Clarification of new cell signaling mediated by intermediairy metabolite of claolesterol

本研究的目的是：1）检测胆固醇中间代谢产物法尼醇和海绵衍生类异戊二烯化合物的生物活性，2）分析这些化合物的化学结构与生物活性之间的关系，3）阐明类异戊二烯衍生物介导的新的细胞信号传导途径。我们发现星草酰胺A抑制钙调蛋白能力和L-型Ca通道活性。我们还从海洋毒素中分离得到了多种类异戊二烯化合物，如司他林酰胺B、C、司他林定A和司他唑A、B、C。对这些甾体酰胺类化合物的化学结构与生物活性关系进行了分析。我们推测生物碱部分的电荷数、类异戊二烯链的长度以及类异戊二烯链与生物碱之间的构型可能是钙调素拮抗作用的重要因素，在另一个实验中，我们还发现了几个化合物在体外对香叶基转移酶、金属蛋白酶（MMP）有抑制作用。从海绵中分离的Massadine和Corticatic acids特异性抑制I型香叶转移酶。相反，Callysponginol硫酸酯A和1-（12-羟基）十八烷基硫酸钠分别抑制MT-1 MMP和MMP 2。这些发现将有望为癌症、动脉粥样硬化和高血压提供新的种子化合物。

The aim of present study is that 1) examination of bioactivity of intermediary metabolite of cholesterol, such as farnesol, and marine sponge derived isoprenoid compounds, such as stellettamlde family, 2) analysis of relationship between chemical structure and bloactivilty in these compounds, and 3) clarification of new cell signaling pathway mediated by isoprenoid derivatives.In the present study, we found that stellettamide A inhibits both calmodulin ability and L-type Ca channel activity. In contrast, farnesol inhibited only IL-type Ca channel activity.We also isolated many asoprenoid compounds from marine toxin, such as stellettamide B, C, Stellettadine A, and Steliettazole A, B, C. The chemical structure-bioactivity relationship aanalysis in these stellettamide family lead. the hypotheyis to us that charge number in alkaloid part, length in isoprenoid chain and configuration between isoprenoid chain and alkaloid may be important for onset of calmodulin antagonistic action.In another experiments, we also found several compounds to inhibit geranyltransferase, metaloprotease (MMP) in vitro. Massadine and Corticatic acids isolated from marine sponges specifically inhibited geranyitransferase type I. In contrast, Callysponginol sulfate A and Sodium 1-(12-hydroxy)octadecanyl sulfate inhibited MT-1 MMP and MMP2, respectively. These findings will hold the promise of new seed compounds for cancer, atherosclerosis and hypertension.