Lai Zhong, Gan Xiangdong, Wei Liuqing, Alliston Kevin R, Yu Hongyi, Li Yue H, Groutas William C
Department of Chemistry, Wichita State University, Wichita, Kansas 67260, USA.
Arch Biochem Biophys. 2004 Sep 15;429(2):191-7. doi: 10.1016/j.abb.2004.06.014.
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.
描述了一类基于机制的人白细胞弹性蛋白酶（HLE）抑制剂的设计、合成及体外生化评价，这类抑制剂的结构中含有1,2,5 - 噻二唑烷 - 3 - 酮1,1 - 二氧化物支架，并带有适当的识别和反应性基团。发现合成的化合物是高效的、时间依赖性的HLE抑制剂。推测抑制剂与HLE的相互作用会导致形成一种高反应性的N - 磺酰基亚胺（一种迈克尔受体），它由酶诱导的磺酰胺断裂级联反应产生。随后的反应最终导致形成相对稳定的酰基酶。本文引用的结果令人信服地证明了在设计（胰凝乳）蛋白酶样丝氨酸蛋白酶抑制剂时，1,2,5 - 噻二唑烷 - 3 - 酮1,1 - 二氧化物支架相对于其他支架（如糖精）的优越性。
