Iminoamido chelated iridium(III) and ruthenium(II) anticancer complexes with mitochondria-targeting ability and potential to overcome cisplatin resistance

A diverse set of neutral half-sandwich iminoamido iridium and ruthenium organometallic complexes is synthesized through the utilization of Schiff base pro-ligands with N˄N donors. Notably, these metal complexes with varying leaving groups (Cl− or OAc−) are formed by employing different quantities of the deprotonating agent NaOAc, and exhibit promising cytotoxicity against various cancer cell lines such as A549 and cisplatin-resistant A549/DDP lung cancer cells, as well as HeLa cells, with IC50 values spanning from 9.26 to 15.98 μM. Cytotoxicity and anticancer selectivity (SI: 1.9–2.4) of these metal complexes remain unaffected by variations in the metal center, leaving group, and ligand substitution. Further investigations reveal that these metal complexes specifically target mitochondria, leading to the depolarization of the mitochondrial membrane and instigating the production of intracellular reactive oxygen species. Furthermore, the metal complexes are found to induce late apoptosis and disrupt the cell cycle, leading to G2/M cell cycle arrest specifically in A549 cancer cells. In light of these findings, it is evident that the primary mechanism contributing to the anticancer effectiveness of these metal complexes is the redox pathway. Synopsis: A series of iridium(III) and ruthenium(II) complexes with different leaving groups were prepared using the same iminoamino ligands. These complexes displayed high cytotoxicity and showed no cross-resistance with cisplatin, which seemed to be associated with the redox-based mechanism via the mitochondrial pathway. [Display omitted] •A series of neutral half-sandwich iridium(III) and ruthenium(II) organometallic complexes chelating iminoamido donors were synthesized.•Mitochondria-targeting and the redox pathway were contributing to the anticancer effectiveness of these complexes.