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Research ArticleArticle

Mechanism, Structure-Activity Studies, and Potential Applications of Glutathione S-Transferase-Catalyzed Cleavage of Sulfonamides

Zhiyang Zhao, Kenneth A. Koeplinger, Tillie Peterson, Robert A. Conradi, Philip S. Burton, Antonino Suarato, Robert L. Heinrikson and Alfredo G. Tomasselli
Drug Metabolism and Disposition September 1999, 27 (9) 992-998;
Zhiyang Zhao
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Kenneth A. Koeplinger
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Tillie Peterson
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Robert A. Conradi
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Philip S. Burton
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Antonino Suarato
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Robert L. Heinrikson
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Alfredo G. Tomasselli
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Abstract

The mechanism of sulfonamide cleavage of PNU-109112, a potent HIV-1 protease inhibitor, by glutathione-S-transferase (GST) was investigated in the presence of reduced GSH. GST-catalyzed sulfonamide cleavage takes place via the nucleophilic attack of GSH on the pyridine moiety of the substrate with formation of the GS-para-CN-pyridinyl conjugate, the corresponding amine, and sulfur dioxide. Structure activity studies with a variety of sulfonamides indicate that an electrophilic center α to the sulfonyl group is required for cleavage. Substituents that withdraw electron density from the carbon atom α- to the sulfonyl group facilitate nucleophilic attack by the GS− thiolate bound to GST. The rate of sulfonamide cleavage is markedly affected by the nature of the electrophilic group; replacement of para-CN bypara-CF3 on the pyridine ring of PNU-109112 confers stability against sulfonamide cleavage. On the other hand, stability of sulfonamides is less dependent on the nature of the amine moiety. These principles can be applied to the synthesis of sulfonamides, labile toward cellular GST, that may serve as prodrugs for release of bioactive amines. Tumors are particularly attractive targets for these sulfonamide prodrugs as GST expression is significantly up-regulated in many cancer cells. Another potential application could be in organic synthesis, where protection of amines as the corresponding activated sulfonamides can be reversed by GST/GSH under mild conditions.

Footnotes

  • Send reprint requests to: Dr. A.G. Tomasselli, 7240–267-118, 301 Henrietta St., Kalamazoo, MI 49007-4940. E-mail:alfredo.tomasselli{at}am.pnu.com

  • ↵1 Present address: Drug Metabolism, Central Research, Pfizer, Inc., Groton, CT 06340.

  • Abbreviations used are::
    GST
    glutathione-S-transferase
    MDR
    multidrug resistance
    EA
    ethacrynic acid
    CDNB
    chlorodinitrobenzene (1-chloro-2,4-dinitrobenzene)
    Hg(II) chloride
    mercuric chloride
    ESI
    electrospray ionization
    MDCK
    Madine-Darby canine kidney
    • Received February 11, 1999.
    • Accepted May 20, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 27 (9)
Drug Metabolism and Disposition
Vol. 27, Issue 9
1 Sep 1999
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Research ArticleArticle

Mechanism, Structure-Activity Studies, and Potential Applications of Glutathione S-Transferase-Catalyzed Cleavage of Sulfonamides

Zhiyang Zhao, Kenneth A. Koeplinger, Tillie Peterson, Robert A. Conradi, Philip S. Burton, Antonino Suarato, Robert L. Heinrikson and Alfredo G. Tomasselli
Drug Metabolism and Disposition September 1, 1999, 27 (9) 992-998;

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Research ArticleArticle

Mechanism, Structure-Activity Studies, and Potential Applications of Glutathione S-Transferase-Catalyzed Cleavage of Sulfonamides

Zhiyang Zhao, Kenneth A. Koeplinger, Tillie Peterson, Robert A. Conradi, Philip S. Burton, Antonino Suarato, Robert L. Heinrikson and Alfredo G. Tomasselli
Drug Metabolism and Disposition September 1, 1999, 27 (9) 992-998;
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