title: Biotransformation of fluorophenyl pyridine carboxylic acids by the model fungus Cunninghamella elegans.
abstract: 1. Fluorine plays a key role in the design of new drugs and recent FDA approvals included two fluorinated drugs, tedizolid phosphate and vorapaxar, both of which contain the fluorophenyl pyridyl moiety. 2. To investigate the likely phase-I (oxidative) metabolic fate of this group, various fluorinated phenyl pyridine carboxylic acids were incubated with the fungus Cunninghamella elegans, which is an established model of mammalian drug metabolism. 3.19F NMR spectroscopy established the degree of biotransformation, which varied depending on the position of fluorine substitution, and gas chromatography-mass spectrometry (GC-MS) identified alcohols and hydroxylated carboxylic acids as metabolites. The hydroxylated metabolites were further structurally characterised by nuclear magnetic resonance spectroscopy (NMR), which demonstrated that hydroxylation occurred on the 4' position; fluorine in that position blocked the hydroxylation. 4. The fluorophenyl pyridine carboxylic acids were not biotransformed by rat liver microsomes and this was a consequence of inhibitory action, and thus, the fungal model was crucial in obtaining metabolites to establish the mechanism of catabolism.
authors.affiliation: a UCD School of Biomolecular and Biomedical Science.
authors.forename: William
authors.initials: W
authors.lastname: Palmer-Brown
authors.affiliation: a UCD School of Biomolecular and Biomedical Science.
authors.forename: Brian
authors.initials: B
authors.lastname: Dunne
authors.affiliation: b UCD School of Chemistry, University College Dublin , Belfield , Ireland , and.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Ortin
authors.affiliation: c Department of Chemistry , University of Durham , Durham , United Kingdom.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Fox
authors.affiliation: c Department of Chemistry , University of Durham , Durham , United Kingdom.
authors.forename: Graham
authors.initials: G
authors.lastname: Sandford
authors.affiliation: a UCD School of Biomolecular and Biomedical Science.
authors.forename: Cormac D
authors.initials: CD
authors.lastname: Murphy
mesh_terms: D001711:Biotransformation; D002264:Carboxylic Acids / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D020093:Cunninghamella / Q000378:metabolism*; D008401:Gas Chromatography-Mass Spectrometry; D007783:Lactones / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000378:metabolism; D010755:Organophosphates / Q000378:metabolism; D010080:Oxazoles / Q000378:metabolism; D011725:Pyridines / Q000378:metabolism*
chemical_list: D002264:Carboxylic Acids; D007783:Lactones; D010755:Organophosphates; D010080:Oxazoles; D011725:Pyridines; C515040:tedizolid phosphate; C530299:vorapaxar
keywords: 19F NMR; Cytochrome P450; fluorine; microbial model