Iridium(III) and rhenium(I) complexes containing an IDO inhibitor induce apoptosis and pyroptosis

Four novel Ir(III)/Re(I)-1-methyl-D-tryptophan conjugates (Ir-MT-1-2 and Re-MT-1-2) were designed and synthesized for the first time, among which 1-methyl-D-tryptophan (1-MT) is an indoleamine 2,3-dioxygenase (IDO) inhibitor. Three (Ir-MT-1-2 and Re-MT-1) of the metal-conjugates showed high-efficient anti-tumor activities against human cervical cancer HeLa cells, with IC₅₀ values of 5.2, 7.1, and 4.4 μM, respectively, and significantly inhibited IDO expression. Mechanistic investigations revealed that these complexes selectively localized to mitochondria, inducing mitochondrial membrane potential (MMP) depolarization, elevating intracellular reactive oxygen species (ROS) levels, activating mitochondrial apoptotic pathways, and simultaneously inducing the cleavage of pyroptosis marker (GSDME) to cause pyroptosis. These results demonstrate the potential of combing transition metals with IDO inhibitors for cancer treatment.