Carbon-Carbon bond cleavage in activation of the prodrug nabumetone

Varfaj, Fatbardha, Zulkifli, Siti N. A., Park, Hyoung-Goo, Challinor, Victoria L., De Voss, James J. and De Montellano, Paul R. Ortiz (2014) Carbon-Carbon bond cleavage in activation of the prodrug nabumetone. Drug Metabolism and Disposition, 42 5: 828-838. doi:10.1124/dmd.114.056903

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Author Varfaj, Fatbardha
Zulkifli, Siti N. A.
Park, Hyoung-Goo
Challinor, Victoria L.
De Voss, James J.
De Montellano, Paul R. Ortiz
Title Carbon-Carbon bond cleavage in activation of the prodrug nabumetone
Journal name Drug Metabolism and Disposition   Check publisher's open access policy
ISSN 1521-009X
0090-9556
Publication date 2014-05-01
Year available 2014
Sub-type Article (original research)
DOI 10.1124/dmd.114.056903
Open Access Status Not Open Access
Volume 42
Issue 5
Start page 828
End page 838
Total pages 11
Place of publication Bethesda, United States
Publisher American Society for Pharmacology and Experimental Therapy
Language eng
Formatted abstract
Carbon-carbon bond cleavage reactions are catalyzed by, among others, lanosterol 14-demethylase (CYP51), cholesterol side-chain cleavage enzyme (CYP11), sterol 17β-lyase (CYP17), and aromatase (CYP19). Because of the high substrate specificities of these enzymes and the complex nature of their substrates, these reactions have been difficult to characterize. A CYP1A2-catalyzed carbon-carbon bond cleavage reaction is required for conversion of the prodrug nabumetone to its active form, 6-methoxy-2-naphthylacetic acid (6-MNA). Despite worldwide use of nabumetone as an anti-inflammatory agent, the mechanism of its carbon-carbon bond cleavage reaction remains obscure. With the help of authentic synthetic standards, we report here that the reaction involves 3-hydroxylation, carbon-carbon cleavage to the aldehyde, and oxidation of the aldehyde to the acid, all catalyzed by CYP1A2 or, less effectively, by other P450 enzymes. The data indicate that the carbon-carbon bond cleavage is mediated by the ferric peroxo anion rather than the ferryl species in the P450 catalytic cycle. CYP1A2 also catalyzes O-demethylation and alcohol to ketone transformations of nabumetone and its analogs.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
School of Chemistry and Molecular Biosciences
 
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