Zhao Z, Koeplinger K A, Peterson T, Conradi R A, Burton P S, Suarato A, Heinrikson R L, Tomasselli A G
Drug Metabolism, Pharmacia & Upjohn, Incorporated, Kalamazoo, Michigan, USA.
Drug Metab Dispos. 1999 Sep;27(9):992-8.
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 alpha to the sulfonyl group is required for cleavage. Substituents that withdraw electron density from the carbon atom alpha- 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 by para-CF(3) 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.
在还原型谷胱甘肽（GSH）存在的情况下，研究了强效HIV-1蛋白酶抑制剂PNU-109112的谷胱甘肽-S-转移酶（GST）催化的磺酰胺裂解机制。GST催化的磺酰胺裂解是通过GSH对底物吡啶部分的亲核攻击进行的，形成GS-对-CN-吡啶基共轭物、相应的胺和二氧化硫。对多种磺酰胺的构效关系研究表明，磺酰基α位的亲电中心是裂解所必需的。从磺酰基α位碳原子上吸电子密度的取代基有利于与GST结合的GS(-)硫醇盐的亲核攻击。磺酰胺裂解速率受亲电基团性质的显著影响；PNU-109112吡啶环上的对-CN被对-CF(3)取代可赋予其对磺酰胺裂解的稳定性。另一方面，磺酰胺的稳定性对胺部分的性质依赖性较小。这些原理可应用于对细胞GST不稳定的磺酰胺的合成，这些磺酰胺可作为释放生物活性胺的前药。肿瘤是这些磺酰胺前药特别有吸引力的靶点，因为在许多癌细胞中GST表达显著上调。另一个潜在应用可能在有机合成中，在温和条件下，GST/GSH可使作为相应活性磺酰胺的胺的保护作用逆转。
