Tetralactam-based Anion Transporters

Synthetic anion transporters provide a promising avenue to treat diseases like cystic fibrosis and cancer. Anion binding site preorganisation is one aspect of transporter design which can be manipulated to enhance binding. Macrocycles possess preorganised binding cavities, enabling more stable, 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. The macrocycles were functionalised with a variety of electron-withdrawing groups. Anion binding and transport assays were used to analyse the substituent effects on scaffold lipophilicity, selectivity, solubility, binding strength, and transport rates. The series was analysed for the ability to bind and transport Cl− and F− anions across lipid bilayers. The predominant mode of anion transport was H+/X− co-transport, with some highly fluorinated tetralactams displaying extremely high levels of Cl− and F− transport activity.