Lysosome-Targeted Phosphine-Imine Half-Sandwich Iridium(III) Anticancer Complexes: Synthesis, Characterization, and Biological Activity

The synthesis, characterization, and catalytic ability of converting coenzyme NADH to NAD(+) and the anticancer activity of half-sandwich iridium(III) complexes with general formula of [(eta(5)-Cp-x)Ir(P<<^>>N)Cl]PF6 (Cp-x: Cp* or biphenyl Cp-xbiph derivatives; P<<^>>N: various phosphine-imine ligands) were investigated. The crystal structure of the complex Ir4 showed a piano-stool geometry around the iridium(III) center. This type of iridium(III) complexes had sufficient stability in aqueous solution. Most of the complexes showed good anticancer activities toward A549 cancer cells, which were higher than the clinical drug cisplatin. In this series, complex Ir8 displayed the highest anticancer activity against A549 cells (IC50 = 4.7 mu M), showing an approximately 4.5-fold more potent activity than cisplatin (IC50 = 21.30 mu M). The structure activity relationship study showed that the cytotoxicity of these complexes may be primarily attributed to the coordination between iridium(III) and the coordinating atoms, and the nature of the imine N-substituents may not be a major factor affecting cytotoxicity. Furthermore, this family of complexes causes cell death by cell stress, inducing apoptosis and necrosis, overproduction of reactive oxygen species, and disruption of the mitochondria] membrane potential. Most interestingly, the use of confocal microscopy provides insights into the microscopic mechanism that the typical complex Ir3 can penetrate into A549 cancer cells through a non-energy-dependent pathway and specifically distribute in lysosomes.