Jump to main content
Jump to site search

Issue 20, 2004
Previous Article Next Article

Mechanism and structure–reactivity relationships for aromatic hydroxylation by cytochrome P450

Author affiliations

Abstract

Cytochrome P450 enzymes play a central role in drug metabolism, and models of their mechanism could contribute significantly to pharmaceutical research and development of new drugs. The mechanism of cytochrome P450 mediated hydroxylation of aromatics and the effects of substituents on reactivity have been investigated using B3LYP density functional theory computations in a realistic porphyrin model system. Two different orientations of substrate approach for addition of Compound I to benzene, and also possible subsequent rearrangement pathways have been explored. The rate-limiting Compound I addition to an aromatic carbon atom proceeds on the doublet potential energy surface via a transition state with mixed radical and cationic character. Subsequent formation of epoxide, ketone and phenol products is shown to occur with low barriers, especially starting from a cation-like rather than a radical-like tetrahedral adduct of Compound I with benzene. Effects of ring substituents were explored by calculating the activation barriers for Compound I addition in the meta and para-position for a range of monosubstituted benzenes and for more complex polysubstituted benzenes. Two structure–reactivity relationships including 8 and 10 different substituted benzenes have been determined using (i) experimentally derived Hammett σ-constants and (ii) a theoretical scale based on bond dissociation energies of hydroxyl adducts of the substrates, respectively. In both cases a dual-parameter approach that employs a combination of radical and cationic electronic descriptors gave good relationships with correlation coefficients R2 of 0.96 and 0.82, respectively. These relationships can be extended to predict the reactivity of other substituted aromatics, and thus can potentially be used in predictive drug metabolism models.

Graphical abstract: Mechanism and structure–reactivity relationships for aromatic hydroxylation by cytochrome P450

Back to tab navigation

Publication details

The article was received on 16 Jul 2004, accepted on 01 Sep 2004 and first published on 28 Sep 2004


Article type: Paper
DOI: 10.1039/B410729B
Org. Biomol. Chem., 2004,2, 2998-3005

  •   Request permissions

    Mechanism and structure–reactivity relationships for aromatic hydroxylation by cytochrome P450

    C. M. Bathelt, L. Ridder, A. J. Mulholland and J. N. Harvey, Org. Biomol. Chem., 2004, 2, 2998
    DOI: 10.1039/B410729B

Search articles by author

Spotlight

Advertisements