New visible-light activated caging groups based on COUPY dyes for anticancer phototherapeutic applications
[eng] This doctoral thesis has addressed the study of several therapeutic applications against cancer of a new family of photolabile protective groups (PPGs) based on COUPY coumarins, photoactivated with visible light. First, the effect of introducing a methyl group in a position adjacent to the pho...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2025 |
| País: | España |
| Institución: | Universidad de Barcelona |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/223763 |
| Acceso en línea: | https://hdl.handle.net/2445/223763 http://hdl.handle.net/10803/695522 |
| Access Level: | acceso embargado |
| Palabra clave: | Cumarines Fototeràpia Fotofarmacologia Càncer Coumarins Phototherapy Photopharmacology Cancer |
| Sumario: | [eng] This doctoral thesis has addressed the study of several therapeutic applications against cancer of a new family of photolabile protective groups (PPGs) based on COUPY coumarins, photoactivated with visible light. First, the effect of introducing a methyl group in a position adjacent to the photolabile bond in the coumarin skeleton was investigated, to evaluate how the formation of a secondary carbocationic intermediate influences the efficiency of the photolysis process. The sequential deprotection of two coumarin-protected functionalities within the same reaction medium was successfully achieved by stepped irradiation using visible light compatible with biological systems. This was carried out first by irradiating with red light to selectively deprotect the coumarin-based PPG COUPY, followed by irradiation with green light to activate the dicyanocoumarin-based PPG. The impact of replacing the pyridine group with a pyrimidine group was also studied, as well as the effect of modifying the outgoing group. The mitochondrial accumulation of COUPY photolabile compounds was confirmed by confocal microscopy in HeLa cells, thus demonstrating that the photoactivation of protected derivatives of 2,4-dinitrophenol takes place specifically in this organelle. Subsequently, the replacement of the methyl group by a phenyl group was explored as a strategy to further stabilize the carbocationic intermediate and improve the efficiency of the photodeprotection process, resulting in COUPY and dicyanocoumarin derivatives with slightly faster photolysis. Secondly, the ability of COUPY coumarin-based PPGs to release biologically active compounds into the mitochondrion was investigated. Specifically, the derivatives of the antitumor agents chlorambucil (CLB) and 4-phenylbutyric acid (4-PBA) showed remarkable phototoxicity in cancer cells after irradiation with green-yellow light, with IC50 values in the nanomolar range. This effect is attributed to a synergy between the release of the drug and the generation of reactive oxygen species (ROS) by coumarin. These results highlight the potential of COUPY coumarin-based PPGs as anticancer agents combining photodynamic therapy (PDT) and photoactivated chemotherapy (PACT). Finally, taking advantage of their activation with visible light, the COUPY derivatives were functionalized with 2,2'-bipyridine, which allowed their incorporation into polypyridyl Ru(II) complexes. Two Ru-COUPPY complexes were synthesized, capable of releasing the antitumor drugs CLB and 4-PBA both under irradiation with green-yellow light and red light in a few minutes with improved photoefficiency compared to PPGs based on COUPY coumarins. Ru-COUBPY complexes show outstanding photocytotoxic activity against CT-26 cancer cells, both under normoxia and hypoxia conditions, with efficacy in the nanomolar range. In addition, they have excellent stability in the dark in culture medium, as well as a high photostability of the resulting photoproduct, which makes them very promising candidates for applications in next-generation anticancer photodynamic therapies. These Ru-coumarin complexes act as dual anticancer agents: they generate reactive oxygen species (ROS) via PDT and, simultaneously, release antitumor drugs through PACT. Therefore, Ru-COUBPY complexes that can be activated with red light represent an innovative and effective alternative to conventional cancer therapies. |
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