15 海綿由来新規アルカロイドcortistatin類の化学構造とHUVECs選択的増殖抑制効果(口頭発表の部)
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概要
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Angiogenesis is the process of generating new capillary blood vessels. Tumor growth and metastasis are highly dependent on angiogenesis. Therefore, specific inhibitors of angiogenesis are expected as promising antitumor agents. In the course of our study of bioactive substances from marine organisms, we focused on a search for anti-angiogenic substances and have isolated four novel steroidal alkaloids named cortistatins A (1), B (2), C (3), and D (4) consisting of abeo-9(10-19)-androstane and isoquinoline skeletons, from the Indonesian marine sponge Corticium simplex. The absolute stereostructures of 1-4 were elucidated by detailed 2D-NMR, CD, and X-ray crystallographic analyses. We have further isolated the abeo-9(10-19)-androstane-type alkaloids named cortistatins E (5), F (6), G (7) and H (8) having N-methyl piperidine or pyridine moiety in the side chain from the same marine sponge. Compounds 1, 2, 3, and 4 inhibited proliferation of human umbilical vein endothelial cells (HUVECs) with high selectivity. Among four substances, 1 showed the strongest anti-proliferative activity (IC_<50>=0.0018μM) against HUVECs, in which selective index was more than 3000-fold in comparison with normal fibroblast or several tumor cells, while 5, 6, 7, and 8 didn't show selective anti-proliferative activity. The anti-angiogenic property of 1 was examined by the migration assay using a chemotactic chamber and the Matrigel tubular formation assay. Compound 1 inhibited migration and tubular formation of HUVECs induced by VEGF or bFGF at 2-200nM concentrations, dose dependently. To elucidate the action mechanism of 1, we examined the influence of 1 on ERK pathway which was activated by growth factor signal. Compound 1 didn't inhibit the ERK phosphorylation at 10nM-1μM concentrations.
- 天然有機化合物討論会の論文
- 2006-09-15
著者
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青木 俊二
兵庫医療大薬
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小林 資正
阪大院薬
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古徳 直之
阪大院薬
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渡部 康雄
阪大院薬
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田辺 大樹
阪大院薬
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青木 俊二
阪大院薬
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真川 万実
阪大院薬
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Kobayashi Masao
Pharmaceutical Research Laboratory Tanabe Seiyaku Co. Ltd.
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