Targeting cancer cell metabolism with mitochondria-immobilized phosphorescent cyclometalated iridium(iii) complexes

摘要

Cancer cell metabolism is reprogrammed to sustain the high metabolic demands of cell proliferation. Recently, emerging studies have shown that mitochondrial metabolism is a potential target for cancer therapy. Herein, four mitochondria-targeted phosphorescent cyclometalated iridium(iii) complexes have been designed and synthesized. Complexes >2 and >4, containing reactive chloromethyl groups for mitochondrial fixation, show much higher cytotoxicity than complexes >1 and >3 without mitochondria-immobilization properties against the cancer cells screened. Further studies show that complexes >2 and >4 induce caspase-dependent apoptosis through mitochondrial damage, cellular ATP depletion, mitochondrial respiration inhibition and reactive oxygen species (ROS) elevation. The phosphorescence of complexes >2 and >4 can be utilized to monitor the perinuclear clustering of mitochondria in real time, which provides a reliable and convenient method for in situ monitoring of the therapeutic effect and gives hints for the investigation of anticancer mechanisms. Genome-wide transcriptional analysis shows that complex >2 exerts its anticancer activity through metabolism repression and multiple cell death signalling pathways. Our work provides a strategy for the construction of highly effective anticancer agents targeting mitochondrial metabolism through rational modification of phosphorescent iridium complexes.