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Drug Metabolism and Disposition Fast Forward
First published on November 12, 2007; DOI: 10.1124/dmd.107.018739

0090-9556/08/3602-353-360$20.00
DMD 36:353-360, 2008

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Influence of Mustard Group Structure on Pathways of in Vitro Metabolism of Anticancer N-(2-Hydroxyethyl)-3,5-dinitrobenzamide 2-Mustard Prodrugsboxs

Nuala A. Helsby, Michael A. Goldthorpe, Magdalene H. Y. Tang, Graham J. Atwell, Eileen M. Smith, William R. Wilson, and Malcolm D. Tingle

Department of Molecular Medicine and Pathology (N.A.H.), Department of Pharmacology (M.A.G., M.H.Y.T., M.D.T.), and Auckland Cancer Society Research Centre (N.A.H., G.J.A, E.M.S., W.R.W.), Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand

The dinitrobenzamide mustards are a class of bioreductive nitro-aromatic anticancer prodrugs, of which a phosphorylated analog (PR-104) is currently in clinical development. They are bioactivated by tumor reductases to form DNA cross-linking cytotoxins. However, their biotransformation in normal tissues has not been examined. Here we report the aerobic in vitro metabolism of three N-(2 hydroxyethyl)-3,5-dinitrobenzamide 2-mustards and the corresponding nonmustard analog in human, mouse, rat, and dog hepatic S9 preparations. These compounds have a range of mustard structures (–N(CH2CH2X)2 where X = H, Cl, Br, or OSO2Me). Four metabolic routes were identified: reduction of either nitro group, N-dealkylation of the mustard, plus O-acetylation, and O-glucuronidation of the hydroxyethyl side chain. Reduction of the nitro group ortho to the mustard resulted in intramolecular alkylation and is considered to be an inactivation pathway, whereas reduction of the nitro group para to the mustard generated potential DNA cross-linking cytotoxins. N-Dealkylation inactivated the mustard moiety but may result in the formation of toxic acetaldehyde derivatives. Increasing the size of the nitrogen mustard leaving group abrogated the ortho-nitroreduction and N-dealkylation routes and thereby improved overall metabolic stability but had little effect on aerobic para-nitroreduction. All four compounds underwent O-glucuronidation of the hydroxyethyl side chain and further studies to elucidate the relative importance of this pathway in vivo are in progress.

Address correspondence to: Dr. Nuala A. Helsby, Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand. E-mail: n.helsby{at}auckland.ac.nz






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