The development of small molecule transmembrane anion transporters for the treatment of disease

• Main Author: Moore, Stephen J.
• Other Authors: Gale, Philip
• Published: University of Southampton 2012
• Subjects: 615.19; QD Chemistry
• Online Access: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.568838

Within this thesis novel receptors capable of binding and facilitating the transmembrane transport of biologically relevant anions are reported. Molecules based on the diindolylurea and tris(2-aminoethyl)amine scaffolds are described and their anion binding properties in both solution and in the solid state are reported. Inspired by the high affinities for oxo-anions measured for these molecules in polar solvent mixtures, the anion transport properties of structurally simple ureas and thioureas were studied. The high Cl-/NO3 - and Cl-/HCO3 - antiport activity observed with some of the thiourea compounds led to the development of more ‘drug-like’ transporters containing trifluoromethyl substituents. Fluorination of the transporter scaffold in this manner enhanced the lipophilicity and increased the acidity of the NH hydrogen-bond donor groups, leading to improvements in both anion affinity and transport activity. This work ultimately produced compounds capable of facilitating ion transport in vitro. A series of bisurea compounds based on the ortho-phenylenediamine scaffold are reported as potent ion transporters, capable of facilitating a range of ion transport processes. The introduction of electron withdrawing substituents was found to increase transporter activity. Of particular note is a para-nitrophenyl functionalised bisurea that facilitates chloride transport at a loading of 0.1 mmol % (with respect to lipid), the lowest loading of a synthetic mobile carrier to facilitate anion transport reported to date. Dual host systems for both M+/Cl- symport (M = Na, K or Rb) and Cl-/HCO3 - antiport are also described. By using different transporters to facilitate each uniport pathway in these coupled transport processes, it was possible to achieve enhanced ion transport rates. Remarkably, this is the first reported example of a dual host approach towards anion antiport.