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Cytochrome P450-Catalyzed Oxidation of N-Benzyl-N-cyclopropylamine Generates Both Cyclopropanone Hydrate and 3-Hydroxypropionaldehyde via Hydrogen Abstraction, Not Single Electron Transfer.
- Source :
-
Journal of the American Chemical Society . 3/15/2006, Vol. 128 Issue 10, p3346-3354. 9p. 6 Diagrams, 1 Chart. - Publication Year :
- 2006
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Abstract
- The suicide substrate activity of N-benzyl-N-cyclopropylamine (1) and N-benzyl-N-(1′-methyl-cyclopropyl)amine (2) toward cytochrome P450 and other enzymes has been explained by a mechanism involving 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 of N-cyclopropyI-N-methylaniline (3) by horseradish peroxidase leads exclusively to ring-opened (noncyclopropyl) 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 have determined the complete metabolic fate of 1 with P450 in vitro. 3-Hydroxypropionaldehyde (3HP), the presumptive ‘signature metabolite’ for SET oxidation of a cyclopropylamine, was observed for the first time in 57% yield, along with cyclopropanone hydrate (34%), cyclopropylamine (9%), benzaldehyde (6%), benzyl alcohol (12%), and benzaldoxime (19%). Unexpectedly, N-benzyI-N-cyclopropyI-N-methylamine (4) was found not to inactivate P450 and not to give rise to 3HP as a metabolite without first undergoing oxidative N-demethylation to 1. These and other observations argue against a role for SET mechanisms in the P450 oxidation of cyclopropylamines. We suggest that a conventional hydrogen abstraction/hydroxyl recombination mechanism (or its equivalent as a one-step ‘insertion’ mechanism) at C-H bonds in 1–4 leads to nonrearranged carbinolamine intermediates and thereby to ‘ordinary’ N-dealkylation products including cyclopropanone hydrate. Alternatively, hydrogen abstraction at the N-H bond of secondary cyclopropylamines 1 gives a neutral aminyl radical which could undergo rapid ring-opening leading either to enzyme inactivation or 3HP formation. [ABSTRACT FROM AUTHOR]
- Subjects :
- *CYTOCHROMES
*ENZYMES
*AMINES
*CHARGE exchange
*OXIDATION
*HYDROGEN
*HYDROGEN bonding
Subjects
Details
- Language :
- English
- ISSN :
- 00027863
- Volume :
- 128
- Issue :
- 10
- Database :
- Academic Search Index
- Journal :
- Journal of the American Chemical Society
- Publication Type :
- Academic Journal
- Accession number :
- 20926484
- Full Text :
- https://doi.org/10.1021/ja054938+