Corrigendum to “Studies on the cytochrome P450 catalyzed oxidation of 13C labeled 1-cyclopropyl-4-phenyl-1,2,3,6-tetrahydropyridine by 13C NMR” [Bioorg. Med. Chem. 13 (2005) 2975]

Bissel, Philippe; Castagnoli, Neal; Penich, Sarah

doi:10.1016/j.bmc.2005.04.077

Cited by 1 publication

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“…Some cyclopropylamines are also suicide substrates for P450. [16][17][18] The cyclopropyl group's unique electronic structure compared to ordinary aliphatic groups 19 and unique ability to inactivate P450 [16][17][18] promoted cyclopropylamines being widely applied as probes of P450 and other oxidative enzymes in many mechanistic studies [20][21][22][23][24][25][26][27][28][29][30] involved in the "HAT-SET controversy".…”

Section: Introductionmentioning

confidence: 99%

Theoretical study of N-dealkylation of N-cyclopropyl-N-methylaniline catalyzed by cytochrome P450: insight into the origin of the regioselectivity

Wang

Yang

et al. 2009

Dalton Trans.

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The mechanism of N-dealkylation of N-cyclopropyl-N-methylaniline () catalyzed by cytochrome P450 (P450) was investigated using density functional theory. This reaction involves two steps. The first one is a Calpha-H hydroxylation on the N-substituent to form a carbinolaniline complex, and the second is a decomposition of the carbinolaniline to yield cyclopropanone (or formaldehyde) and N-methylaniline (or N-cyclopropylaniline). Our calculations demonstrate that the first step proceeds in a spin-selective mechanism (SSM), mostly on the low-spin (LS) doublet state. The rate-limiting Calpha-H activation is an isotope-sensitive hydrogen atom transfer (HAT) step. The environmental effect switches the regioselectivity of this reaction from a competition between N-decyclopropylation and N-demethylation to a clear preference for N-demethylation. This preference is consistent with former experimental studies. However, it is not in accord with the normal DeltaE-BDE correlation since the BDE of Calpha-H on the methyl group is higher than that on the cyclopropyl group. Insight into the origin of the preference for N-demethylation reveals that tertiary amine is different from normal hydrocarbons, possessing a unique piPh-piC-N conjugated system. The electron delocalization effect of the piPh-piC-N conjugated system in makes the transition state pose a polar character, and the bulk polarity and hydrogen bonding capability of the protein pocket can exert a remarkable effect on the regioselectivity of N-dealkylation of . Decomposition of carbinolaniline is a water-assisted proton-transfer process in the nonenzymatic environment. The ring-intact cyclopropanone formed in the reaction sheds some light on the inability of to inactivate P450 during its N-decyclopropylation.

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