Teshirogi I, Matsutani S, Shirahase K, Fujii Y, Yoshida T, Tanaka K, Ohtani M
Shionogi Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan.
J Med Chem. 1996 Dec 20;39(26):5183-91. doi: 10.1021/jm960437a.
We prepared several types of derivatives of thielocin B3, a very potent naturally occurring inhibitor for human nonpancreatic secretory PLA2 (sPLA2-II), and conducted a structure-activity relationship study to identify potent sPLA2-II inhibitors with the aim of developing antiinflammatory drugs. The total number of aromatic rings is critical for sPLA2-II inhibition, and the best result was obtained in the case of six rings. The structure of the central part of the inhibitors was not specific, and potent inhibitors were found among the sulfide, sulfone, ether, methylene, and amino derivatives. Although a diester of the terminal carboxylic acid lost its inhibitory activity, having both of the carboxylic acids was not necessary for expression of activity, as illustrated by a glycine derivative with the benzyl ester group 36. Among the newly synthesized derivatives, 18, 20, 29, and 36 showed very potent human sPLA2-II inhibitory activity comparable to that of natural thielocin B3. Their IC50 values are in the range 0.069-0.14 microM, and they are a class of compounds showing the most potent sPLA2-II inhibition to date.
我们制备了几种硫洛辛B3的衍生物，硫洛辛B3是一种对人非胰腺分泌型磷脂酶A2（sPLA2-II）有很强抑制作用的天然产物，我们进行了构效关系研究，以确定有效的sPLA2-II抑制剂，旨在开发抗炎药物。芳环的总数对sPLA2-II抑制作用至关重要，六元环的情况得到了最佳结果。抑制剂中心部分的结构不具有特异性，在硫化物、砜、醚、亚甲基和氨基衍生物中发现了有效的抑制剂。虽然末端羧酸的二酯失去了抑制活性，但如具有苄酯基团的甘氨酸衍生物36所示，对于活性表达而言，同时拥有两个羧酸并非必要条件。在新合成的衍生物中，18、20、29和36表现出与天然硫洛辛B3相当的非常强的人sPLA2-II抑制活性。它们的IC50值在0.069 - 0.14微摩尔范围内，是迄今为止显示出最强sPLA2-II抑制作用的一类化合物。
