Mitochondria-targeted neutral and cationic iridium(iii) anticancer complexes chelating simple hybrid sp2-N/sp3-N donor ligands

Abstract

Most platinum group-based cyclometalated neutral and cationic anticancer complexes with the general formula [(C^N)₂Ir(XY)]^0/+ (neutral complex: XY = bidentate anionic ligand; cationic complex: XY = bidentate neutral ligand) are notable owing to their intrinsic luminescence properties, good cell permeability, interaction with some biomolecular targets and unique mechanisms of action (MoAs). We herein synthesized a series of neutral and cationic amine–imine cyclometalated iridium(III) complexes using Schiff base ligands with sp²-N/sp³-N N^NH₂ chelating donors. The cyclometalated iridium(III) complexes were identified by various techniques. They were stable in aqueous media, displayed moderate fluorescence and exhibited affinity toward bovine serum albumin (BSA). The complexes demonstrated promising cytotoxicity against lung cancer A549 cells, cisplatin-resistant lung cancer A549/DDP cells, cervical carcinoma HeLa cells and human liver carcinoma HepG2 cells, with IC₅₀ values ranging from 9.98 to 19.63 μM. Unfortunately, these complexes had a low selectivity (selectivity index: 1.62–1.98) towards A549 cells and BEAS-2B normal cells. The charge pattern of the metal center (neutral or cationic) and ligand substituents showed little influence on the cytotoxicity and selectivity of these complexes. The study revealed that these complexes could target mitochondria, cause depolarization of the mitochondrial membrane, and trigger the production of intracellular ROS. Additionally, the complexes were observed to induce late apoptosis and perturb the cell cycle in the G₂/M or S phase in A549 cells. Based on these results, it appears that the anticancer efficacy of these complexes was predominantly attributed to the redox mechanism.