Synthesis, characterization and biological evaluation of two cyclometalated iridium(III) complexes containing a glutathione S-transferase inhibitor

The cyclometalated iridium(III) compounds have been intensively studied for health-related applications due to their outstanding luminescent properties and multiple anticancer modes of action. Herein, two iridium(III) compounds Ir-1 and Ir-3 containing glutathione S-transferase inhibitor (GSTi) were developed and studied together with two unfunctionalized compounds Ir-2 and Ir-4 as a comparison. Biological study indicated that GSTi-bearing complexes Ir-1 and Ir-3 exert a synergistic effect on the inhibition of cancer cells. The photo -physical properties of Ir-1 similar to Ir-4 were investigated by UV/vis absorption and fluorescence spectroscopy and rationalized with TD-DFT calculations. As expected, GSTi-bearing complexes Ir-1 and Ir-3 exhibited considerable cytotoxicity against both A549 and cisplatin-resistant A549/cis cancer cells, much higher than the unfunction-alized iridium compounds Ir-2 and Ir-4. Further study indicated that Ir-1 and Ir-3 mainly localize in the mitochondria of tumor cells, and exert their cytotoxicity via generating ROS and inhibiting GST activity. The flow cytometry investigations demonstrated that Ir-1 and Ir-3 can arrest the cell cycle in S phase and induce the cell death through apoptosis process. Overall, the complexation of GST inhibitors with cyclometalated iridium(III) agents provides an effective way for potentiating the cytotoxicity of iridium(III) anticancer agents and resensi-tizing the efficacy against cisplatin resistant cancer cells.