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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.

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Authors

William Palmer-Brown

Brian Dunne

Yannick Ortin

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 Mar 28, 2024
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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