Exploring Selective Anion Transport in Novel and Existing Small Molecules

Abstract

Synthetic anion receptors capable of transporting anions through membranes can potentially be used as therapeutics for channelopathies, such as cystic fibrosis, or in cancer treatment. Over recent years there has been significant progress and the principles and parameters determining successful anion transporters are clearer. This thesis aims to develop novel anion transporter scaffolds and investigate their properties, and to improve the methodology available for monitoring anion transport. The anion binding, transport ability and selectivity, and in-vitro activity of a series of indole-pyrrole based anion receptors were investigated. Substituent modifications were included to study hydrogen bond donor strength, encapsulation, and lipophilicity in relation to anion binding and transport. Strong binding affinities and remarkable anion transport abilities were observed, the mechanism of chloride transport was determined, and there was an interesting structure activity relationship of late onset cytotoxicity evident in cell studies. A series of published tren-based tris-thiourea receptors were revisited to further explore the anion transport properties. The transport mechanism was established and uniport assays allowed quantification of chloride, nitrate and sulfate uniport, and observation of bicarbonate uniport. Development of anion transport selectivity assays and optimisation of previously reported assays afforded more accurate results. Finally, the effect of increasing steric hindrance and preorganisation of receptors on anion binding, transport and selectivity was examined with tren-based tris-thiourea receptors. Synthetic methodology was developed, yielding unsymmetrical receptors. Anion binding studies revealed increasing steric hinderance increased binding affinity for chloride. Selectivity towards chloride transport over undesired H+/OH- transport was observed for preorganised receptors.