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J Med Chem. 2008 Dec 25;51(24):8173-7. doi: 10.1021/jm8010417.

The fourth molybdenum containing enzyme mARC: cloning and involvement in the activation of N-hydroxylated prodrugs.

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1
Pharmaceutical Institute, Department of Pharmaceutical and Medicinal Chemistry, Christian-Albrechts-University of Kiel, Gutenbergstrasse 76, D-24118 Kiel, Germany.

Abstract

The recently discovered mammalian molybdoprotein mARC1 is capable of reducing N-hydroxylated compounds. Upon reconstitution with cytochrome b(5) and b(5) reductase, benzamidoxime, pentamidine, and diminazene amidoximes, N-hydroxymelagatran, guanoxabenz, and N-hydroxydebrisoquine are efficiently reduced. These substances are amidoxime/N-hydroxyguanidine prodrugs, leading to improved bioavailability compared to the active amidines/guanidines. Thus, the recombinant enzyme allows prediction about in vivo reduction of N-hydroxylated prodrugs. Furthermore, the prodrug principle is not dependent on cytochrome P450 enzymes.

PMID:
19053771
DOI:
10.1021/jm8010417
[Indexed for MEDLINE]
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