Indispensable Role of Indazole −NH in Cyclometalated Ir(III) Complexes to Drive ES-PCET with High Phototherapeutic Index

Photodynamic therapy (PDT) of cancer has limited use in solid tumors due to its dependence on molecular oxygen for efficiency. Excited-state proton-coupled electron transfer (ES-PCET), a pathway capable of acting without oxygen, may bring a paradigm shift in PDT. Here, we report a rationale to promote ES-PCET in cyclometalated Ir(III) complexes using ligands with vicinal -NH groups with respect to the Ir(III). Systematic tuning from imidazole to indazole enhanced the phototherapeutic index (PI) to 6600, while N-methylation of indazole abolished the PI increasing dark toxicity, thus underscoring the essential role of -NH. No organic or metal-containing ES-PCET-based PDT agents show such high PI. The results suggest that irradiation of the indazole-based Ir(III) complex leads to PCET involving the metal center and the vicinal - NH group of the coordinated nitrogen. In the presence of NADH (sacrificial donor), the process is photocatalytic in reducing cytochrome c and p-quinone, ultimately deregulating the mitochondrial ETC and inducing immunogenic apoptotic cell death.