Photo-Uncaging by C(sp 3 )–C(sp 3 ) Bond Cleavage Restores β-Lapachone Activity

β-Lapachone is an ortho -naphthoquinone natural product with significant antiproliferative activity but suffers from adverse systemic toxicity. The use of photoremovable protecting groups to covalently inactivate a substrate and then enable controllable release with light in a spatiotemporal manner is an attractive prodrug strategy to limit toxicity. However, visible light-activatable photocages are nearly exclusively enabled by linkages to nucleophilic functional sites such as alcohols, amines, thiols, phosphates, and sulfonates. Herein, we report covalent inactivation of the electrophilic quinone moiety of β-lapachone via a C(sp 3 )–C(sp 3 ) bond to a coumarin photocage. In contrast to β-lapachone, the designed prodrug remained intact in human whole blood and did not induce methemoglobinemia in the dark. Under light activation, the C–C bond cleaves to release the active quinone, recovering its biological activity when evaluated against the enzyme NQO1 and human cancer cells. Investigations into this report of a C(sp 3 )–C(sp 3 ) photoinduced bond cleavage suggest a nontraditional, radical-based mechanism of release beginning with an initial charge-transfer excited state. Additionally, caging and release of the isomeric para -quinone, α-lapachone, are demonstrated. As such, we describe a photocaging strategy for the pair of quinones and report a unique light-induced cleavage of a C–C bond. We envision that this photocage strategy can be extended to quinones beyond β- and α-lapachone, thus expanding the chemical toolbox of photocaged compounds.