Development of a novel antitumor agent based on a marine alkaloid lamellarin

片藻素是一组多巴衍生的多环生物碱，首次从拟鳃软体动物片藻中分离出来，其中许多成员具有细胞毒性、免疫调节活性、HIV-1整合酶抑制活性和耐多药逆转活性等有趣的生物活性。我们首次完成了板藻素D （1a）和H （1b）的全合成，并发现前者对几种细胞系表现出强大的细胞毒性。为了获得片层蛋白的构效关系的基本信息，合成了10个改变双亲环上取代基的1a衍生物，并从抑制HeLa细胞集落形成的角度评价了它们的细胞毒性。结果表明，1a的C-8和C-20位置的羟基对活性的表达是重要的，而C-14位置的羟基和C-13和C-21位置的两个甲氧基对活性的表达不是必需的。

The lamellarins are a group of DOPA-derived polycyclic alkaloids which were first isolated from the prosobranch mollusc Lamellaria sp.and a number of the members are known to exhibit interesting biological activities involving cytotoxicity, immunomodulatory activity, HIV-1 integrase inhibitory activity, and MDR reversal activity.We have accomplished first total syntheses of lamellarin D (1a) and H (1b) and found that the former showed potent cytotoxicity against several cell lines. In order to obtain a basic information on the structure-activity relationship of lamellarins, ten derivatives of 1a varying the substituents on the parent ring-system were synthesized and their cytotoxicities were evaluated in terms of the inhibition of colony formation using HeLa cells.As the result, it appeared that the hydroxyl groups at C-8 and C-20 positions of 1a were important for expression of the activity, while the hydroxyl group at C-14 position and the two methoxy groups at C-13 and C-21 positions were not essential for the activity.