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

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Received for publication September 6, 2007.
Revised November 8, 2007.
Accepted for publication November 9, 2007.

Influence of mustard group structure on pathways of in vitro metabolism of anticancer N-(2-hydroxyethyl)-3,5-dinitrobenzamide 2-mustard prodrugs

Nuala A. Helsby 1*, Michael A. Goldthorpe 1, Magdalene H.Y. Tang 1, Graham J. Atwell 1, Eileen M. Smith 1, William R. Wilson 2, Malcolm D. Tingle 3

1 University of Auckland 2 The University of Auckland 3 University of Auckland - Sch. of Medicine/Hlth. Sci.

* Address correspondence to: E-mail: n.helsby{at}auckland.ac.nz

Abstract

The dinitrobenzamide mustards (DNBM) are a class of bioreductive nitroaromatic anticancer prodrugs, of which a phosphorylated analogue (PR-104) is currently in clinical development. They are bioactivated by tumour 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 non-mustard analogue 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, 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, while 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.


Key words: anticancer agents, bioactivation, prodrugs


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