A study of the effect of structure and conformation on the transport properties of ionophores using NMR

Abstract

The first part of this work is a study of cation transport mediated by salinomycin and narasin, two polyether antibiotics. The transport rates were measured in phosphatidylcholine vesicles using 7Li, 23Na and 39K nmr. The results showed that salinomycin and narasin both transport potassium more rapidly than sodium. Lithium is transported two orders of magnitude slower still. Thermodynamically, salinomycin prefers potassium to sodium, while narasin shows little preference for either cation. A brief study on dihydrosalinomycin shows that this transports sodium at rates an order of magnitude slower than seen for salinomycin itself. The second section is concerned with the total assignment of the 1H and 13C nmr spectra of the alkali metal salts of narasin and salinomycin. This was achieved by the use of two dimensional nmr techniques, including COSY, NOESY and XHCORD spectra. The chemical shifts of certain sites were seen to be dependent on the cation present. These sites were mostly situated near the "hinge" regions of the molecules where conformational changes can occur during the complexation process. This showed that these sites are also important in the accommodation of different sized cations. The basic conformation of the molecule remains the same, it is only at certain sites that there is flexibility. The final portion of this work is a brief study of transport mediated by synthetic ionophores. This involved synthesising materials expected to be carriers for both cations and anions and testing them for transport properties. It was also necessary to develop a contrast reagent for halide ions, to enable their transport to be observed and measured by nmr. It was found that nitroxyl radicals and dextran magnetite were both ineffective as contrast reagents, Manganous ions were found to be good relaxation agents but were seen to destroy the vesicles, except at low pH. Alternative methods of stabilising the vesicles using hydroxymethyl substituted pyridinium salts were unsuccessful. The anion carriers attempted were hydroxylated tetra-alkylammonium and pyridinium salts. The transport studies carried out showed that these were only slightly more effective ion carriers than their non-hydroxylated homologues. In a study of cation transport it was tried, unsuccessfully, to synthesise various proton ionisable crown ethers.