Robins, Peter George; (1995) Synthetic studies of some biologically important molecules. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Potassium channels play a crucial part in cellular homeostasis and disruptions in their function are implicated in a variety of disease states including diabetes and cardiac arrhythmias. Consequently, a wide variety of potassium channel modulators are in therapeutic use but few of them appear to act as antagonists. However, apamin, from bee venom has been shown to be an extremely potent blocker of the small conductance, calcium-activated potassium channel (SK) and the main body of this thesis is concerned with extending previous work on the structure-activity relationships of this compound. Two salient, positively-charged nitrogen atoms on adjacent arginine residues in the peptide, arranged at an appropriate spacing seem to be the seat of activity and the assumption that this is the pharmacophore provides the basis of the work. Thus a series of bis-quaternary ammonium salts were synthesised by the substitution of various amines onto one of a number of rigid, aromatic frameworks which were chosen because they arranged the cationic centres approximately 11 Å apart, the posited crucial distance, as well as providing a hydrophobic bridge. 2,6- and 2,7-dimethylanthracene, 3,6- and 1,6-dimethylphenanthrene and trans-2,4'- and trans 4,4'-dimethylstiIbene were synthesised according to established procedures. All compounds, including p-xylene and 2,6-dimethylnaphthalene, were bis-brominated in the benzylic position with N-bromosuccinimide or bromine. The first three frameworks in the list above were then substitued with piperidine, pyrrolidine and morpholine and quaternised with iodomethane to give 9 compounds of medium to negligible activity in blocking the SK current in rat sympathetic neurones. Substitution of a mixture of 2,5-dimethylpyrrolidines followed by iodomethylation produced a series of compounds with good activity whilst the synthesis of a series of compounds containing cis-2,6-dimethylpiperidine could not be completed. 1.4-diazabicyclo[2.2.2]octane (DABCO) and N-substituted derivatives, together with quinuclidine were also used as substituents, but did not improve on previous results. An attempt to make tricationic derivatives of benzene could not be completed in the time available. The results of the assay and inferences are presented together with spectral data for all new compounds. The second part of the thesis deals with a series of attempts to generate the lithium dianion of pyruvic acid and effect its addition to various electrophiles. No evidence was found for the presence of the ion so attempts were made to stabilise it by the use of esters and hindered thioesters of the acid which included tert-butyl and 1,1-diethylpropyl thiopyruvate and methyl and ethyl pyruvate. A number of O-trialkylsilyl enol ethers was also synthesised and their reactions with electrophiles in the presence of Lewis acids were investigated. No conditions were found under which reaction was observed to occur so the Diels-Alder and inverse-demand Diels-Alder reactions of the silyl enol ethers were briefly investigated.

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