Systematic Investigation of Coordination Chemistry in Iridium(III) and Ruthenium(II) Complexes Derived from Pyridyl–Amine Ligands and Their Anticancer Evaluation

Abstract

A systematic investigation of the coordination chemistry of iridium(III) and ruthenium(II) complexes synthesized from pyridyl–amine ligands was performed, focusing on how ligand steric hindrance and metal centers affect oxidation behavior, coordination modes, and biological activities. The study revealed that steric hindrance at the ligand’s bridge carbon strongly influenced both oxidation behavior and coordination modes. Smaller substituents (e.g., H and Me) facilitated oxidation to form pyridyl–imine species under adventitious oxygen, whereas bulky substituents (e.g., i-Bu and mesityl) suppressed oxidation, yielding stable pyridyl–amine or 16-electron pyridyl–amido complexes. Moreover, iridium(III) complexes were more prone to oxidation than the corresponding ruthenium(II) complexes under similar conditions. The aqueous stability of the newly synthesized complexes was confirmed. Cytotoxicity assays demonstrated that most of the complexes exhibited notable anticancer potency against A549, HeLa and cisplatin-resistant A549/DDP cancer cells. Mechanistic studies suggested a redox-driven pathway involving the catalytic oxidation of NADH to NAD⁺, the elevation of ROS levels and depolarization of the mitochondrial membrane. Notably, pyridyl–amine complexes induced apoptosis, while 16-electron pyridyl–amido complexes did not, though both caused S phase cell cycle arrest. Additionally these complexes can inhibit A549 cell migration, suggesting their potential to reduce cancer metastasis.