Evaluation of fluorinated biphenyl ether pro-drug scaffolds employing the chemical-microbial approach

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Title: Evaluation of fluorinated biphenyl ether pro-drug scaffolds employing the chemical-microbial approach
Authors: Hampton, Alex S.Mikulski, LenaPalmer-Brown, WilliamMurphy, Cormac D.Sandford, Graham
Permanent link: http://hdl.handle.net/10197/10827
Date: 1-May-2016
Online since: 2019-07-01T13:32:32Z
Abstract: Incorporation of fluorine in a drug can dramatically affect its metabolism and methods to assess the effect of fluorine substitution on drug metabolism are required for effective drug design. Employing a previously developed chemical-microbial method the metabolism of a series of fluorinated biphenyl ethers was determined. The substrates were synthesized via Ullmann-type condensation reactions between bromotoluene and fluorophenol. The ethers were incubated with the fungus Cunninghamella elegans, which oxidises xenobiotics in an analogous fashion to mammals, generating a number of hydroxylated biphenyl ethers and acids. The propensity of the fluorinated ring to be hydroxylated depended upon the position of the fluorine atom, and the oxidation of the methyl group was observed when it was meta to the oxygen. The experiments demonstrate the applicability of the method to rapidly determine the effect of fluorine substitution on CYP-catalysed biotransformation of pro-drug molecules.
Funding Details: European Commission - Seventh Framework Programme (FP7)
Type of material: Journal Article
Publisher: Elsevier BV
Journal: Bioorganic & Medicinal Chemistry Letters
Volume: 26
Issue: 9
Start page: 2255
End page: 2258
Copyright (published version): 2016 Elsevier
Keywords: FluorineDrug designPhase 1 metabolismUllmann condensationMicrobial model
DOI: 10.1016/j.bmcl.2016.03.053
Language: en
Status of Item: Peer reviewed
Appears in Collections:Biomolecular and Biomedical Science Research Collection

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