Double Disguise: Camouflaging Photocages for Bioorthogonally Controlled Conditional Activation.

Photocages provide excellent spatiotemporal control over biological processes; however, strategies to restrict their activation to specific conditions remain limited. In this work, we demonstrate that our recently introduced photocages based on the aminofluorone (rhodol) choromophore can be rendered completely inactive through a single substitution on the oxygen auxochrome. These 'camouflaged' photocages are entirely colorless, preventing photouncaging in their disabled state. Bioorthogonal removal of the camouflaging group restores the photoactivity of the cages, introducing an additional layer of control for photoassisted delivery systems. We further demonstrate this concept of substitution-dependent, bioorthogonally regulated photoactivation in a cellular context, where both a bioorthogonal reagent and light were required to release a potent topoisomerase inhibitor, SN38.