CORRELATION BETWEEN SITE-SPECIFICITY AND ELECTROPHILIC FRONTIER VALUES IN THE METABOLIC HYDROXYLATION OF BIPHENYL, DI-AROMATIC AND CYP2D6 SUBSTRATES - A MOLECULAR MODELING STUDY

1. A series of biphenyl, di-aromatic and CYP2D6 substrates known to un dergo metabolic aromatic hydroxylation was derived from the literature , several animal species were represented. 2. Molecular orbital calcul ations were performed on the substrates using the AM1 semi-empirical f orce field and the electrophilic frontier values (f(E)) plotted for ea ch available aromatic site. 3. A qualitative correlation was observed between the sites of oxidation and high f(E) values, suggesting the ro le of frontier orbitals in the metabolic hydroxylation of these substr ates. 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 foll owed by oxygen rebound. 5. The method can be helpful in indicating reg io-specificity in the metabolic hydroxylation of bi-phenyls, related d i-aromatic compounds and possibly CYP2D6 aromatic substrates.