Photoactivated Prodrugs Based on Julolidine-o-Nitrophenethyl Photocages for Traceless Release of Amine Payloads.

Light-controlled therapies provide a powerful strategy to enhance cancer selectivity through on-demand drug release. This approach frequently relies on organic photoremovable protecting groups (photocages) that combine stability in living systems with controlled uncaging under visible or near-infrared (NIR) light. Here, we report novel, redshifted o-nitrophenethyl (o-NPE) photocages based on an electron-rich julolidine scaffold that enable the traceless release of amine-bearing payloads upon visible-light or two-photon NIR activation. Electron donor-enhanced o-NPE photoremovable protecting groups with redshifted absorption were conjugated to doxorubicin and a combretastatin A-4 (CA-A4) analogue, yielding stable prodrugs under biomimetic dark conditions. Upon UV/visible irradiation or two-photon NIR excitation, these prodrugs undergo light-triggered uncaging via an aci-nitro/β-elimination pathway. The resulting photoactivated prodrugs exhibit robust light-dependent cytotoxicity with negligible dark activity, achieving selective activation in cancer cell lines. These findings position redshifted julolidine-based o-NPE cages as versatile platforms for visible/NIR-addressable amine prodrugs and establish design principles that advance organic photocaging strategies toward in vivo application and clinical translation.