A theoretical study on the oxidative metabolism of 4-chloroacetanilide by cytochrome P450: Alternative mechanisms for migration of 4-substituents during enzymatic oxidation

✍ Scribed by L. M. H. Koymans; W. M. P. B. Menge; G. M. Donné-Op Den Kelder; J. M. Te Koppele; N. P. E. Vermeulen; J. H. van Lenthe

• Publisher: Elsevier Science
• Year: 2010
• Tongue: English
• Weight: 450 KB
• Volume: 112
• Category: Article
• ISSN: 0165-0513
• DOI: 10.1002/recl.19931120217

✦ Synopsis

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).