Cally J. E. Haynes

Octafluorocalix[4]pyrrole: a chloride/bicarbonate antiport agent

meso-Octamethyloctafluorocalixpyrrole, a simple tetrapyrrolic macrocycle, has been shown to function as both a chloride/nitrate and a chloride/bicarbonate antiport agent for lipid bilayer transmembrane anion transport. This is the first example of a synthetic macrocyclic pyrrole-based receptor capable of transmembrane bicarbonate transport.

Structurally simple lipid bilayer transport agents for chloride and bicarbonate

A new series of structurally simple compounds containing thiourea groups have been shown by a combination of ion-selective electrode and 13C NMR techniques to be potent chloride-bicarbonate exchange agents that function at low concentration in POPC and POPC/cholesterol membranes.

Chloride, carboxylate and carbonate transport by ortho-phenylenediamine-based bisureas

Highly potent but structurally simple transmembrane anion transporters are reported that function at receptor to lipid ratios as low as 1:1000000. The compounds, based on the simple ortho-phenylenediamine-based bisurea scaffold, have been studied for their ability to facilitate chloride/nitrate and chloride/bicarbonate antiport, and HCl symport processes using a combination of ion selective electrode and fluorescence techniques. In addition, the transmembrane transport of dicarboxylate anions (maleate and fumarate) by the compounds was examined. Molecular dynamics simulations showed that these compounds permeate the membrane more easily than other promising receptors corroborating the experimental efflux data. Moreover, cell based assays revealed that the majority of the compounds showed cytotoxicity in cancer cells, which may be linked to their ability to function as ion transporters.

Oligoether-strapped calix[4]pyrrole: an ion-pair receptor displaying cation-dependent chloride anion transport

A ditopic ion-pair receptor (1), which has tunable cation- and anion-binding sites, has been synthesized and characterized. Spectroscopic analyses provide support for the conclusion that receptor 1 binds fluoride and chloride anions strongly and forms stable 1:1 complexes ([1·F](-) and [1·Cl](-)) with appropriately chosen salts of these anions in acetonitrile. When the anion complexes of 1 were treated with alkali metal ions (Li(+), Na(+), K(+), Cs(+), as their perchlorate salts), ion-dependent interactions were observed that were found to depend on both the choice of added cation and the initially complexed anion. In the case of [1·F](-), no appreciable interaction with the K(+) ion was seen. On the other hand, when this complex was treated with Li(+) or Na(+) ions, decomplexation of the bound fluoride anion was observed. In contrast to what was seen with Li(+), Na(+), K(+), treating [1·F](-) with Cs(+) ions gave rise to a stable, host-separated ion-pair complex, [F·1·Cs], which contains the Cs(+) ion bound in the cup-like portion of the calix[4]pyrrole. Different complexation behavior was seen in the case of the chloride complex, [1·Cl](-). Here, no appreciable interaction was observed with Na(+) or K(+). In contrast, treating with Li(+) produces a tight ion-pair complex, [1·Li·Cl], in which the cation is bound to the crown moiety. In analogy to what was seen for [1·F](-), treatment of [1·Cl](-) with Cs(+) ions gives rise to a host-separated ion-pair complex, [Cl·1·Cs], in which the cation is bound to the cup of the calix[4]pyrrole. As inferred from liposomal model membrane transport studies, system 1 can act as an effective carrier for several chloride anion salts of Group 1 cations, operating through both symport (chloride+cation co-transport) and antiport (nitrate-for-chloride exchange) mechanisms. This transport behavior stands in contrast to what is seen for simple octamethylcalix[4]pyrrole, which acts as an effective carrier for cesium chloride but does not operates through a nitrate-for-chloride anion exchange mechanism.

Synthetic transporters for sulfate: a new method for the direct detection of lipid bilayer sulfate transport

The transmembrane transport of anions by small synthetic molecules is a growing field in supramolecular chemistry and has focussed mainly on the transmembrane transport of chloride. On the other hand, the transport of the highly hydrophilic sulfate anion across lipid bilayers is much less developed, even though the inability to transport sulfate across cellular membranes has been linked to a variety of genetic diseases. Tris-thioureas possess high sulfate affinities and have been shown to be excellent chloride and bicarbonate transporters. Herein we report the sulfate transport abilities of a series of tris-ureas and tris-thioureas based on a tris(2-aminoethyl)amine or cyclopeptide scaffold. We have developed a new technique based on 33S NMR that can be used to monitor sulfate transport, using 33S-labelled sulfate and paramagnetic agents such as Mn2+ and Fe3+ to discriminate between intra- and extravesicular sulfate. Reasonable sulfate transport abilities were found for the reported tris-ureas and tris-thioureas, providing a starting point for the development of more powerful synthetic sulfate transporters that can be used in the treatment of certain channelopathies or as a model for biological sulfate transporters.

Towards predictable transmembrane transport: QSAR analysis of anion binding and transport

The transport of anions across biological membranes by small molecules is a growing research field due to the potential therapeutic benefits of these compounds. However, little is known about the exact mechanism by which these drug-like molecules work and which molecular features make a good transporter. An extended series of 1-hexyl-3-phenylthioureas were synthesized, fully characterized (NMR, mass spectrometry, IR and single crystal diffraction) and their anion binding and anion transport properties were assessed using 1H NMR titration techniques and a variety of vesicle-based experiments. Quantitative structure–activity relationship (QSAR) analysis revealed that the anion binding abilities of the mono-thioureas are dominated by the (hydrogen bond) acidity of the thiourea NH function. Furthermore, mathematical models show that the experimental transmembrane anion transport ability is mainly dependent on the lipophilicity of the transporter (partitioning into the membrane), but smaller contributions of molecular size (diffusion) and hydrogen bond acidity (anion binding) were also present. Finally, we provide the first step towards predictable anion transport by employing the QSAR equations to estimate the transmembrane transport ability of four new compounds.

Acylthioureas as anion transporters: the effect of intramolecular hydrogen bonding

Small molecule synthetic anion transporters may have potential application as therapeutic agents for the treatment of diseases including cystic fibrosis and cancer. Understanding the factors that can dictate the anion transport activity of such transporters is a crucial step towards their application in biological systems. In this study a series of acylthiourea anion transporters were synthesised and their anion binding and transport properties in POPC bilayers have been investigated. The transport activity of these receptors is dominated by their lipophilicity, which is in turn dependent on both substituent effects and the formation and strength of an intramolecular hydrogen bond as inferred from DFT calculations. This is in contrast to simpler thiourea systems, in which the lipophilicity depends predominantly on substituent effects alone.

Tunable transmembrane chloride transport by bis-indolylureas

A series of bis-indolylureas have been found to mediate chloride transport across vesicle bilayers. The anion transport activity of these receptors may be readily modulated by small structural changes to the receptor scaffold as shown by the combination of experimental chloride efflux studies and molecular dynamics simulations in water and POPC bilayers.

Highly effective yet simple transmembrane anion transporters based upon ortho-phenylenediamine bis-ureas

Simple, highly fluorinated receptors are shown to function as highly effective transmembrane anion antiporters with the most active transporters rivalling the transport efficacy of natural anion transporter prodigiosin for bicarbonate.

Blockable Zn10L15 Ion Channels through Subcomponent Self‐Assembly

Metal-organic anion channels based on Zn10 L15 pentagonal prisms have been prepared by subcomponent self-assembly. The insertion of these prisms into lipid membranes was investigated by ion-current and fluorescence measurements. The channels were found to mediate the transport of Cl- anions through planar lipid bilayers and into vesicles. Tosylate anions were observed to bind and plug the central channels of the prisms in the solid state and in solution. In membranes, dodecyl sulfate blocked chloride transport through the central channel. Our Zn10 L15 prism thus inserts into lipid bilayers to turn on anion transport, which can then be turned off through addition of the blocker dodecyl sulfate.