ArticleDrug metabolism and disposition: the biological fate of chemicals2014
Carbon-carbon bond cleavage in activation of the prodrug nabumetone.
Article in Drug metabolism and disposition: the biological fate of chemicals, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 41 citations in OpenAlex.
- Stereoselective Biotransformation: Transfer of Learning to Advance Drug Metabolism and Biocatalysis.Angewandte Chemie (International ed. in English) · 2026Review
- CYP3A-Mediated Carbon-Carbon Bond Cleavages in Drug Metabolism.Biomolecules · 2024Review
- Updates on Mechanisms of Cytochrome P450 Catalysis of Complex Steroid Oxidations.International journal of molecular sciences · 2024Review
- SelectiveACS catalysis · 2024Article
- Oxygen-18 Labeling Defines a Ferric Peroxide (Compound 0) Mechanism in the Oxidative Deformylation of Aldehydes by Cytochrome P450 2B4.ACS catalysis · 2024Article
- Dissecting CYP1A2 Activation by Arylalkanoic Acid Prodrugs toward the Development of Anti-Inflammatory Agents.International journal of molecular sciences · 2023Article
- Biotransformation novel advances - 2021 year in review.Drug metabolism reviews · 2022Review
- Presence or absence of microbiome modulates the response of mice organism to administered drug nabumetone.Physiological research · 2020Article
- Gel Formulation of Nabumetone and a Newly Synthesized Analog: Microemulsion as a Photoprotective Topical Delivery System.Pharmaceutics · 2020Article
- Practical Catalytic Cleavage of C(spAngewandte Chemie (International ed. in English) · 2019Article
- Mechanisms of Cytochrome P450-Catalyzed Oxidations.ACS catalysis · 2018Article
- Formation and Cleavage of C-C Bonds by Enzymatic Oxidation-Reduction Reactions.Chemical reviews · 2018Review
- Diverging Mechanisms: Cytochrome-P450-Catalyzed Demethylation and γ-Lactone Formation in Bacterial Gibberellin Biosynthesis.Angewandte Chemie (International ed. in English) · 2018Article
- Isotope-Labeling Studies Support the Electrophilic Compound I Iron Active Species, FeO(3+), for the Carbon-Carbon Bond Cleavage Reaction of the Cholesterol Side-Chain Cleavage Enzyme, Cytochrome P450 11A1.Journal of the American Chemical Society · 2016Article
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Authors and funding
6 authors at 3 institutions in 3 countries.
Funding
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.