Carbon-Carbon Bond Cleavage in Activation of the Prodrug Nabumetone

Abstract

Carbon-carbon bond cleavage reactions are catalyzed by, among others, lanosterol 14-demethylase (CYP51), cholesterol side-chain cleavage enzyme (CYP11), sterol 17b-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.

Oxygen Surrogate Systems for Supporting Human Drug-Metabolizing Cytochrome P450 Enzymes

“…DMD # 90555 6 oxygen atom to the P450 ferric heme (Hrycay and O'Brien, 1971b;Kadlubar et al, 1973;Cho et al, 2007).Various OSs have been identified to support P450 catalysis (Hrycay and O'Brien, 1971a;Hrycay et al, 1972;Kadlubar et al, 1973;Chance et al, 1979;Tan et al, 1983;Lindstrom and Aust, 1984;Hecker et al, 1987;Weiss et al, 1987;Vaz et al, 1990;Plastaras et al, 2000) including most commonly, CuOOH, tert-BuOOH, H2O2 and iodosylbenzene (PhIO). They have been particularly used in investigations of the interactions of P450s with their redox partners concerning potential allosteric effects, the mechanisms of P450 inhibition, the exploration of the P450-redox partner interaction surface and other mechanistic questions Keizers et al, 2005;Lin et al, 2012;Varfaj et al, 2014;Yoshimoto et al, 2016).…”

Diverging Mechanisms: Cytochrome‐P450‐Catalyzed Demethylation and γ‐Lactone Formation in Bacterial Gibberellin Biosynthesis

“…[9] In CYPs these early stages of the catalytic cycle can be bypassed by using H 2 O 2 or tert -butyl hydroperoxide ( t BuOOH) as the reducing agent instead of molecular oxygen and electrons from NADPH (Scheme S2). [10] However, while the overall activity of Et CYP112 with H 2 O 2 is significantly lower, limiting conversion of GA 12 to GA 15 and GA 24 , it is able drive the conversion of GA 15 to GA 24 and GA 9 , as well as GA 24 to GA 9 .…”

“…[10–11] Thus, the proposed mechanisms are adaptable to CYPs (Schemes S3 and S4). In addition, CYPs are known to catalyze reactions via ferryl-hydroxo (Compound II), ferric-superoxo, ferric-peroxo, [9] or ferric-hydroperoxo species (Compound 0) as well (Scheme S2). [12] However, the ability of Et CYP112 to use H 2 O 2 or t BuOOH to drive this transformation precludes the use of either the superoxo or peroxo complexes, or Compound 0, respectively.…”

Pharmacokinetic and Pharmacodynamic Interaction of Andrographolide and Standardized Extract of Andrographis paniculata (Nees) with Nabumetone in Wistar Rats

“…6‐MNA is a close structural analog of naproxen which is more potent and more selective inhibitor of cyclooxygenase‐2 compared with the parent drug (Dahl, ; Davies, ). CYP1A2 plays an important role in the metabolism of NAB to the active metabolite 6‐MNA along with other enzymes like CYP2C6, CYP2C11 in rats and CYP2A6, CYP2C9, CYPC19, CYP2D6, CYP3A4 in human, (Turpeinen et al , ; Matsumoto et al , , Varfaj et al , ). So any substance influencing the CYP1A2 enzyme may affect the metabolism of NAB.…”