{"doi":"10.1002/anie.202405197","title":"CYP3A Mediates an Unusual C(sp<sup>2</sup>)−C(sp<sup>3</sup>) Bond Cleavage via <i>Ipso</i>‐Addition of Oxygen in Drug Metabolism","abstract":"<jats:title>Abstract</jats:title><jats:p>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(sp<jats:sup>2</jats:sup>)−C(sp<jats:sup>3</jats:sup>) 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 <jats:sup>18</jats:sup>O<jats:sub>2</jats:sub> and H<jats:sub>2</jats:sub><jats:sup>18</jats:sup>O enriched systems reveal two unusual distinct mechanisms of C−C bond cleavage: one bond is cleaved by CYP3A‐mediated <jats:italic>ipso</jats:italic>‐addition of oxygen to a C(sp<jats:sup>2</jats:sup>) site of <jats:italic>N</jats:italic>‐protected pyridin‐2‐amines, and the other occurs by a pseudo‐retro‐aldol reaction after hydroxylation of a C(sp<jats:sup>3</jats:sup>) site. This is the first report of CYP3A‐mediated C−C bond cleavage in drug metabolism via <jats:italic>ipso</jats:italic>‐addition of oxygen mediated mechanism. CYP3A‐mediated <jats:italic>ipso</jats:italic>‐addition is also implicated in the regioselective C−C cleavages of several pexidartinib analogs. The regiospecificity of CYP3A‐catalyzed oxygen <jats:italic>ipso</jats:italic>‐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.</jats:p>","journal":"Angewandte Chemie International Edition","year":2024,"id":646750,"datarank":0.26876392038420827,"base_score":1.791759469228055,"endowment":1.791759469228055,"self_citation_contribution":0.26876392038420827,"citation_network_contribution":0.0,"self_endowment_contribution":0.26876392038420827,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":459723,"name":"Yong Wang","orcid":"0000-0003-2507-8333","position":1,"is_corresponding":false},{"id":761823,"name":"Qiuji Ye","orcid":"0000-0002-3812-3001","position":2,"is_corresponding":false},{"id":1196730,"name":"John M. 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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 <jats:sup>18</jats:sup>O<jats:sub>2</jats:sub> and H<jats:sub>2</jats:sub><jats:sup>18</jats:sup>O enriched systems reveal two unusual distinct mechanisms of C−C bond cleavage: one bond is cleaved by CYP3A‐mediated <jats:italic>ipso</jats:italic>‐addition of oxygen to a C(sp<jats:sup>2</jats:sup>) site of <jats:italic>N</jats:italic>‐protected pyridin‐2‐amines, and the other occurs by a pseudo‐retro‐aldol reaction after hydroxylation of a C(sp<jats:sup>3</jats:sup>) site. This is the first report of CYP3A‐mediated C−C bond cleavage in drug metabolism via <jats:italic>ipso</jats:italic>‐addition of oxygen mediated mechanism. CYP3A‐mediated <jats:italic>ipso</jats:italic>‐addition is also implicated in the regioselective C−C cleavages of several pexidartinib analogs. The regiospecificity of CYP3A‐catalyzed oxygen <jats:italic>ipso</jats:italic>‐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.</jats:p>","is_dataset_classified":null,"base_score":1.791759469228055,"endowment":1.791759469228055,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"38574245","pmcid":"PMC11126355","openalex_id":"https://openalex.org/W4393951960","authors":[],"funders":[{"funder_name":"National Institute of Child Health and Human Development","grant_id":"R33HD099995","title":null},{"funder_name":"National Institute of Child Health and Human Development","grant_id":"P01HD087157","title":null},{"funder_name":"National Institute of Diabetes and Digestive and Kidney Diseases","grant_id":"R01DK121970","title":null},{"funder_name":"National Institute on Aging","grant_id":"P01AG066606","title":null},{"funder_name":"NICHD NIH HHS","grant_id":"R61 HD099995","title":null}],"total_grants":5,"fwci":1.7783,"citation_percentile":0.82615125,"influential_citations":0,"citation_trend":[{"year":2025,"count":3},{"year":2026,"count":2}],"oa_status":"green","license":"http://onlinelibrary.wiley.com/termsAndConditions#vor","oa_locations":[{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC11126355/pdf/nihms-1986608.pdf","host_type":"repository"},{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC11126355/pdf/nihms-1986608.pdf","host_type":"repository"},{"url":"https://onlinelibrary.wiley.com/doi/pdf/10.1002/anie.202405197","host_type":"publisher"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/11126355","host_type":"repository"},{"url":"https://doi.org/10.1002/anie.202405197","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/38574245","host_type":"repository"},{"url":"https://digitalcommons.library.tmc.edu/baylor_docs/315","host_type":"repository"}],"fields_of_study":["Pharmacogenetics and Drug Metabolism","Metal-Catalyzed Oxygenation Mechanisms","Cancer Treatment and Pharmacology","Oxygen","Cytochrome P-450 CYP3A","Humans","Molecular Structure","Carbon","Oxidation-Reduction"],"mesh_terms":["Carbon","Humans","Oxidation-Reduction","Oxygen","Molecular Structure","Cytochrome P-450 CYP3A"],"keywords":["Cleave","CYP3A","Bond cleavage","Cleavage (geology)","Chemistry","Stereochemistry","Metabolism","Cytochrome P450","Carbon fibers","Oxygen","Enzyme","Biochemistry","Biology","Organic chemistry","Catalysis","Materials science","Retro-aldol","Carbon-carbon Bond Cleavage","Pexidartinib","Ipso Addition"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Life in Land"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-09T14:46:16.298998Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}