101(P-36) 海綿由来の血管新生阻害物質bastadin 6の合成研究(ポスター発表の部)
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概要
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Angiogenesis, a formation of new blood capillaries from preexisting blood vessels, is critical for tumor growth and metastasis, and angiogenic inhibitor have attracted much attention as novel chemotherapeutic agents for the treatment of cancer. In the course of our study on the bioactive substances from marine organisms, we focused on search for anti-angiogenic substances and isolated bastadins from Indonesian marine sponge Ianthella basta. Bastadin 6 (1), a major constituent of bastadins, showed a selective growth inhibitiory activity against human umbilical vein endothelial cells (HUVECs) comparing with fibroblast or some tumor cells. In order to establish a practical synthetic method, we studied total synthesis of bastadin 6 (1). The key reaction of our synthetic route is oxidative coupling of o,o'-dibromophenol derivative. In the initial study, oxidative coupling reaction of phenol 4 was smoothly proceeded by Ce(NH_4)_2(NO_3)_6 (CAN), but no coupling product was obtained in the case of phenol 5. We speculated that oxime moiety in the molecule might interrupt the reaction. Indeed, the coupling of oxime-protected derivative 6 gave the desired product 7 in acceptable yield. Condensation of the two segments gave compound 9, and subsequent macrocycle formation and deprotection gave bastadin 6 (1), total 9 steps in 23 % overall yield. Protection of oxime moiety was found to be also crucial for the amide bond formation in the segment coupling and intramolecular cyclization. We also studied structure-activity relationship of bastadin 6 (1) in order to analyze the structure-requirement for the anti-angiogenic activity of 1. Protection of oxime moiety was found to cause a complete loss of the growth inhibitory activity of HUVEC, and non-oxime analog 16 also showed a significantly weak activity. Debrominated analog 17 showed the similar activity as 16. Further biological studies are in progress.
- 天然有機化合物討論会の論文
- 2004-10-01
著者
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青木 俊二
阪大院・薬
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古徳 直之
阪大院・薬
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趙 碩煥
阪大院・薬
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辻田 博昭
阪大院・薬
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小林 資正
阪大院・薬
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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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平松 篤
阪大院・薬
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森 千夏
阪大院・薬
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Kobayashi Masao
Pharmaceutical Research Laboratory Tanabe Seiyaku Co. Ltd.
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