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Abstract: 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 mecha… Show more

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Cited by 35 publications
(48 citation statements)
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References 67 publications
(63 reference statements)
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“…The calculated energy barriers for nicotine 5 -hydroxylation are higher than the barriers for amine C ␣ -H hydroxylation [102,103]. This is because the amines used in the previous studies are deprotonated, whereas the nicotine used in this study is a protonated one, with a proton on the pyrrolidine nitrogen.…”
Section: Nicotine Oxidationmentioning
confidence: 60%
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“…The calculated energy barriers for nicotine 5 -hydroxylation are higher than the barriers for amine C ␣ -H hydroxylation [102,103]. This is because the amines used in the previous studies are deprotonated, whereas the nicotine used in this study is a protonated one, with a proton on the pyrrolidine nitrogen.…”
Section: Nicotine Oxidationmentioning
confidence: 60%
“…A subsequent DFT study on N-cyclopropyl-N-methylaniline (CMA) [103] shows similar electron delocalization effect of the Ph -N C conjugated system. The electron delocalization effect of the Ph -N C conjugated system makes the transition state possess a polar character, and therefore, the bulk polarity and hydrogen bonding capability of the protein pocket exert a remarkable effect on the regioselectivity of the CMA N-dealkylation reaction and cause a preference for N-demethylation over N-decyclopropylation.…”
Section: Amine N-dealkylationmentioning
confidence: 99%
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“…with hydrogen-abstraction and rebound steps, of which the first is rate limiting. Because of the importance of understanding these reaction types in drug degradation, a number of theoretical studies have been performed, in several cases including the non-enzymatic reaction, 62,71,72,[74][75][76][77] as are summarized in Figure 5.…”
Section: Ligandmentioning
confidence: 99%
“…Previous studies have reported that the activation energy for decomposition of carbinolaniline is greatly reduced by the participation of a water molecule in the reaction (Wang et al, 2007;Li et al, 2009). This may imply that the N-dealkylation process is favorable in the presence of water.…”
mentioning
confidence: 99%