2026-06-22T22:58:14Zhttps://riubu.ubu.es/oai/requestoai: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
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.
2024-09-26
2024-09-26
2024-09
info:eu-repo/semantics/article
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/
http://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
Atribución 4.0 Internacional
Cell Press