Synthesis and antitumor mechanism investigation of iridium(III)/rhenium(I) complexes with 4-phenylimidazole ligands.

In recent years, in addition to their potential diagnostic and therapeutic properties, the immunogenic cell death (ICD) induction activity of iridium(III) and rhenium(I) complexes has been extensively reported. 4-Phenylimidazole (4-PIM), as an indoleamine 2,3-dioxygenase (IDO) inhibitor, can improve the immunosuppressive environment and enhance the efficacy of chemotherapy drugs. In this study, a series of Ir(III)/Re(I)-PIM complexes [Ir-PIM-(1-3) and Re-PIM-(1-3)] by coordination 4-PIM with iridium(III)/rhenium(I) metal centers were designed and synthesized to study their antitumor mechanisms. Among the six complexes screened, four compounds Ir-PIM-(1-3) and Re-PIM-1 showed good antitumor activity against human triple negative breast cancer (MDA-MB-231) cells. And Ir-PIM-(1-3)/Re-PIM-1 exhibited potential IDO inhibitory activity, which can suppress the expression of IDO protein. Further mechanistic studies indicate that Ir-PIM-(1-3)/Re-PIM-1 can effectively enter MDA-MB-231 cells, and induce the depolarization of mitochondrial membrane potential, the elevation of reactive oxygen species, G2/M phase cell cycle arrest and the release of damage-related molecular patterns, exhibiting dual activity in inducing both apoptosis and ICD.