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Carbon-carbon bond cleavage in activation of the prodrug nabumetone
Fatbardha Varfaj1, Siti N A Zulkifli, Hyoung-Goo Park
1Department of Pharmaceutical Chemistry, University of California, San Francisco, California (F.V., H.P., P.R.O.M.); Department of Chemistry, University of Queensland, St. Lucia, Brisbane, Australia (S.N.A.Z., V.L.C., J.J.D.V.); and Department of Biological Sciences, Konkuk University, Seoul, Korea (H.P.).
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.
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