Ir(III) Half-Sandwich Photosensitizers with a -Expansive Ligand for Efficient Anticancer Photodynamic Therapy

One approach to reduce the side effects of chemotherapy in cancer treatment is photodynamic therapy (PDT), which allows spatiotemporal control of the cytotoxicity. We have used the strategy of coordinating pi-expansive ligands to increase the excited state lifetimes of Ir(III) half-sandwich complexes in order to facilitate the generation of O-1(2). We have obtained derivatives of formulas [Cp*Ir((CN)-N-boolean AND)Cl] and [Cp*Ir((CN)-N-boolean AND)L]BF4 with different degrees of pi-expansion in the (CN)-N-boolean AND ligands. Complexes with the more pi-expansive ligand are very effective photosensitizers with phototoxic indexes PI > 2000. Furthermore, PI values of 63 were achieved with red light. Time-dependent density functional theory (TD-DFT) calculations nicely explain the effect of the pi-expansion. The complexes produce reactive oxygen species (ROS) at the cellular level, causing mitochondrial membrane depolarization, cleavage of DNA, nicotinamide adenine dinucleotide (NADH) oxidation, as well as lysosomal damage. Consequently, cell death by apoptosis and secondary necrosis is activated. Thus, we describe the first class of half-sandwich iridium cyclometalated complexes active in PDT.