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Synthesis of 1,2,4-trioxepanes via application of thiol-olefin Co-oxygenation methodology

Amewu, R., Stachulski, A. V., Berry, N. G., Ward, Stephen ORCID:, Davies, Jill, Labat, G., Rossignol, J. F. and O'Neill, P. M. (2006) 'Synthesis of 1,2,4-trioxepanes via application of thiol-olefin Co-oxygenation methodology'. Bioorganic & Medicinal Chemistry Letters, Vol 16, Issue 23, pp. 6124-6130.

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Thiol-olefin co-oxygenation (TOCO) of substituted allylic alcohols generates beta-hydroxy peroxides that can be condensed in situ with various ketones, to afford a series of functionalised 1,2,4-trioxepanes in good yields. Manipulation of the phenylsulfenyl group in 8a-8c allows for convenient modification to the spiro-trioxepane substituents. Surprisingly, and in contrast to the 1,2,4-trioxanes examined, 1,2,4-trioxepanes are inactive as antimalarials up to 1000 nM and we rationalize this observation based on the inherent stability of these systems to ferrous mediated degradation. FMO calculations clearly show that the sigma* orbital of the peroxide moiety of 1,2,4-trioxane derivatives 4a and 14b are lower in energy and more accessible to attack by Fe(II) compared to their trioxepane analogues 8b and 9b. (c) 2006 Published by Elsevier Ltd.

Item Type: Article
Uncontrolled Keywords: artemisinin 1,2,4-trioxane endoperoxide malaria mechanism of action antimalarial drug artemisinin endoperoxides malaria pharmacophore chemotherapy efficacy
Subjects: QV Pharmacology > Anti-Inflammatory Agents. Anti-Infective Agents. Antineoplastic Agents > QV 256 Antimalarials
QV Pharmacology > QV 34 Experimental pharmacology (General)
Faculty: Department: Groups (2002 - 2012) > Molecular & Biochemical Parasitology Group
Digital Object Identifer (DOI):
Depositing User: Ms Julia Martin
Date Deposited: 17 Jan 2011 11:44
Last Modified: 06 Feb 2018 13:01


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