Journal Article Ppublish
PubMed: 40293412 DOI: 10.1021/acs.jmedchem.5c00550
Exploring the Phototherapeutic Applications of Mitochondria-Targeted COUPY Photocages of Antitumor Drugs.
J Med Chem 68(9):9741-9754
Authors: Marta López-Corrales, Eduardo Izquierdo-García, Manel Bosch, Tapas Das, Amadeu Llebaria, Laia Josa-Culleré, Vicente Marchán
Affiliations
- Departament de Química Inorgànica i Orgànica, Secció de Química Orgànica, Universitat de Barcelona (UB), and Institut de Biomedicina de la Universitat de Barcelona (IBUB), Martí i Franquès 1-11, E-08028 Barcelona, Spain.
- Unitat de Microscòpia Òptica Avançada, Centres Científics i Tecnològics (CCiTUB), Universitat de Barcelona (UB), Av. Diagonal 643, E-08028 Barcelona, Spain.
- Department of Chemistry, National Institute of Technology Jamshedpur, Jamshedpur, Jharkhand 831014, India.
- MCS, Department of Biological Chemistry, Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), Jordi Girona 18-26, 08034 Barcelona, Spain.
Abstract
Photocleavable 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 a remarkable phototoxicity against cancer cells upon green-yellow light irradiation, with IC 50 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.
MeSH
Pharmaceutical Preparations, Antineoplastic Agents, Mitochondria, Therapeutics