Title
A theoretical study on the oxidative metabolism of 4-chloroacetanilide by cytochrome P450: Alternative mechanisms for migration of 4-substituents during enzymatic oxidation
Author
Koymans, L.M.H.
Menge, W.M.P.B.
Donné-Op Den Kelder, G.M.
te Koppele, J.M.
Vermeulen, N.P.E.
van Lenthe, J.H.
Instituut voor verouderings- en vaatziekten onderzoek TNO
Publication year
1993
Abstract
The oxidative metabolism of 4-chloroacetanilide (4-ClAA, 1) by cytochrome P450 has been studied theoretically using ab-initio energy and spin-distribution calculations. A mechanism of oxidation for 4-ClAA is proposed which is in accordance with recent views on the mechanism of metabolic oxidation of substrates by cytochrome P450. An initial one-electron-oxidation step in the metabolic activation of 4-ClAA is suggested to be a hydrogen abstraction from nitrogen in the acetylamino side chain. Spin-delocalisation and subsequent radical recombination reactions between a hydroxyl radical and the reactive centres of the substrate radical can explain the formation of N-HO- and 2-HO-4-ClAA (4, 9), two known metabolites of 4-ClAA. Furthermore, the formation of a 2,5-cyclohexadien-1-imine intermediate (6) is proposed. Hypothetical addition-elimination mechanisms for the decomposition of this intermediate, which are supported by experimental data on analogous compounds, explain the formation of 4-HOAA, 3-HO-4-ClAA (10), and 3-Cl-4-HOAA (11), three other known metabolites of 4-ClAA (1).
Subject
Health
To reference this document use:
http://resolver.tudelft.nl/uuid:71720dfb-36ad-416f-80b2-18c0829d3084
DOI
https://doi.org/10.1002/recl.19931120217
TNO identifier
281024
Source
Recueil des travaux chimiques aux Pays-Bas, 112, 186-190
Document type
article