Ion Binding and Transport by Synthetic Molecular Assemblies

Abstract

Self-assembly of small synthetic molecular building blocks has been applied to generate functional structures capable of binding and transporting cations and anions. Major discoveries from the research include a self-assembled ion pair receptor, ligands capable of K+-selective transport through membranes, a compound that forms Cl--selective ion channels in planar and cellular membranes, and a series of efficient chloride transporters. Calix[4]arene-guanosine conjugates cG 2.26 and cG 2.34 are shown to assemble into Na+-templated tubular architectures by 1H NMR, transmission electron microscopy and isothermal titration calorimetry, and to selectively transport K+ over Na+ and Cs+ across liposome membranes by fluorescent assays. The more lipophilic cG 2.34 forms a water-mediated dimer capable of extracting alkali halide salts from water into organic solution. These conclusions are supported by 1H and 23Na NMR, pulsed-field gradient NMR, ion chromatography and circular dichorism spectroscopy. The (cG 2.34)2(H2O)n dimer is held together by an intermolecular hydrogen-bonded guanosine quartet, based on 1D and 2D NMR experiments, and provides a rare example of a self-assembled ion pair receptor.

Calix[4]arene tetrabutylamide 3.1 forms voltage-dependent chloride-selective ion channels in planar bilayers and cell membranes based on voltage and patch clamp experiments. Compound 3.1 selectively transports Cl- over HSO4- across liposome membranes, is capable of binding and transporting HCl, and can alter the pH inside liposomes experiencing a chloride gradient, based on fluorescent assays and 1H NMR experiments. X-ray crystal structures of calix[4]arene tetramethylamide 2.30HCl complexes (2.30 is an analogue of 3.1) provides a rationale for how ions are moved across a membrane by 3.1.

From a series of linear analogues of 3.1, oligophenoxyacetamide trimer 3.5 was identified as the most potent chloride transporter. Transport of chloride and H+/Cl- pairs was demonstrated by fluorescent assays and 35Cl NMR. Trimer 3.5 also induces a stable potential into liposomes experiencing a transmembrane anionic gradient, an unprecedented function for a synthetic compound. Compounds capable of transporting chloride or H+/Cl- pairs have potential as drugs for the treatment of cystic fibrosis and cancer.