Nakagawa Yu, Irie Kazuhiro, Yanagita Ryo C, Ohigashi Hajime, Tsuda Ken-ichiro, Kashiwagi Kaori, Saito Naoaki
Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan.
J Med Chem. 2006 May 4;49(9):2681-8. doi: 10.1021/jm050857c.
Conventional (alpha, betaI, betaII, gamma) and novel (delta, epsilon, eta, theta) protein kinase C (PKC) isozymes are main targets of tumor promoters, such as phorbol esters and indolactam-V (ILV). We have recently found that 1-hexyl derivatives of indolinelactam-V (2, 3), in which the indole ring of ILV was replaced with the indoline ring, showed a binding preference for novel PKCs over conventional PKCs. To develop a new ILV analogue displaying increased synthetic accessibility and improved binding selectivity for novel PKCs, we have designed 8-octyl-benzolactam-V9 (4), a simple analogue without the pyrrolidine moiety of 2 and 3. Compound 4 showed significant binding selectivity for isolated C1B domains of novel PKCs. Moreover, 4 translocated PKC epsilon and eta from the cytoplasm to the plasma membrane of HeLa cells at 1 microM, whereas other PKC isozymes did not respond even at 10 microM. These results indicate that 4 could be a selective activator for PKC epsilon and eta.
传统的（α、βI、βII、γ）和新型的（δ、ε、η、θ）蛋白激酶C（PKC）同工酶是肿瘤启动子的主要作用靶点，如佛波酯和吲哚内酰胺-V（ILV）。我们最近发现，吲哚内酰胺-V（2,3）的1-己基衍生物，其中ILV的吲哚环被二氢吲哚环取代，对新型PKC的结合偏好高于传统PKC。为了开发一种新的ILV类似物，使其具有更高的合成可及性和对新型PKC更好的结合选择性，我们设计了8-辛基-苯并内酰胺-V9（4），一种不含2和3中吡咯烷部分的简单类似物。化合物4对新型PKC的分离C1B结构域表现出显著的结合选择性。此外，4在1微摩尔浓度下可使PKCε和η从HeLa细胞的细胞质转位到质膜，而其他PKC同工酶即使在10微摩尔浓度下也无反应。这些结果表明4可能是PKCε和η的选择性激活剂。
