7-和15-癸基苯并内酯-V8对蛋白激酶C同工酶C1结构域的合成及结合选择性

Synthesis and binding selectivity of 7- and 15-decylbenzolactone-V8 for the C1 domains of protein kinase C isozymes.

作者信息

Nakagawa Yu, Irie Kazuhiro, Yamanaka Nobuhiro, Ohigashi Hajime, Tsuda Ken-ichiro

机构信息

Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan.

出版信息

Bioorg Med Chem Lett. 2003 Sep 15;13(18):3015-9. doi: 10.1016/s0960-894x(03)00637-1.

DOI:10.1016/s0960-894x(03)00637-1

Abstract

Benzolactone-V8 (4) is a lactone analogue of the artificial tumor promoter benzolactam-V8 (1). To investigate the effect of hydrophobic substituents at positions 7 and 15 of 4 on binding selectivity for protein kinase C (PKC) isozymes, 7- and 15-decylbenzolactone-V8 (7, 8) were synthesized and their binding affinities for synthetic PKC isozyme C1 peptides were examined. Compound 8 showed moderate selectivity for novel PKC isozymes similar to 9-decylbenzolactone-V8 (5), while 7 was less selective. Compounds 7 and 8 showed no significant selectivity among novel PKC isozymes unlike 8-decylbenzolactone-V8 (6). These results indicate that the introduction of a hydrophobic substituent at position 8 of 4 is most effective in the development of PKC epsilon- and PKCeta-selective binders.

摘要

苯并内酯-V8（4）是人工肿瘤启动子苯并内酰胺-V8（1）的内酯类似物。为了研究4的7位和15位疏水取代基对蛋白激酶C（PKC）同工酶结合选择性的影响，合成了7-和15-癸基苯并内酯-V8（7、8），并检测了它们对合成PKC同工酶C1肽的结合亲和力。化合物8对新型PKC同工酶表现出适度的选择性，类似于9-癸基苯并内酯-V8（5），而7的选择性较低。与8-癸基苯并内酯-V8（6）不同，化合物7和8在新型PKC同工酶之间没有表现出显著的选择性。这些结果表明，在4的8位引入疏水取代基对开发PKCε和PKCη选择性结合剂最为有效。

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