Red and near-infrared light offer deep tissue penetration and spatiotemporal control for photodynamic therapy and localized drug release. However, selective release of phosphorus-containing prodrugs under long-wavelength irradiation remains challenging, owing to a lack of functional group designs that balance efficient photochemical activation with high dark stability. This study reports indolizine-based photocages with a phosphate, phosphinate, or thiophosphate moiety embedded as a robust C(sp2)-P bond at the indolizine C3 position. A practical synthesis was performed using indolizinylphosphonic dichlorides, generated in situ from 2-methoxyindolizines and POCl3, yielding diverse phosphoryl indolizines, including a gemcitabine conjugate. These conjugates efficiently uncaged to release their respective phosphorus(V) species under 660-808 nm irradiation with catalytic photosensitizers. Mechanistic studies using 18O-labeled water and specific scavengers indicated that water and singlet oxygen drive a photooxidative pathway leading to selective C(sp2)-P bond scission. To extend this reactivity to anticancer applications, we created approximately 1 nm-sized gold nanoclusters bearing indolizine-gemcitabine phosphonates, cyclic RGD (Arg-Gly-Asp) peptides, and chlorophyll-derived photosensitizers. The trifunctional nanoconjugates enabled red-light-triggered drug release, exhibiting pronounced light-dependent cytotoxicity against cancerous HeLa cells while maintaining low dark toxicity to normal fibroblasts. Collectively, the singlet-oxygen-driven C(sp2)-P bond cleavage of indolizines represents a promising strategy for developing photochemotherapeutic light-activatable phosphorus(V) prodrugs.
Watanabe et al. (Fri,) studied this question.