William Palmer-Brown
Biotransformation of fluorophenyl pyridine carboxylic acids by the model fungus Cunninghamella elegans
Palmer-Brown, William; Dunne, Brian; Ortin, Yannick; Fox, Mark A.; Sandford, Graham; Murphy, Cormac D.
Authors
Brian Dunne
Yannick Ortin
Dr Mark Fox m.a.fox@durham.ac.uk
Assistant Professor
Graham Sandford
Cormac D. Murphy
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.
Citation
Palmer-Brown, W., Dunne, B., Ortin, Y., Fox, M. A., Sandford, G., & Murphy, C. D. (2016). Biotransformation of fluorophenyl pyridine carboxylic acids by the model fungus Cunninghamella elegans. Xenobiotica, 47(9), 763-770. https://doi.org/10.1080/00498254.2016.1227109
Journal Article Type | Article |
---|---|
Acceptance Date | Aug 17, 2016 |
Online Publication Date | Sep 15, 2016 |
Publication Date | Sep 15, 2016 |
Deposit Date | Sep 8, 2017 |
Publicly Available Date | Sep 15, 2017 |
Journal | Xenobiotica |
Print ISSN | 0049-8254 |
Electronic ISSN | 1366-5928 |
Publisher | Taylor and Francis Group |
Peer Reviewed | Peer Reviewed |
Volume | 47 |
Issue | 9 |
Pages | 763-770 |
DOI | https://doi.org/10.1080/00498254.2016.1227109 |
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Copyright Statement
This is an Accepted Manuscript of an article published by Taylor & Francis in Xenobiotica on 15/09/2016 available online: http://www.tandfonline.com/10.1080/00498254.2016.1227109
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