Correlation between site specificity and electrophilic frontier values in the metabolic hydroxylation of biphenyl, di-aromatic and CYP2D6 substrates: a molecular modelling study

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Abstract
1. A series of biphenyl, di-aromatic and CYP2D6 substrates known to undergo metabolic aromatic hydroxylation was derived from the literature, several animal species were represented. 2. Molecular orbital calculations were performed on the substrates using the AM1 semi-empirical force field and the electrophilic frontier values (f(E)) plotted for each available aromatic site. 3. A qualitative correlation was observed between the sites of oxidation and high fE values, suggesting the role of frontier orbitals in the metabolic hydroxylation of these substrates. 4. The mechanistic implications for the involvement of frontier orbitals in aromatic hydroxylation are discussed. It is proposed that electron abstraction occurs in the region of high electron density to form a radical cation. Hydrogen abstraction by Fe4+O- then occurs followed by oxygen rebound. 5. The method can be helpful in indicating regio-specificity in the metabolic hydroxylation of bi-phenyls, related di-aromatic compounds and possibly CYP2D6 aromatic substrates.