RT Journal Article SR Electronic T1 Mechanism, Structure-Activity Studies, and Potential Applications of Glutathione S-Transferase-Catalyzed Cleavage of Sulfonamides JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 992 OP 998 VO 27 IS 9 A1 Zhiyang Zhao A1 Kenneth A. Koeplinger A1 Tillie Peterson A1 Robert A. Conradi A1 Philip S. Burton A1 Antonino Suarato A1 Robert L. Heinrikson A1 Alfredo G. Tomasselli YR 1999 UL http://dmd.aspetjournals.org/content/27/9/992.abstract AB 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. The American Society for Pharmacology and Experimental Therapeutics