Kinetic deuterium isotope effects on the N-demethylation of tertiary amides by cytochrome P-450.

Hall, Larry R.; Hanzlik, Robert P.

doi:10.1016/s0021-9258(19)38353-x

Cited by 66 publications

(33 citation statements)

References 34 publications

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“…28 In contrast, large intramolecular hydrogen isotope effects ( 2 k/ 1 k > 7) observed during the oxidation of amides provided evidence that the C-H bond was initially cleaved. 18,21,29 Further, N-demethylation of dimethylanilines by P450 enzymes showed similar hydrogen isotope effect profiles as for H-atom abstraction by tert-butoxy radicals 17,30 suggesting a HAT mechanism as the initial step. However, hydrogen isotope effects are often masked by rate determining steps other than the C-H cleavage and may show a rather large variability even in the absence of masking.…”

Section: Introductionmentioning

confidence: 74%

Cytochrome P450-catalyzed dealkylation of atrazine byRhodococcussp. strain NI86/21 involves hydrogen atom transfer rather than single electron transfer

et al. 2014

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Cytochrome P450 enzymes are responsible for a multitude of natural transformation reactions. For oxidative N-dealkylation, single electron (SET) and hydrogen atom abstraction (HAT) have been debated as underlying mechanisms. Combined evidence from (i) product distribution and (ii) isotope effects indicate that HAT, rather than SET, initiates N-dealkylation of atrazine to desethyl- and desisopropylatrazine by the microorganism Rhodococcus sp. strain NI86/21. (i) Product analysis revealed a non-selective oxidation at both the αC and βC-atom of the alkyl chain, which is expected for a radical reaction, but not SET. (ii) Normal (13)C and (15)N as well as pronounced (2)H isotope effects (εcarbon: -4.0‰ ± 0.2‰; εnitrogen: -1.4‰ ± 0.3‰, KIEH: 3.6 ± 0.8) agree qualitatively with calculated values for HAT, whereas inverse (13)C and (15)N isotope effects are predicted for SET. Analogous results are observed with the Fe(iv)[double bond, length as m-dash]O model system [5,10,15,20-tetrakis(pentafluorophenyl)porphyrin-iron(iii)-chloride + NaIO4], but not with permanganate. These results emphasize the relevance of the HAT mechanism for N-dealkylation by P450.

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Section: Introductionmentioning

confidence: 74%

Cytochrome P450-catalyzed dealkylation of atrazine byRhodococcussp. strain NI86/21 involves hydrogen atom transfer rather than single electron transfer

et al. 2014

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“…Deuterated compounds are highly important for the metabolic analysis of bioactive agents as well as the mechanistic study of chemical and enzymatic reactions. , Moreover, the incorporation of deuterium into pharmaceutical molecules has recently attracted growing interest due to its beneficial effects to improve their therapeutic and metabolic profiles . Consequently, vigorous efforts have been made to develop various catalytic deuteration reactions .…”

Section: Introductionmentioning

confidence: 99%

Deuterodechlorination of Aryl/Heteroaryl Chlorides Catalyzed by a Palladium/Unsymmetrical NHC System

et al. 2016

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The catalytic deuterodechlorination of aryl/heteroaryl chlorides was developed with a palladium/unsymmetrical NHC system, and the precisely controlled introduction of deuterium into a variety of aryl/heteroaryl compounds was achieved with a high level of efficiency, selectivity, and deuteration degree. This method was also successfully applied to the transformation of bioactive agents even in a gram-scale synthesis. The crystal structure analysis of Pd-NHC complexes led to the observation of Pd-arene interaction.

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“…65-85 kJ mol Ϫ1 , 6 and, although the analogous value is unknown for an amide bound in the P450 active site, it is known that the rotation rate increases with decreasing solvent polarity and that the P450 active site is non-polar. 7 Acyclic amides, therefore, are unable to provide insights into the regioselectivity of the dealkylation process, although semi-empirical AM1 SCF MO calculations imply that the carbon-centred radical formed from the E-alkyl group is 4-5 kJ mol Ϫ1 more stable than the corresponding radical from the Z-alkyl group. 3,8 Consequently, we have chosen to examine the conformationally rigid lactams 5-8.…”

mentioning

confidence: 99%

Chemical and microsomal oxidation of tertiary amides: regio- and stereoselective aspects

Iley

Tolando

Constantino

2001

J. Chem. Soc., Perkin Trans. 2

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Kinetic deuterium isotope effects on the N-demethylation of tertiary amides by cytochrome P-450.

Cited by 66 publications

References 34 publications

Cytochrome P450-catalyzed dealkylation of atrazine byRhodococcussp. strain NI86/21 involves hydrogen atom transfer rather than single electron transfer

Cytochrome P450-catalyzed dealkylation of atrazine byRhodococcussp. strain NI86/21 involves hydrogen atom transfer rather than single electron transfer

Deuterodechlorination of Aryl/Heteroaryl Chlorides Catalyzed by a Palladium/Unsymmetrical NHC System

Chemical and microsomal oxidation of tertiary amides: regio- and stereoselective aspects

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