Tetralactam-based anion transporters

Abstract

Synthetic anion transporters provide a promising avenue to treat diseases such as cystic fibrosis and cancer. Anion binding site preorganization is one aspect of transporter design that can be manipulated to enhance binding. Macrocycles possess preorganized binding cavities, enabling more selective and efficient anion binding and transport. In this study, we build on a macrocyclic tetralactam scaffold by preparing a series of fluorinated and non-fluorinated tetralactam anion transporters. Anion binding and transport assays were used to analyze the substituent effects on scaffold lipophilicity, selectivity, solubility, binding strength, and transport rates. The series was analyzed for the ability to bind and transport Cl⁻ and F⁻ anions across lipid bilayers. Some highly fluorinated tetralactams display extremely high levels of Cl⁻ and F⁻ transport activity, showing record activities in 8-hydroxypyrene-1,3,6-trisulfonic acid (HPTS) assays and a Eu(III) probe-based F⁻ transport assay.