Targeting cancer cell metabolism with mitochondria-immobilized phosphorescent cyclometalated iridium(<scp>iii</scp>) complexes

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 <b>2</b> and <b>4</b>, containing reactive chloromethyl groups for mitochondrial fixation, show much higher cytotoxicity than complexes <b>1</b> and <b>3</b> without mitochondria-immobilization properties against the cancer cells screened. Further studies show that complexes <b>2</b> and <b>4</b> induce caspase-dependent apoptosis through mitochondrial damage, cellular ATP depletion, mitochondrial respiration inhibition and reactive oxygen species (ROS) elevation. The phosphorescence of complexes <b>2</b> and <b>4</b> can be utilized to monitor the perinuclear clustering of mitochondria in real time, which provides a reliable and convenient method for <i>in situ</i> monitoring of the therapeutic effect and gives hints for the investigation of anticancer mechanisms. Genome-wide transcriptional analysis shows that complex <b>2</b> 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.