Uncaging Iridium(III) Complexes for Combined Photodynamic and Photoactivated Chemotherapy.

Inorganic photochemotherapy enables precise spatial and temporal control over anticancer drug activation, offering a promising strategy to reduce systemic toxicity. Two iridium(III) complexes of general formula [Ir(L)(ppy)(terpy)]PF6 with L = N-acetyl-L-cysteinato methyl ester (cys) or N-acetyl-L-selenocysteinato methyl ester (sec), were developed as light-activatable prodrugs with sulfur- and selenium-based "caging" groups. Both complexes are stable in the dark but undergo light induced bond cleavage upon visible light activation, following distinct photochemical pathways dictated by the coordinated chalcogen. For the cys complex, an initial oxygen-dependent formation of a sulfinato intermediate is followed by Ir─S bond cleavage. In contrast, the selenium complex first releases dehydroalanine due to Se─C bond cleavage, forming an unprecedented selenite intermediate [Ir(SeO3)(ppy)(terpy)], which was characterized by single crystal x-ray diffraction. The photoactivation leads to high singlet oxygen production quantum yields (40%-48%), consistent with a type II photodynamic therapy (PDT) mechanism. Both complexes exhibit minimal dark toxicity (EC50 > 150 µM) but potent photocytotoxicity in A549 cells under blue and green light photoactivation (460 and 520 nm). This new class of photocaged iridium(III) pro-sensitizer shows promise for combined PACT/PDT applications and demonstrates how chalcogen coordination modulates the photoreactivity and therapeutic efficacy of metal complexes.