2026-05-28T17:27:39Zhttps://riubu.ubu.es/oai/request

oai:riubu.ubu.es:10259/95722024-09-27T10:00:17Zcom_10259_3924com_10259_5086com_10259_2604col_10259_3925

Tuning pH-dependent cytotoxicity in cancer cells by peripheral fluorine substitution on pseudopeptidic cages Tapia, Lucía Pérez, Yolanda Carreira Barral, Israel Bujons, Jordi Bolte, Michael Bedia, Carmen Solà, Jordi Quesada Pato, Roberto Alfonso, Ignacio Supramolecular chemistry Cages Anion binding Ionophores Cancer cells pH Aqueous-lipid interphase Ion transport NMR Molecular dynamics Bioquímica Química orgánica Biochemistry Chemistry, Organic The acidic microenvironment of solid tumors is a potential source of selectivity in the anti-cancer activity of ionophores, which requires delicate control of their biophysical properties. In this context, we have systematically studied fluorine substitutions in the aromatic side chains of HCl-binding pseudopeptidic cages. Interconnected factors like chloride binding, protonation, lipophilicity, and conformation and diffusiveness of the cages can impact their ability to transport HCl through the aqueous-lipid interphase, as demonstrated by robust experimental (X-ray, nuclear magnetic resonance [NMR], fluorescence) and theoretical results. The fine-tuning of these properties allows the modulation of their pH-dependent cytotoxicity against cancer cells, from essentially non-cytotoxic at pH 7.5 (like the extracellular surroundings of healthy tissues) to highly toxic in slightly acidic microenvironments (like those around solid tumors). Thus, a distal fluorine substitution produces a big impact on the physicochemical and biological properties of the cages, improving their selectivity as potential therapeutic ionophores. We are thankful for the funding from the Spanish Research Agency of the Spanish Ministry of Science, Innovation and Universities MICIU/AEI/10.13039/501100011033 (grants PID2021-128411NB-I00 and PID2020-117610RB-I00 ) and the European Social Fund. 2024-09-26T12:19:43Z 2024-09-26T12:19:43Z 2024-09 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion 2666-3864 http://hdl.handle.net/10259/9572 10.1016/j.xcrp.2024.102152 eng Cell Reports Physical Science. 2024, V. 5, n. 9, 102152 https://doi.org/10.1016/j.xcrp.2024.102152 info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica, Técnica y de Innovación 2021-2023/PID2021-128411NB-I00/ES/SISTEMAS QUIMICOS COMPLEJOS DINAMICOS: APLICACIONES EN ORGANOCATALISIS Y RECONOCIMIENTO BIOMOLECULAR/ info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica, Técnica y de Innovación 2017-2020/PID2020-117610RB-I00/ES/SMALL MOLECULE TRANSMEMBRANE ANION CARRIERS FOR BIOLOGICAL APPLICATIONS/ Atribución 4.0 Internacional http://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess application/pdf application/zip video/mp4 Cell Press https://riubu.ubu.es/bitstream/10259/9572/4/Tapia-crps_2024.pdf.jpg Hispana TEXT http://creativecommons.org/licenses/by/4.0/ RIUBU. Repositorio Institucional de la Universidad de Burgos http://hdl.handle.net/10259/9572