title: Evaluation of fluorinated biphenyl ether pro-drug scaffolds employing the chemical-microbial approach.
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.
authors.affiliation: Department of Chemistry, Durham University, South Road, Durham DH1 3LE, UK.
authors.forename: Alex S
authors.initials: AS
authors.lastname: Hampton
authors.affiliation: UCD School of Biomolecular and Biomedical Science, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Lena
authors.initials: L
authors.lastname: Mikulski
authors.affiliation: UCD School of Biomolecular and Biomedical Science, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: William
authors.initials: W
authors.lastname: Palmer-Brown
authors.affiliation: UCD School of Biomolecular and Biomedical Science, University College Dublin, Belfield, Dublin 4, Ireland. Electronic address: Cormac.d.murphy@ucd.ie.
authors.forename: Cormac D
authors.initials: CD
authors.lastname: Murphy
authors.affiliation: Department of Chemistry, Durham University, South Road, Durham DH1 3LE, UK. Electronic address: graham.sandford@durham.ac.uk.
authors.forename: Graham
authors.initials: G
authors.lastname: Sandford
mesh_terms: D001713:Biphenyl Compounds / Q000737:chemistry / Q000494:pharmacology*; D004987:Ethers / Q000737:chemistry; D005461:Fluorine / Q000737:chemistry*; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D001713:Biphenyl Compounds; D004987:Ethers; D005461:Fluorine; D011355:Prodrugs; C010574:biphenyl
keywords: Drug design; Fluorine; Microbial model; Phase 1 metabolism; Ullmann condensation