Potent inhibition of human leukocyte elastase by 1,2,5-thiadiazolidin-3-one 1,1 dioxide-based sulfonamide derivatives
| Autor: | Kevin R. Alliston, Hongyi Yu, Liuqing Wei, Yue He Li, Xiangdong Gan, William C. Groutas, Zhong Lai |
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| Rok vydání: | 2004 |
| Předmět: |
chemistry.chemical_classification
Proteases Sulfonamides Magnetic Resonance Spectroscopy Stereochemistry Imine Biophysics Biochemistry In vitro Sulfonamide Cyclic S-Oxides Serine chemistry.chemical_compound Thiazoles Enzyme chemistry Michael reaction Humans Reactivity (chemistry) Enzyme Inhibitors Leukocyte Elastase Molecular Biology |
| Zdroj: | Archives of biochemistry and biophysics. 429(2) |
| ISSN: | 0003-9861 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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