延伸至S和S'结合位点的纤溶酶抑制剂：S1和S2之间的协同相互作用

Inhibitors of plasmin that extend into both the S and S' binding sites: cooperative interactions between S1 and S2.

作者信息

Abato Paul, Yuen Courtney M, Cubanski Jeanne Y, Seto Christopher T

机构信息

Department of Chemistry, Brown University, 324 Brook Street, Box H, Providence, Rhode Island 02912, USA.

出版信息

J Org Chem. 2002 Feb 22;67(4):1184-91. doi: 10.1021/jo0160569.

DOI:10.1021/jo0160569

PMID:11846661

Abstract

A new procedure for the synthesis of cyclohexanone-based inhibitors of serine proteases is reported. In this procedure the reactive ketone functionality is carried through the synthesis in masked form as a TBDMS-protected alcohol. Deprotection followed by oxidation of the alcohol generates the final form of the inhibitor. Two new inhibitors, which interact with the S1-S3 and S2' subsites of plasmin, are synthesized using this procedure. Inhibitors 1 and 2 have IC50 values against plasmin of 20 and 24 microM, respectively. The inhibition studies show that cooperative binding of inhibitors in the S1 and S2 subsites of plasmin is important for determining inhibitor selectivity.

摘要

报道了一种合成基于环己酮的丝氨酸蛋白酶抑制剂的新方法。在该方法中，反应性酮官能团在合成过程中以TBDMS保护的醇的掩蔽形式存在。脱保护后醇的氧化生成抑制剂的最终形式。使用该方法合成了两种与纤溶酶的S1 - S3和S2'亚位点相互作用的新抑制剂。抑制剂1和2对纤溶酶的IC50值分别为20和24 microM。抑制研究表明，抑制剂在纤溶酶的S1和S2亚位点的协同结合对于确定抑制剂的选择性很重要。