Search for New Anti-Cancer Seeds Targeting for cell Differentiation and cell Cycle

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In search of new anti-cancer substance from marine organisms, we have constructed the following four bioassay systems and screened the extracts of the marine sponges, which we have collected in the fields.(1) Search for differentiation inducer against K562 cells to erythrocyte or macrophage(2) search for inducer of neuronal differentiation against neuroblastoma Neuro 2A cells(3) search for inducer against ras-transformed cells to normal cell(4) search for selective inhibitor of cell cycle. we have screened about 400 extracts of marine sponges, and the active extracts were further subjected to fractionation and isolation on the guidance of the above bioassay systems. The results summarize as follows.1. As for the neuritogenic long-chain polyketide, lembehyne A, we achieved the first total synthesis. Further analong synthesis of lembehyne A and structure-activity relationship study clarified that 3R-hydroxy-1-yen structure and proper length of long-chain play a important role for neurito … More genic activity of lembehyne A. Lembehyne A induced increase of cycline-dependent kinase P21 and arrested cell cycle of Neuro 2A cell at the G1 phase and also esterase. In order to elucidate target protein of lembehyne A, we designed and synthesized a radioactive photoaffinity probe of lembehyne A.2. An alkaloid, hymenialdisine, isolated from Indonesian marine sponge induced differentiation of K562 cells to macrophage. Hymenialdisine induced morphological changes, G2/M arrest of cell cycle, reduction of NBT, and increase of acetylcholine esterase against K562 cells. Hymenialdisine also inhibited CDK1/cvcB complex, which might be one of target protein.3. Pyridoacridine alkaloids isolated from Indonesian marine sponge induced neuritogenesis against Neuro 2A cell and increase of acetylcholine esterase lebel and arresed cell cycle at the G2/M phase.4. A novel anthracycline, komodoquinone A, isolated from the solid-state fermentation of streptomyces sp. Induced differentiation and G1 arrest against Neuro 2A cells. Less