Hampton, Alex S.Alex S.HamptonMikulski, LenaLenaMikulskiPalmer-Brown, WilliamWilliamPalmer-BrownMurphy, Cormac D.Cormac D.MurphySandford, GrahamGrahamSandford2019-07-012019-07-012016 Elsev2016-05-01Bioorganic & Medicinal Chemistry Letters0960-894Xhttp://hdl.handle.net/10197/10827Incorporation 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.Print-ElectronicenThis is the author’s version of a work that was accepted for publication in Bioorganic & Medicinal Chemistry Letters. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Bioorganic Medicinal Chemistry Letters (26, 9, (2016)) https://doi.org/10.1016/j.bmcl.2016.03.053FluorineDrug designPhase 1 metabolismUllmann condensationMicrobial modelJournal Article2692255225810.1016/j.bmcl.2016.03.0532019-06-25FP7-PEO-PLE-2013-ITN-60778https://creativecommons.org/licenses/by-nc-nd/3.0/ie/