López-Corrales, MartaIzquierdo-García, EduardoBosch Marimon, ManelDas, TapasLlebaria Soldevila, AmadeuJosa-Culleré, LaiaMarchán Sancho, Vicente2025-05-232025-04-280022-2623https://hdl.handle.net/2445/221188Photocleavable protecting groups hold great promise in photopharmacology to control the release of bioactive molecules from their caged precursors within specific subcellular compartments. Herein, we describe a series of photocages based on a COUPY scaffold, incorporating chlorambucil (CLB) and 4-phenylbutyric acid (4-PBA) as bioactive payloads that can be efficiently activated with visible light. Confocal microscopy confirmed the preferential accumulation of CLB and 4-PBA N-hexyl COUPY photocages in the mitochondria, which exhibited aremarkable phototoxicity against cancer cells upon green-yellow light irradiation, with IC50 values in the nanomolar range. This effect was attributed to a synergistic mechanism involving the photorelease of the bioactive payloads and the intrinsic photogeneration of Type I and Type II ROS by the COUPY scaffold within mitochondria. Thus, COUPY-caged derivatives of CLB and 4-PBA underscore the potential of COUPY-caging groups as a versatile platform to develop innovative light-activated agents operating simultaneously through photodynamic therapy and photoactivated chemotherapy.1 p.application/pdfeng(c) American Chemical Society, 2025MitocondrisCumarinesFototeràpiaMitochondriaCoumarinsPhototherapyinfo:eu-repo/semantics/article7585122025-05-23info:eu-repo/semantics/embargoedAccess