Multinuclear silver N‐heterocyclic carbene complexes provoke potent anticancer activity via mitochondrial dysfunction and cell necrosis induction

Abstract

AbstractThree silver N‐heterocyclic carbene (NHC) complexes (Ag1–Ag3) were designed and synthesized using quinoline‐functionalized benzoimidazole salts (L1–L3). Both NHC precursors and resultant silver‐NHC complexes were characterized by NMR, FT‐IR spectroscopy, and elemental analysis. X‐ray diffraction analysis was additionally performed to investigate the crystal structures of these silver‐NHC complexes. The results showed that Ag1 is a dinuclear silver complex with a deviated linear geometry. Ag2 has a disilver core in which two silver atoms are coordinated by two quinoline‐functionalized carbene ligands and one acetonitrile molecule. The silver‐NHC complex Ag3 is composed of a silver‐triangle formed by three silver atoms and three carbene ligands. The in vitro cytotoxic studies revealed that silver‐NHC complexes had stronger antitumor activity than their corresponding NHC precursors. Notably, after a 24‐h exposure to cancer cells, Ag2 presented the highest cytotoxicity with a half maximal inhibitory concentration (IC50) at 1.74 ± 0.08 μM in A2780 cells, which was approximately 14‐fold lower than that of the clinically approved metallodrug cisplatin (IC50 = 24.74 ± 1.35 μM). Detailed mechanistic studies suggested that the complex Ag2 provoked intracellular reactive oxygen species (ROS) overproduction and mitochondrial membrane depolarization, which eventually resulted in mitochondrial dysfunction and cell potent necrosis. Overall, our studies show that NHC‐coordinated silver complexes can be readily constructed and used as an attractive class of anticancer agents, which is conductive for further investigation of their therapeutic potential for treating cisplatin‐resistant cancers.