Pharmacological study of intarcellular signal transduction using marine natural products as pharmacological tools.

近年来，细胞内信号转导的研究取得了很大的进展。然而，仍然需要使用高度选择性的药理学工具。本研究从海洋生物中分离筛选出具有细胞内信号转导通路活性的化合物，并将其作为药理学工具。在此，我们成功地发现了从输入到输出影响细胞内信号转导途径的化合物，例如（1）细胞内Ca动员，（2）PI-3激酶，和（3）细胞增殖素。从藤壶中分离的葛藤碱类似物对主动脉平滑肌具有强的血管舒张活性。这种作用是通过抑制电压依赖性钙通道介导的。从海绵中分离的Bisplacin促进肌浆网钙释放的机制与咖啡因相同。我们研究了已知的钙拮抗剂eudistomin D的构效关系。β-咔啉C-5和C-7位的卤素是Ca释放所必需的。此外，C-9位的甲基在Ca释放活性中也起着关键作用。我们还以从海绵中分离的卤醌为药理学工具，研究了PI-3激酶在细胞凋亡中的作用。我们还发现影响细胞增殖的goniodomin A抑制细胞迁移。

The study of intracellular signal transduction achieved a great advance in these days. However, highly selective pharmacological tools are still required for usage. In our study, we have search the bioactive compounds which target to intracellular signal transduction pathway, isolated from marine organisms and have applied as pharmacological tools. Here, we have succeeded in finding the compounds which affect from input to output of intracellular signal transduction pathway such as on (1) intracellular Ca mobilization, (2) PI-3 kinase, and (3) cytoskelton. Gramine analogues isolated from barnacle showed potent vasorelaxing activity on aortic smooth muscle. This effect was mediated by inhibition of voltage dependent Ca channel. Bisplacin isolated from marine sponge promoted Ca release from sarcoplasmic reticulum with same mechanism as caffeine. We have studied structure-activity relationship of eudistomin D, the known Ca releaser. Halogens in C-5 and C-7 of β-carboline are shown to be necessary for Ca release. Furthermore, methyl moiety in C-9 also representing critical role in Ca releasing activity.We have also studied the role of PI-3 kinase in apoptosis by using halenaquinone isolated from marine sponge as pharmacological tool. We have also showed that goniodomin A which affect on cytoskelton inhibit cell migration.