Inhibition of autophagic flux by cyclometalated iridium(iii) complexes through anion transportation.

Synthetic anion transporters that can interfere with the intracellular pH homeostasis are gaining increasing attention for tumor therapy, however, the biological mechanism of anion transporters remains to be explored. In this work, two phosphorescent cyclometalated Ir(iii) complexes containing 2-phenylpyridine (ppy) as the cyclometalated ligand, and 2,2'-biimidazole (Hbiim, ) or 2-(1-imidazol-2-yl)pyridine (Hpyim, ) as the ancillary ligands have been synthesized and characterized. Due to the protonation and deprotonation process of the N-H groups on Hbiim and Hpyim, and display pH-dependent phosphorescence and can specifically image lysosomes. Both and can act as anion transporters mainly through the anion exchange mechanism with higher potency observed for . Mechanism investigation shows that and can induce caspase-independent cell death through reactive oxygen species (ROS) elevation. As and can alkalinize lysosomes through anion disturbance, they can inhibit autophagic flux. Our work provides a novel anticancer mechanism of metal complexes, which gives insights into the innovative structure-based design of new metallo-anticancer agents.