77(P64) コルヒチン部位に結合するチューブリン重合阻害剤のデザインと活性構造の探索(ポスター発表の部)
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概要
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Combretastatin A-4 isolated from Combretum caffrum is reported to be one of the most potent anti-mitotic agents which strongly inhibits the polymerization of brain tubulin by binding to the colchicine site (CLC site). Common elements can be found among the structures of the active combretastatins congeners and of other well-known CLC site ligands such as colchicine, steganacin and podophyllotoxin. It has been proposed that CLC site ligands retain optically active conformation at the binding site of tubulin. Although Combretastatin A-4 is not a chiral molecule, it is expected to exist as chiral conformer induced by the binding to tubulin. A series of conformationary restricted heterocyclic combretastatin analogs have been synthesized from (R,R)-6, (S,S)-6 and (RS,SR)-6 and their inhibitory activity of microtubule assembly was evaluated. (4S,5S)-4-(4-Methoxyphenyl)-5-(3,4,5-trimethoxyphenyl)-1,3-dioxolane ((S,S)-9) showed moderate antimitotic activity while its enantiomer and other diastereomers synthesized were inactive. Curacin A is a powerful antimitotic agent isolated from an Caribbean cyanobacterium Lyngbya majuscula in 1994. Altough curacin A binds to CLC site as combretastatin A-4 does, there is no structural similarity to other known CLC site ligands. A variety of side chain analogs of curacin A were synthesized and the effect to in vitro micritubule polymerization was examined. However, compounds synthesized showed weak or no activity suggesting that the side chain was restrictly recognided by microtubule proteins.
- 1997-07-20
著者
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小磯 邦子
東大分生研
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岩崎 成夫
東大分生研
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岩崎 成夫
北里研究所:生物機能研究所
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高橋 正人
東大分生研
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白井 隆一
東大分生研
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西川 明日香
東大分生研
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白井 隆一
奈良先端科学技術大学院大学:物質科学教育研究センター
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小野田 俊彦
東大分生研
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岡部 拓郎
東大分生研
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西川 明日香
奈良先端大物質科学センター
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