CYP3A Mediates an Unusual C(sp2)-C(sp3) Bond Cleavage via Ipso-Addition of Oxygen in Drug Metabolism

Authors

Xuan Qin
Yong Wang
Qiuji Ye
John M Hakenjos
Jin Wang
Mingxing Teng
Lei Guo
Zhi Tan
Damian W Young
Kevin R MacKenzie
Feng Li

Publication Date

6-3-2024

Journal

Angewandte Chemie

DOI

10.1002/anie.202405197

PMID

38574245

PMCID

PMC11126355

PubMedCentral® Posted Date

6-3-2024

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Oxygen, Cytochrome P-450 CYP3A, Humans, Molecular Structure, Carbon, Oxidation-Reduction, CYP3A, carbon-carbon bond cleavage, ipso addition, retro-aldol, pexidartinib

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 H218O 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.

Comments

Associated Data