Cytochrome P450-Catalyzed Oxidation of N-Benzyl-N-cyclopropylamine Generates Both Cyclopropanone Hydrate and 3-Hydroxypropionaldehyde via Hydrogen Abstraction, Not Single Electron Transf
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- 作者：Matthew A. Cerny and Robert P. Hanzlik
- 刊名：Journal of the American Chemical Society
- 出版年：2006
- 出版时间：March 15, 2006
- 年：2006
- 卷：128
- 期：10
- 页码：3346 - 3354
- 全文大小：128K
- 年卷期：v.128,no.10(March 15, 2006)
- ISSN：1520-5126
文摘
The suicide substrate activity of N-benzyl-N-cyclopropylamine (1) and N-benzyl-N-(1'-methylcyclopropyl)amine (2) toward cytochrome P450 and other enzymes has been explained by a mechanisminvolving single electron transfer (SET) oxidation, followed by ring-opening of the aminium radical cation(protonated aminyl radical) and reaction with the P450 active site. Although the SET oxidation ofN-cyclopropyl-N-methylaniline (3) by horseradish peroxidase leads exclusively to ring-opened (non-cyclopropyl) products, P450 oxidation of 3 leads to formation of cyclopropanone hydrate and no ring-opened products, and 3 does not inactivate P450. To help reconcile these discrepant behaviors we havedetermined the complete metabolic fate of 1 with P450 in vitro. 3-Hydroxypropionaldehyde (3HP), thepresumptive "signature metabolite" for SET oxidation of a cyclopropylamine, was observed for the firsttime in 57% yield, along with cyclopropanone hydrate (34%), cyclopropylamine (9%), benzaldehyde (6%),benzyl alcohol (12%), and benzaldoxime (19%). Unexpectedly, N-benzyl-N-cyclopropyl-N-methylamine (4)was found not to inactivate P450 and not to give rise to 3HP as a metabolite without first undergoingoxidative N-demethylation to 1. These and other observations argue against a role for SET mechanismsin the P450 oxidation of cyclopropylamines. We suggest that a conventional hydrogen abstraction/hydroxylrecombination mechanism (or its equivalent as a one-step "insertion" mechanism) at C-H bonds in 1-4leads to nonrearranged carbinolamine intermediates and thereby to "ordinary" N-dealkylation productsincluding cyclopropanone hydrate. Alternatively, hydrogen abstraction at the N-H bond of secondarycyclopropylamines 1 gives a neutral aminyl radical which could undergo rapid ring-opening leading eitherto enzyme inactivation or 3HP formation.