Li Dongmei, Wang Yong, Yang Chuanlu, Han Keli
State Key Laboratory of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China.
Dalton Trans. 2009 Jan 14(2):291-7. doi: 10.1039/b810767j. Epub 2008 Nov 19.
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.
利用密度泛函理论研究了细胞色素P450（P450）催化的N-环丙基-N-甲基苯胺（）的N-脱烷基化反应机理。该反应包括两个步骤。第一步是N-取代基上的Cα-H羟基化反应，形成甲醇胺络合物，第二步是甲醇胺分解生成环丙酮（或甲醛）和N-甲基苯胺（或N-环丙基苯胺）。我们的计算表明，第一步以自旋选择性机制（SSM）进行，主要发生在低自旋（LS）双峰态。限速的Cα-H活化是一个同位素敏感的氢原子转移（HAT）步骤。环境效应将该反应的区域选择性从N-脱环丙基化和N-脱甲基化之间的竞争转变为明显偏向N-脱甲基化。这种偏向与以前的实验研究一致。然而，它不符合正常的ΔE-BDE相关性，因为甲基上Cα-H的BDE高于环丙基上的BDE。对N-脱甲基化偏好起源的深入研究表明，叔胺不同于普通烃类，具有独特的πPh-πC-N共轭体系。πPh-πC-N共轭体系中的电子离域效应使过渡态具有极性特征，蛋白质口袋的整体极性和氢键能力可对的N-脱烷基化区域选择性产生显著影响。在非酶环境中，甲醇胺的分解是一个水辅助的质子转移过程。反应中形成的环完整的环丙酮为在其N-脱环丙基化过程中无法使P450失活提供了一些线索。
