Structure-activity studies of ion channel mimics




James, Tony David

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A sub-unit approach to synthetic ion channels is employed which allows for easy construction of a set of candidate structures. The construction set includes cores, walls and head groups. The cores are crown ethers derived from tartaric acid: 2R,3R- or 2R,3S-(18C61)-2,3-dicarboxylic acid, 2R,3R,11R,- 12R- or 2R,3S,llR,12S-(18C61)-2,3,ll,12-tetracarboxylic acid and 2R,3R,8R,- 9R,14R,15R-(18C61)-2,3,8,9,14,15-hexacarboxylic acid. The crown ether is attached via an ester and a three carbon spacer to a wall unit by a thioether linkage. The walls are macrocyclic diene tetraesters derived from maleic anhydride and diols: (compounds 2, 7, 11, 21 and 27). A Michael reaction with 3-thiopropanol produces the thioether linkage. The monoalcohol produced is converted to an iodide; the esters to the crown ethers are then obtained by nucleophilic displacement of this iodide by a crown ether carboxlate. The resulting di-, tetra- and hexaene intermediates are converted to the final compounds by addition of head groups by a second Michael reaction, with (β-D- 1-thioglucose, thioacetic acid or 3-thiopropanol. Using the construction set, twenty-one compounds were prepared for transport evaluation. The transport of alkali metal cations across lipid bilayers of large unilamellar vesicles was monitored by the collapse of a proton gradient. Of the twenty one compounds surveyed, twelve of the most active were studied in 118C6=1,4,7,10,13,16-hexaoxocyclooctadecane detail (compounds 44, 45, 46, 47, 48, 49, 50, 51, 55, 56, 62 and 63); the other nine compounds (compounds 52, 53, 54, 57, 58, 59, 60, 61 and 64) were not sufficiently active for full characterisation. Transport mechanisms for the twelve active compounds were investigated in parallel with gramicidin D (a channel) and valinomycin (a carrier). The transport properties examined were concentration dependence of transporter, cation selectivity and concentration dependence, and inhibition of the transport of K+ or Na+ by Li+. Catior selectivities and inhibition studies proved the best tool for differentiating the channel or carrier behaviours. Carriers exhibited Eisenman cation selectivity sequences III or IV for metal ions and showed no inhibition of Na+ or K+ transport by added Li+. Conversely, channels exhibited non-Eisenman cation selectivities and transport of Na+ or K+ is inhibited by Li+. From comparative studies, five of the twelve compounds have strong similarities to valinomycin and are presumed to act as ion carriers (compounds 44, 47, 48, 50 and 55). The remaining seven are similar to gramicidin (compounds 45, 46, 49, 51, 56, 62 and 63). Within the group of ion channels, two classes of behaviour were encountered. Most compounds produce a first order decay of the imposed proton gradient (compounds 49, 51, 56 and 63) but some showed a zero order decay in the proton gradient (compounds 45, 46 and 62). These results are rationalised by a qualitative model which focuses on the relative rates of transfer of ion channel between vesicles, the gating or activation of the ion channel and the equilibration of a vesicle by the ion channel in an open form.



Ion channels, Biological transport, Active