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Research ArticleArticle

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, Michael A. Goldthorpe, Magdalene H. Y. Tang, Graham J. Atwell, Eileen M. Smith, William R. Wilson and Malcolm D. Tingle
Drug Metabolism and Disposition February 2008, 36 (2) 353-360; DOI: https://doi.org/10.1124/dmd.107.018739
Nuala A. Helsby
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Michael A. Goldthorpe
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Magdalene H. Y. Tang
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Graham J. Atwell
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Eileen M. Smith
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William R. Wilson
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Malcolm D. Tingle
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Abstract

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.

Footnotes

  • Financial support for this project was provided by the Auckland Medical Research Foundation and the Health Research Council of New Zealand.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.107.018739.

  • ABBREVIATIONS: DNBM, dinitrobenzamide mustard; 2,4-DNBM, 2,4-dinitrobenzamide 5-mustard; SN 23862, bischloroethyl-2,4-dinitrobenzamide; 3,5-DNBM, 3,5-dinitrobenzamide 2-mustard; PR-104, 2-((2-bromoethyl)-2-{[(2-hydroxyethyl)amino]carbonyl}-4,6-dinitroanilino)ethyl methanesulfonate phosphate ester; CB 1954, 5-(aziridin-1-yl)-2,4-dinitrobenzamide; SN 27858, 2-((2-bromoethyl)-2-{[(2-hydroxyethyl)amino]carbonyl}-4,6-dinitroanilino)ethyl methanesulfonate, PR-104A, 1; SN 29546, 2-((2-chloroethyl)-2-{[(2-hydroxyethyl)amino]carbonyl}-4,6-dinitroanilino)ethyl methanesulfonate, 2; SN 27686, 2-[bis(2-bromoethyl)amino]-N-(2-hydroxyethyl)-3,5-dinitrobenzamide, 3; SN 29893, 2-(diethylamino)-N-(2-hydroxyethyl)-3,5-dinitrobenzamide, 4; LC, liquid chromatography; MS, mass spectrometry; HPLC, high-performance liquid chromatography; UDPGA, UDP-glucuronic acid; Rt, retention time; amu, atomic mass units.

  • ↵s⃞ The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

    • Received September 5, 2007.
    • Accepted November 9, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 36 (2)
Drug Metabolism and Disposition
Vol. 36, Issue 2
1 Feb 2008
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Research ArticleArticle

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, Michael A. Goldthorpe, Magdalene H. Y. Tang, Graham J. Atwell, Eileen M. Smith, William R. Wilson and Malcolm D. Tingle
Drug Metabolism and Disposition February 1, 2008, 36 (2) 353-360; DOI: https://doi.org/10.1124/dmd.107.018739

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Research ArticleArticle

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, Michael A. Goldthorpe, Magdalene H. Y. Tang, Graham J. Atwell, Eileen M. Smith, William R. Wilson and Malcolm D. Tingle
Drug Metabolism and Disposition February 1, 2008, 36 (2) 353-360; DOI: https://doi.org/10.1124/dmd.107.018739
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