Affiliation:
1. Chemical Synthesis and Pollution Control Key Laboratory of Sichuan Province, College of Chemistry and Chemical Engineering China West Normal University Nanchong People's Republic of China
2. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School Sichuan University Chengdu People's Republic of China
Abstract
AbstractThe reaction mechanism of cytochrome P450‐mediated intramolecular cyclization of 2‐aminoamide compounds to imidazolinone was studied by density functional theory. The cyclization reaction involves three steps: hydrogen abstraction, dehydration of intermediates to zwitterions and final ring closure. Interestingly, high spin (HS) state P450‐catalyzed dehydration exhibits a mechanism distinct from conventional processes such as in low spin state. In HS pathways, the hydroxyl group after hydrogen abstraction does not rebound but produce an intermediate, which makes the second hydrogen abstraction regioselective. Regioselectivity leads to diverse intermediates and mechanisms to zwitterion, which implies different functions of the high and low spin states P450. The alkylamine nitrogen and amide group are key groups to enables regioselectivity of in HS pathway. Small changes of molecular structure can affect the molecular transformation process, indicating the complex regulation of electronic state to reaction process. The results lay the theoretical basis for the regioselectivity determined by P450 enzyme and substrate structure together. The research establishes a foundation for the drug design, drug metabolite, and synthesis of nitrogen‐containing heterocyclic drugs.
Subject
Physical and Theoretical Chemistry,Condensed Matter Physics,Atomic and Molecular Physics, and Optics
Cited by
1 articles.
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