Biotransformation of fluorophenyl pyridine carboxylic acids by the model fungus Cunninghamella elegans

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Title: Biotransformation of fluorophenyl pyridine carboxylic acids by the model fungus Cunninghamella elegans
Authors: Palmer-Brown, WilliamDunne, BrianOrtin, YannickMurphy, Cormac al.
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Date: 19-Aug-2016
Online since: 2019-07-01T13:40:58Z
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.
Funding Details: European Commission - Seventh Framework Programme (FP7)
Type of material: Journal Article
Publisher: Taylor & Francis
Journal: Xenobiotica
Volume: 47
Issue: 9
Start page: 763
End page: 770
Copyright (published version): 2016 Informa UK
Keywords: Cytochrome P450CunninghamellaCarboxylic AcidsLactonesOxazolesPyridinesChromatography, High Pressure LiquidMagnetic Resonance SpectroscopyFluorineMass SpectrometryGas Chromatography-Mass SpectrometryMicrobial model19F NMR
DOI: 10.1080/00498254.2016.1227109
Language: en
Status of Item: Peer reviewed
Appears in Collections:Biomolecular and Biomedical Science Research Collection

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