Chloride Transport Across Lipid Bilayers and Transmembrane Potential Induction by an Oligophenoxyacetamide

Abstract

This contribution describes the discovery and properties of a synthetic, low-molecular weight compound that transports Cl^- across bilayer membranes. Such compounds have potential as therapeutics for cystic fibrosis and cancer. The H⁺/Cl^- co-transport activities of acyclic tetrabutylamides 1 − 6 were compared by using a pH-stat assay with synthetic EYPC liposomes. The ion transport activity of the most active compound, trimer 3, was an order of magnitude greater than that of calix[4]arene tetrabutylamide C1 a macrocycle known to function as a synthetic ion channel. Trimer 3 has an unprecedented function for a synthetic compound, as it induces a stable potential in liposomes experiencing a transmembrane Cl^-/SO₄^2- gradient. Data from both pH-stat and ³⁵Cl NMR experiments indicate that 3 co-transports H⁺/Cl^-. Although 3 transports both Cl^- and H⁺ the overall process is not electrically silent. Thus, trimer 3 induces a stable potential in LUVs due to a transmembrane anionic gradient. The ability of trimer 3 to transport Cl^-, to maintain a transmembrane potential, along with its high activity at uM concentrations, its low molecular weight, and its simple preparation, make this compound a valuable lead in drug development for diseases caused by Cl^- transport malfunction.