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

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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.