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
Year available 2014
Sub-type Article (original research)
DOI 10.1124/dmd.114.056903
Open Access Status
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
Collection year 2015
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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