Novel lysosome-targeted cyclometalated Iridium(III) anticancer complexes containing imine-N-heterocyclic carbene ligands: Synthesis, spectroscopic properties and biological activity

A series of luminescent cyclometalated iridium(III) anticancer complexes of the type [Ir(ppy)(2)((CN)-N-boolean AND)]PF6(where (CN)-N-boolean AND are imine-N-heterocyclic carbene ligands with various substituents and ppy is 2-phenylpyridine) was synthesized and fully characterized. All complexes Ir1-Ir5 showed potent cytotoxicity toward A549 and HeLa cancer cells with IC50 values ranging within 1.78-4.95 and 1.97-7.35 mu M, respectively. Ir5 was particularly potent towards A549 cancer cells (IC50 = 1.78 mu M) and had ca. 12-fold higher cytotoxicity than the clinical platinum drug cisplatin. Complexes Ir2 and Ir5 had moderate binding affinity to BSA. Mechanism studies showed that these complexes exerted their anticancer efficacy by cell-cycle arrest, inducing apoptosis, increasing the intracellular reactive oxygen species level, and reducing the mitochondrial membrane potential. Interestingly, the use of confocal microscopy provided insight into the microscopic mechanism of the most typical and active complex Ir5, which was found to enter A549 lung cancer cells mainly through an energy dependent pathway and was located in the lysosome.