Designing novel tridentate iridium(III) complexes comprising functionalized benzothiazole ligands to improve anticancer activity by targeting mitochondria.

In recent years, organo‑iridium anticancer agents have shown promising antitumor activity toward cancer cells. In this paper, two benzothiazole-based tridentate ligands, 2,2'-(5-(tert-butyl)-1,3-phenylene)bis(benzo[d]thiazole) (L) and 2,2'-(5-(methyl)-1,3-phenylene)bis(benzo[d]thiazole) (L), have been designed and synthesized, and then combined with 2,2'-bipyridine (bipy) and 1,10-phenanthroline (phen) ancillary ligands to form a series of novel [Ir(N^C^N)(N^N)Cl]-type iridium(III) complexes (Ir1-Ir4). The phosphorescence properties of these complexes facilitate the visualization of their subcellular localization and interactions with other biomolecules. Among them, complex Ir2 has the best cytotoxicity activity toward A549 cells and its antitumor activity was further evaluated. Laser confocal assay reveals that Ir2 followed an energy-dependent cellular uptake mechanism and specifically accumulates in mitochondria (Pearson colocalization coefficient: 0.89). The anticancer mechanism has been explored through apoptosis, cell cycle arrest, western blotting (WB), reactive oxygen species (ROS) levels and mitochondrial membrane potential (MMP) changes. The antitumor activity in vivo confirms that Ir2 could effectively inhibit tumor growth with an inhibitory rate of 71.60 %, which is superior to cisplatin. To the best of our knowledge, Ir2 is a rare example of [Ir(N^C^N)(N^N)Cl]-type complexes as potential anticancer agents.