2026-10-13T10:34:00Zhttps://riubu.ubu.es/oai/request

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

00925njm 22002777a 4500 dc Tapia, Lucía author Pérez, Yolanda author Carreira Barral, Israel author Bujons, Jordi author Bolte, Michael author Bedia, Carmen author Solà, Jordi author Quesada Pato, Roberto author Alfonso, Ignacio author 2024-09 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. 2666-3864 http://hdl.handle.net/10259/9572 10.1016/j.xcrp.2024.102152 Supramolecular chemistry Cages Anion binding Ionophores Cancer cells pH Aqueous-lipid interphase Ion transport NMR Molecular dynamics Tuning pH-dependent cytotoxicity in cancer cells by peripheral fluorine substitution on pseudopeptidic cages