The synthesis and characterization of different pseudopeptidic hosts derived from open chain systems with C₂ and C₃ symmetry has been achieved. These receptors are based on structures containing phenylalanine amino acid residues and amine, amide, urea and thiourea groups as the structural elements providing their capability to interact with anions. The transport of chloride and organic anions of biological relevance (L-lactate, L-maleate and L-aspartate) through lipid bilayer membranes has been studied for these receptors. The chloride-binding properties of the selected hosts have been studied in solution by NMR titrations. In addition, in order to rationalize the results, lipophilicity studies have been carried out. It has been observed that transport activity is affected by the nature of the aliphatic central spacer and the side chains, the most active receptors being 9b, derived from a tripodal precursor with the shortest aliphatic side chain and 3c, derived from a bis(amino amide) but having the longest spacer. These hosts are more selective for the anion chloride than for the studied organic anions.

Exceptionally powerful anion receptors have been constructed by placing squaramide groups in axial positions on a steroidal framework. The steroid preorganizes the squaramide NH groups such that they can act cooperatively on a bound anion, while maintaining solubility in nonpolar media. The acidic NH groups confer higher affinities than previously-used ureas or thioureas. Binding constants exceeding 10¹⁴ M⁻¹ have been measured for tetraethylammonium salts in chloroform by employing a variation of Cram’s extraction procedure. The receptors have also been studied as transmembrane anion carriers in unilamellar vesicles. Unusually their activities do not correlate with anion affinities, thus suggesting an upper limit for binding strength in the design of anion carriers.

Exceptionally powerful anion receptors have been constructed by placing squaramide groups in axial positions on a steroidal framework. The steroid preorganizes the squaramide NH groups such that they can act cooperatively on a bound anion, while maintaining solubility in nonpolar media. The acidic NH groups confer higher affinities than previously-used ureas or thioureas. Binding constants exceeding 10¹⁴ M⁻¹ have been measured for tetraethylammonium salts in chloroform by employing a variation of Cram’s extraction procedure. The receptors have also been studied as transmembrane anion carriers in unilamellar vesicles. Unusually their activities do not correlate with anion affinities, thus suggesting an upper limit for binding strength in the design of anion carriers.

Niedermolekulare transmembranäre Anionentransporter für potenzielle Anwendungen in der Ionenkanalersatztherapie zur Behandlung von Krankheiten mit dysreguliertem Ionentransport (wie Mukoviszidose) und Krebs (durch Störung chemischer Gradienten in Zellen und Auslösen von Zelltod) sind derzeit ein intensiv bearbeitetes Forschungsgebiet. Dieser Kurzaufsatz fasst jüngste Entwicklungen beim Design niedermolekularer transmembranärer Anionentransporter zusammen. Ein Schwerpunkt liegt auf Studien zur Anwendung dieser Verbindungen in biologischen Systemen.

The development of small-molecule lipid-bilayer anion transporters for potential future use in channel replacement therapy for the treatment of diseases caused by dysregulation of anion transport (such as cystic fibrosis), and in treating cancer by perturbing chemical gradients within cells, thus triggering apoptosis, is an area of intense current interest. This Minireview looks at recent developments in the design of small-molecule transmembrane anion transporters and focuses on the progress so far in employing these compounds in biological systems.

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.

Complexation of dihydrogen phosphate by an anion receptor containing six hydrogen bond donor groups has been shown to reduce the pK_a of the bound anionic species to such an extent that addition of further aliquots of dihydrogen phosphate result in deprotonation of the bound species with the resultant formation of a monohydrogen phosphate receptor complex. X-ray crystallographic studies confirm monohydrogen phosphate complex formation in the solid state. In this way, this study explains the formation of complexes with unusual stoichiometries when investigating the binding of dihydrogenphosphate anion to hydrogen-bonding receptors.

1,3-Diindolylureas and thioureas have been synthesised and their anion complexation properties in solution studied. Whilst diindolylthioureas showed only moderate affinities and selectivities, diindolylureas show remarkably high affinity for dihydrogen phosphate in solution for an acyclic, neutral receptor in water/[D₆]DMSO mixtures. These easy-to-make compounds adopt relatively planar conformations in the solid-state and are able to donate four hydrogen bonds and yet not fill the coordination sphere of carbonate or phosphate, allowing two or three receptors to bind to each anion in the solid-state.