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

beta-Lapachone is an ortho-naphthoquinonenaturalproduct with significant antiproliferative activity but suffers fromadverse systemic toxicity. The use of photoremovable protecting groupsto covalently inactivate a substrate and then enable controllablerelease with light in a spatiotemporal manner is an attractive prodrugstrategy to limit toxicity. However, visible light-activatable photocagesare nearly exclusively enabled by linkages to nucleophilic functionalsites such as alcohols, amines, thiols, phosphates, and sulfonates.Herein, we report covalent inactivation of the electrophilic quinonemoiety of beta-lapachone via a C-(sp(3))-C-(sp(3)) bond to a coumarin photocage. In contrast to beta-lapachone,the designed prodrug remained intact in human whole blood and didnot induce methemoglobinemia in the dark. Under light activation,the C-C bond cleaves to release the active quinone, recoveringits biological activity when evaluated against the enzyme NQO1 andhuman cancer cells. Investigations into this report of a C-(sp(3))-C-(sp(3)) photoinduced bond cleavage suggesta nontraditional, radical-based mechanism of release beginning withan initial charge-transfer excited state. Additionally, caging andrelease of the isomeric para-quinone, alpha-lapachone,are demonstrated. As such, we describe a photocaging strategy forthe pair of quinones and report a unique light-induced cleavage ofa C-C bond. We envision that this photocage strategy can beextended to quinones beyond beta- and alpha-lapachone, thus expandingthe chemical toolbox of photocaged compounds.