Potent inhibition of human leukocyte elastase by 1,2,5-thiadiazolidin-3-one 1,1 dioxide-based sulfonamide derivatives
Lai, Zhong Gan, Xiangdong Wei, Liuqing Alliston, Kevin R. Yu, Hongyi Li, Yue He Groutas, William C.
Lai, Zhong
Gan, Xiangdong
Wei, Liuqing
Alliston, Kevin R.
Yu, Hongyi
Li, Yue He
Groutas, William C.
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2004-09-15
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Article
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Research Support, Non-U.S. Gov't,Research Support, U.S. Gov't, P.H.S.
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Citation
Archives of biochemistry and biophysics. 2004 Sep 15; 429(2): 191-7.
Abstract
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.
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Elsevier
Journal
Archives of Biochemistry and Biophysics
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0003-9861