Triphenylphosphine-Modified IridiumIII, RhodiumIII, and RutheniumII Complexes to Achieve Enhanced Anticancer Selectivity by Targeting Mitochondria

The incorporation of an organelle-targeting moiety into compounds has proven to be an effective strategy in the development of targeted anticancer drugs. We herein report the synthesis, characterization, and biological evaluation of novel triphenylphosphine-modified half-sandwich iridium^III, rhodium^III, and ruthenium^II complexes. The primary goal was to enhance anticancer selectivity through mitochondrial targeting. All these triphenylphosphine-modified complexes exhibited promising cytotoxicity in the micromolar range (5.13–23.22) against A549 and HeLa cancer cell lines, surpassing the activity of comparative complexes that lack the triphenylphosphine moiety. Noteworthy is their good selectivity toward cancer cells compared to normal BEAS-2B cells, underscored by selectivity index ranging from 7.3 to >19.5. Mechanistically, these complexes primarily target mitochondria rather than interacting with DNA. The targeting of mitochondria and triggering mitochondrial dysfunction were confirmed using both confocal microscopy and flow cytometry. Their ability to depolarize mitochondrial membrane potential (MMP) and enhance reactive oxygen species (ROS) was observed, thereby leading to intrinsic apoptotic pathways. Moreover, these complexes lead to cell cycle arrest in the G₂/M phase and demonstrated antimigration effects, significantly inhibiting the migration of A549 cells in wound-healing assays.