Enhanced AnticancerSelectivity of CyclometalatedImidazole/Pyrazole-Imine Iridium^III Complexes Through theSwitch from Cationic to Zwitterionic Forms

Cyclometalated iridium^III complexes have shown promising anticancer properties, with variations in charge and ligand substitution significantly influencing their biological activity. However, zwitterionic iridium^III complexes remain scarcely explored. Herein, we report a series of zwitterionic cyclometalated imidazole/pyrazole-imine iridium^III complexes and compare their biological activity to analogous cationic complexes with sulfonate counteranions. X-ray crystallography confirmed the structural differences between the cationic and zwitterionic forms. These complexes exhibited cytotoxicity against A549, HeLa, and HepG2 cancer cells, with IC₅₀ values ranging from 14.35 to 69.12 μM. While cationic complexes showed higher cytotoxicity, zwitterionic complexes demonstrated enhanced selectivity for A549 cancer cells over BEAS-2B normal cells (selectivity index: 3.72–5.90 for zwitterionic forms vs 1.16–1.44 for cationic forms). This selectivity is attributed to distinct cellular uptake mechanisms: zwitterionic complexes use an energy-dependent pathway in cancer cells and an energy-independent pathway in normal cells, leading to differences in cellular accumulation and redox activity. Mechanistic studies revealed that both complex types induce ROS generation and mitochondrial membrane depolarization (MMP), with apoptosis as the primary cell death pathway.