Chloride Selective, Nonprotonophoric Ion Transport with Macrocyclic Halogen Bonding Anionophores

Synthetic ion transporters hold promise as both chemical probes and potential therapeutics for diseases linked to malfunctioning protein ion transporters. However, their application in biological systems is limited, partly due to the cytotoxicity arising from unselective ion transport. Here, we demonstrate that highly active and selective anionophores can be accessed by combining halogen bonding anion recognition with macrocyclic anion encapsulation. Anion transport experiments in large unilamellar vesicles (LUVs) revealed over 300-fold selectivity for chloride transport over proton/hydroxide ions, which is key for potential future therapeutic applications, where the dissipation of cellular pH gradients must be avoided. The mechanism underpinning selectivity is studied through Density Functional Theory (DFT) calculations and molecular dynamics (MD) simulations at the membrane interface, demonstrating that the cyclic structure imposes an energetic preference for chloride binding over hydroxide, as well as a greater desolvation of hydroxide, which further disfavors its transport. We anticipate that these results will accelerate the transition toward the use of artificial chloride transport in biology.