Coles, Christopher John (1970) Studies concerning the piericidins. PhD thesis, University of Warwick.

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Abstract

The chemical similarities and contrasting biochemical properties of piericidin A and ubiquinone are presented and discussed. The former, a penta-substituted pyridine and a metabolite of Streptomyces mobaraensis, is an inhibitor of mitochondrial electron transport, whilst the latter is an electron carrier. A scheme to account for this difference is proposed involving an olefinic linkage of the long hydrocarbon side-chain. This was shown not to be responsible for the inhibitory action of piericidin A, since hydrogenation of the olefinic function did not noticeably reduce inhibitory potency.

Piericidin A was labelled with tritium in order to investigate its binding to mitochondria. It was found to be bound unspecifically in a linear manner up to 10 mu moles/mgm. protein, but washing with bovine serum albumen removed most of this piericidin A. However a quantity corresponding to that required for the inhibition of NADH oxidation (0.02 mu moles/mgm. protein) could not be removed in this way. It is concluded that this piericidin A was bound in a site specific manner. This specifically bound inhibitor was recovered unchanged on extraction of the mitochondrial lipids with acetone. Hence it is concluded that the inhibitor is not covalently bound to the mitochondria.

A number of analogues of piericidin A were synthesised. None of these compounds approached the potency of piericidin A as inhibitors, although those with lipophilic and phenolic properties were more effective in this respect than those without, suggesting the possible involvement of hydrophobic interactions and of a phenolic function during inhibition.

The possible tautomers of the proposed structure of piericidin A are considered in relation to its spectroscopic and chemical properties. Contrary to the behaviour expected from this structure, the molecule appears to exist as a pyridinol, rather than the 1-(H)-4-pyridone tautomer.

The evidence for the proposed structure of piericidin A is critically discussed. That for the arrangement of substituents on the pyridine nucleus depends partly on ultraviolet spectroscopic data, and more significantly, on two fragments arising from ozonolysis. The identity of one of these fragments (the 2,4-DlrP of methyl pyruvate) is in doubt, since its properties differ from those of either of two fully characterised isomers of authentic material synthesised specially. It is concluded that piericidin A may be a β-hydroxypyridine, rather than the proposed Ɣ-hydroxypyridine, since the remaining evidence is no longer conclusive. The spectroscopic properties of piericidin A mentioned above also favour this proposal.

Two fully substituted β-hydroxypyridines, isomeric with the proposed pyridine nucleus of piericidin A, were synthesised. Neither had properties corresponding to piericidin A. With these and other hydroxypyridines, the comparative studies pertaining to piericidin A were extended, using the techniques of UV, IR H1NMR.and mass spectroscopy. A particularly simple diagnosis of hydroxypyridines by 1H NMR spectroscopy was developed, involving the use of trichloroacetylisocyanate. In addition base catalysed deuterium exchange of protons in the methyl groups of substituted pyridines was studied.
As a result of these studies, distinctions can be made between β, and α or Ɣsubstituted methyl- and hydroxy-pyridines. Piericidin A appears to be a β-hydroxypyridine, its most likely structure being 2-alkyl-3,6-dimethoxy-5-hydroxy-4-methylpyridine.

It is also concluded from the mass spectrum of piericidin A that there is an olefinic bond between carbon atoms 5 and 6 of the side-chain, rather than between carbon atoms 4 and 5 as published.

Item Type:	Thesis (PhD)
Subjects:	Q Science > QD Chemistry
Library of Congress Subject Headings (LCSH):	Biochemistry, Organic compounds, Mitochondria, Electron transport, Streptomyces mobaraensis
Official Date:	1970
Dates:	Date Event 1970 Submitted
Institution:	University of Warwick
Theses Department:	Department of Chemistry
Thesis Type:	PhD
Publication Status:	Unpublished
Supervisor(s)/Advisor:	Hutchinson, D. W.(David Wesley)
Sponsors:	Science Research Council (Great Britain)
Extent:	234 leaves
Language:	eng

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