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pH‐Dependent Chloride Transport by Pseudopeptidic Cages for the Selective Killing of Cancer Cells in Acidic Microenvironments
Author(s) -
Tapia Lucía,
Pérez Yolanda,
Bolte Michael,
Casas Josefina,
Solà Jordi,
Quesada Roberto,
Alfonso Ignacio
Publication year - 2019
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201905965
Subject(s) - chemistry , lipophilicity , protonation , chloride , aqueous solution , selectivity , symporter , cytotoxicity , combinatorial chemistry , biophysics , stereochemistry , transporter , biochemistry , organic chemistry , in vitro , ion , catalysis , biology , gene
Acidic microenvironments in solid tumors are a hallmark of cancer. Inspired by that, we designed a family of pseudopeptidic cage‐like anionophores displaying pH‐dependent activity. When protonated, they efficiently bind chloride anions. They also transport chloride through lipid bilayers, with their anionophoric properties improving at acidic pH, suggesting an H + /Cl − symport mechanism. NMR studies in DPC micelles demonstrate that the cages bind chloride within the lipid phase. The chloride affinity and the chloride‐exchange rate with the aqueous bulk solution are improved when the pH is lowered. This increases cytotoxicity towards lung adenocarcinoma cells at the pH of the microenvironment of a solid tumor. These properties depend on the nature of the amino‐acid side chains of the cages, which modulate their lipophilicity and interactions with the cell membrane. This paves the way towards using pH as a parameter to control the selectivity of cytotoxic ionophores as anticancer drugs.