile character in vitro displays antiproliferative activity toward human cells in the low micromolar range which is exclusively due to their neutral open form according to speciation studies. All the complexes induce mitochondrial membrane depolarization, likely succeeding to apoptotic cell death.© 2025 WILEY‐VCH GmbH

Figures