A theoretical study on the oxidative metabolism of 4-chloroacetanilide by cytochrome P450: Alternative mechanisms for migration of 4-substituents during enzymatic oxidation
Donné-Op Den Kelder, G.M.
te Koppele, J.M.
van Lenthe, J.H.
Instituut voor verouderings- en vaatziekten onderzoek TNO
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).
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Recueil des travaux chimiques aux Pays-Bas, 112, 186-190