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CYP3A Mediates an Unusual C(sp2)-C(sp3) Bond Cleavage via Ipso-Addition of Oxygen in Drug Metabolism.
Qin, Xuan; Wang, Yong; Ye, Qiuji; Hakenjos, John M; Wang, Jin; Teng, Mingxing; Guo, Lei; Tan, Zhi; Young, Damian W; MacKenzie, Kevin R; Li, Feng.
Afiliación
  • Qin X; Center for Drug Discovery, Department of Pathology and Immunology, Baylor College of Medicine, 1 Baylor Plaza, Houston, Texas, 77030, USA.
  • Wang Y; Center for Drug Discovery, Department of Pathology and Immunology, Baylor College of Medicine, 1 Baylor Plaza, Houston, Texas, 77030, USA.
  • Ye Q; Center for Drug Discovery, Department of Pathology and Immunology, Baylor College of Medicine, 1 Baylor Plaza, Houston, Texas, 77030, USA.
  • Hakenjos JM; Center for Drug Discovery, Department of Pathology and Immunology, Baylor College of Medicine, 1 Baylor Plaza, Houston, Texas, 77030, USA.
  • Wang J; Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, 1 Baylor Plaza, Houston, Texas, 77030, USA.
  • Teng M; Center for Drug Discovery, Department of Pathology and Immunology, Baylor College of Medicine, 1 Baylor Plaza, Houston, Texas, 77030, USA.
  • Guo L; Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, 1 Baylor Plaza, Houston, Texas, 77030, USA.
  • Tan Z; National Center for Toxicological Research, U.S. Food and Drug Administration, 3900 NCTR Rd, Jefferson, Arkansas, USA.
  • Young DW; Center for Drug Discovery, Department of Pathology and Immunology, Baylor College of Medicine, 1 Baylor Plaza, Houston, Texas, 77030, USA.
  • MacKenzie KR; Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, 1 Baylor Plaza, Houston, Texas, 77030, USA.
  • Li F; Center for Drug Discovery, Department of Pathology and Immunology, Baylor College of Medicine, 1 Baylor Plaza, Houston, Texas, 77030, USA.
Angew Chem Int Ed Engl ; 63(23): e202405197, 2024 06 03.
Article en En | MEDLINE | ID: mdl-38574245
ABSTRACT
Mammalian cytochrome P450 drug-metabolizing enzymes rarely cleave carbon-carbon (C-C) bonds and the mechanisms of such cleavages are largely unknown. We identified two unusual cleavages of non-polar, unstrained C(sp2)-C(sp3) bonds in the FDA-approved tyrosine kinase inhibitor pexidartinib that are mediated by CYP3A4/5, the major human phase I drug metabolizing enzymes. Using a synthetic ketone, we rule out the Baeyer-Villiger oxidation mechanism that is commonly invoked to address P450-mediated C-C bond cleavages. Our studies in 18O2 and H2 18O enriched systems reveal two unusual distinct mechanisms of C-C bond cleavage one bond is cleaved by CYP3A-mediated ipso-addition of oxygen to a C(sp2) site of N-protected pyridin-2-amines, and the other occurs by a pseudo-retro-aldol reaction after hydroxylation of a C(sp3) site. This is the first report of CYP3A-mediated C-C bond cleavage in drug metabolism via ipso-addition of oxygen mediated mechanism. CYP3A-mediated ipso-addition is also implicated in the regioselective C-C cleavages of several pexidartinib analogs. The regiospecificity of CYP3A-catalyzed oxygen ipso-addition under environmentally friendly conditions may be attractive and inspire biomimetic or P450-engineering methods to address the challenging task of C-C bond cleavages.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Oxígeno / Citocromo P-450 CYP3A Límite: Humans Idioma: En Revista: Angew Chem Int Ed Engl Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Alemania
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Oxígeno / Citocromo P-450 CYP3A Límite: Humans Idioma: En Revista: Angew Chem Int Ed Engl Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Alemania