Potent inhibition of human leukocyte elastase by 1,2,5-thiadiazolidin-3-one 1,1 dioxide-based sulfonamide derivatives
- 作者：Lai ; Zhong ; Gan ; Xiangdong ; Wei ; Liuqing ; Alliston ; Kevin R. ; Yu ; Hongyi ; Li ; Yue H. ; Groutas ; William C.
- 关键词：Mechanism-based inhibitors ; Human leukocyte elastase ; 1 ; 2 ; 5-Thiadiazolidin-3-one 1 ; 1 dioxide scaffold
- 刊名：Archives of Biochemistry and Biophysics
- 出版年：2004
- 期刊代码：116_00039861
- 类别：ch
- 出版时间：September 15, 2004
- 卷：429
- 期：2
- 页码：191-197
- 文件大小：272 K
摘要
The design, synthesis, and in vitro biochemical evaluation of a class of mechanism-based inhibitors of human leukocyte elastase (HLE) that incorporate in their structure a 1,2,5-thiadiazolidin-3-one 1,1 dioxide scaffold with appropriate recognition and reactivity elements appended to it is described. The synthesized compounds were found to be efficient, time-dependent inhibitors of HLE. The interaction of the inhibitors with HLE is postulated to lead to the formation of a highly reactive N-sulfonyl imine (a Michael acceptor) that arises from an enzyme-induced sulfonamide fragmentation cascade. Subsequent reaction ultimately leads to the formation of a relatively stable acyl enzyme. The results cited herein demonstrate convincingly the superiority of the 1,2,5-thiadiazolidin-3-one 1,1 dioxide scaffold over other scaffolds (e.g., saccharin) in the design of inhibitors of (chymo)trypsin-like serine proteases.