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From Anion Receptors to Transporters

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Philip A. Gale*

School of Chemistry, University of Southampton, Southampton, SO17 1BJ, United Kingdom

Acc. Chem. Res., 2011, 44 (3), pp 216–226

DOI: 10.1021/ar100134p

Publication Date (Web): January 5, 2011

*E-mail: philip.gale@soton.ac.uk. Telephone: +44 23 8059 3332. Fax +44 23 8059 6805.

Biography

Philip A. Gale received a B.A. (Honors) in chemistry in 1992, a M.A. in 1995, and a D.Phil. in 1995 from the University of Oxford. He then moved as a Fulbright Postdoctoral Fellow to the University of Texas at Austin in 1995, returning to the University of Oxford in 1997 as a Royal Society University Research Fellow and moving in 1999 to the University of Southampton, where he is now Professor of Supramolecular Chemistry and Head of the School of Chemistry. A major focus of his research is the supramolecular chemistry of anionic species. He was won a number of research awards including the RSC’s Corday-Morgan Medal and Prize.

Section:

Pharmacology

Abstract

Cystic fibrosis is the most well-known of a variety of diseases termed channelopathies, in which the regulation of ion transport across cell membranes is so disrupted that the threshold of a pathology is passed. The human toll exacted by these diseases has led a number of research groups, including our own, to create compounds that mediate ion transport across lipid bilayers.

In this Account, we discuss three classes of synthetic compounds that were refined to bind and transport anions across lipid bilayer membranes. All of the compounds were originally designed as anion receptors, that is, species that would simply create stable complexes with anions, but were then further developed as transporters. By studying structurally simple systems and varying their properties to change the degree of preorganization, the affinity for anions, or the lipophilicity, we have begun to rationalize why particular anion transport mechanisms (cotransport or antiport processes) occur in particular cases. For example, we have studied the chloride transport properties of receptors based on the closely related structures of isophthalamide and pyridine-2,6-dicarboxamide: the central ring in each case was augmented with pendant methylimidazole groups designed to cotransport H⁺ and Cl⁻. We observed that the more preorganized pyridine-based receptor was the more efficient transporter, a finding replicated with a series of isophthalamides in which one contained hydroxyl groups designed to preorganize the receptor. This latter class of compound, together with the natural product prodigiosin, can transport bicarbonate (as part of a chloride/bicarbonate antiport process) across lipid bilayer membranes.

We have also studied the membrane transport properties of calix[4]pyrroles. Although the parent meso-octamethylcalix[4]pyrrole functions solely as a Cs⁺/Cl⁻ cotransporter, other compounds with increased anion affinities can function through an antiport process. One example is octafluoro-meso-octamethylcalix[4]pyrrole; with its electron-withdrawing substituents, it can operate through a chloride/bicarbonate antiport process. Moreover, calix[4]pyrroles with additional hydrogen bond donors can operate through a chloride/nitrate antiport process. Thus, increasing the affinity of the receptor in these cases allows the compound to transport an anion in the absence of a cation.

Finally, we have studied the transport properties of simple thioureas and shown that these compounds are highly potent chloride/bicarbonate antiport agents that function at low concentrations. In contrast, the urea analogues are inactive. The higher hydrophobicity (reflected in higher values for the logarithm of the water−octanol partition constant, or log P) and lower polar surface areas of the thiourea compounds compared to their urea analogues may provide a clue to the high potency of these compounds. This observation might serve as a basis for designing future small-molecule transporters.

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This article has been cited by 6 ACS Journal articles (5 most recent appear below).

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