Cell Death Mechanism of Organometallic Ruthenium(II) and Iridium(III) Arene Complexes on HepG2 and Vero Cells

[Image: see text] Due to side effects and toxicity associated with platinum-derived metal-based drugs, extensive research has been conducted on ruthenium (Ru) complexes. We aim to synthesize a highly oil soluble Ru(II)–p-cymene complex (Ru1) with an aliphatic chain group, a bimetallic Ru(II)–p-cymene complex (Ru2) with N,S,S triple-coordination and a bimetallic Ir(III)–pentamethylcyclopentadienyl complex (Ir1) with S,S double-coordination. Subsequently, we investigate the effects of these complexes on Vero and HepG2 cell lines, focusing on cell death mechanisms. Characterization of the complexes is performed through nuclear magnetic resonance spectroscopy ((1)H and (13)C NMR) and Fourier-transform infrared spectroscopy. The effective doses are determined using the (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide) (MTT) assay, applying different doses of the complexes to the two cell lines for 24 and 48 h, respectively. Immunoreactivities of Bax, Bcl2, caspase-3, RIP3, and RIPK1 are analyzed using the indirect immunoperoxidase technique. Notably, all the complexes (Ru1, Ru2, and Ir1) exhibit distinct cell death mechanisms, showing greater effectiveness than cisplatin. This study reveals the diverse mechanisms of action of Ru and Ir complexes based on different ligands. To the best of our knowledge, this study represents the first investigation of a novel RAED-type complex (Ru1) and unexpected bimetallic complexes (Ru2 and Ir1).