Tomlinson, James Allen (1968) The structure and properties of dicoumarol and related compounds. PhD thesis, University of Warwick.

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Abstract

Previous analysis of the i.r. and u.v. spectra of dicoumarol (a powerful anticoagulant and uncoupler of oxidative phosphorylation) has failed to establish the detailed structure of the molecule. In this thesis the i.r. and u.v. spectra of dicoumarol and its derivatives have been re-examined, and with the additional data available from n.m.r. spectroscopy the structure of the molecule has been found to be the hydrogen bonded structure below.

The pKa values of dicoumarols have been shown to be consistent with this formulation.

Other compounds (such as dimethones and 4-hydroxy-6-methyl-x-pyrones) have been shown to have a similar structure. The tautomerism of dimedone has been investigated by n.m.r spectroscopy, and interpreted in terms of an equilibrium between keto, enol and enol dimers, the last mentioned involving hydrogen bonding between the hydroxyl protons and carbonyl groups of two enol tautomers.

A number of coumarin derivatives have been added to respiring beef heart mitochondria and variations in the rate of respiration of the mitochondria with changing concentration of coumarin noted. On the basis of the mode of interaction of the compound and the mitochondria, the compounds tested may be divided into three classes, a) those that uncouple and inhibit b) those that only uncouple, and c) those that are inactive. All compounds in the class a) are capable of intramolecular hydrogen bonding in which the hydrogen bonded hydroxyl proton and the carbonyl group to which it is bonded form part of an 8-membered ring. Those of the class b) are able to form only intermolecular hydrogen bonds. The mechanism of action of these compounds is consistent with their action at two different sites in the energy-linked oxidation reactions of respiring mitochondria. A comparison of the activity of the compounds as uncouplers and inhibitors of oxidative phosphorylation with their activity as anticoagulants suggests there may well be a connection between the two processes, though the present state of knowledge does not permit any common mechanism to be put forward.

Item Type:	Thesis or Dissertation (PhD)
Subjects:	Q Science > QD Chemistry R Medicine > RM Therapeutics. Pharmacology
Library of Congress Subject Headings (LCSH):	Dicumarol -- Spectra, Dicumarol -- Structure, Tautomerism, Mitochondria, Phosphorylation
Official Date:	April 1968
Dates:	Date Event April 1968 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:	Imperial Chemical Industries, ltd.
Extent:	137 leaves.
Language:	eng

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