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    Description

    The synthesis of hydroxylated and O- or N-dealkylated human drug metabolites (HDMs) via selective monooxygenation remains a challenging task for synthetic organic chemists. Here we report that aromatic peroxygenases (APOs; EC 1.11.2.1) secreted by the agaric fungi Agrocybe aegerita and Coprinellus radians catalyzed the H2O2-dependent selective monooxygenation of diverse drugs, including acetanilide, dextrorphan, ibuprofen, naproxen, phenacetin, sildenafil and tolbutamide. Reactions included the hydroxylation of aromatic rings and aliphatic side chains, as well as O- and N-dealkylations and exhibited different regioselectivities depending on the particular APO used. At best, desired HDMs were obtained in yields greater than 80% and with isomeric purities up to 99%. Oxidations of tolbutamide, acetanilide and carbamazepine in the presence of H2 18O2 resulted in almost complete incorporation of 18O into the corresponding products, thus establishing that these reactions are peroxygenations. The deethylation of phenacetin-d1 showed an observed intramolecular deuterium isotope effect [(kH/kD)obs] of 3.1 ± 0.2, which is consistent with the existence of a cytochrome P450-like intermediate in the reaction cycle of APOs. Our results indicate that fungal peroxygenases may be useful biocatalytic tools to prepare pharmacologically relevant drug metabolites.

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    Citation

    Poraj-Kobielska, Marzena; Kinne, Matthias; Ullrich, René; Scheibner, Katrin; Kayser, Gernot; Hammel, Kenneth E.; Hofrichter, Martin. 2011. Preparation of human drug metabolites using fungal peroxygenases. Biochemical Pharmacology. 82: 789-796. DOE 10.1016/j.bcp.2011.06.020.

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    Keywords

    Peroxidase, Peroxygenation, Hydroxylation, O-Dealkylation, N-Dealkylation, Cytochrome P450

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