Regulators of Microtubule Assembly : Molecular Recognition Mechanism and Developement of New Regulators.

微管组装调节器：分子识别机制和新型调节器的开发。

• 批准号: 05453178
• 负责人: IWASAKI Shigeo
• 金额: $ 4.8万
• 依托单位: Institute of Molecular and Cellular Biosciences The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (B)
• 财政年份: 1993
• 资助国家: 日本
• 起止时间: 1993 至 1994
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-05453178/
• 关键词: microtubules; tubulin; molecular recognition; ustiloxin; aza-combretastatin; curacin; 有糸分裂阻害剤; 分子確認; キュラシンA; 微小管機能制御物質; 分子認識; リゾキシン; フォモプシン

In the course of our studies on the antimitotic agents, inhibitors of microtubule assembly, we have discovered a number of inhibitors as the natural and synthetic compounds. Their action mechanisms have also been clarified. In this research project, the followings have been achieved.Ustiloxins A-D,13-membered cyclic peptides, were isolated from the water extract of false smut balls (ina-kouji), and their structures were determined. Ustiloxins A-D strongly inhibited microtubule assembly. The IC_<50> values were ; A (0.7 uM), B (2.8 uM), C (4.4 uM), D (6.6 uM). Competitive binding assys revealed that their binding site on tubulin is identical to that of rhizoxin/phomopsin. Approaches to find the minimal structure of ustiloxin/phomopsin class antibiotics to bind to tubulin have been attempted by both chemical transformation of ustiloxin D and total synthasis.Aza-analogs of combretastatin were deviced as the colchicine-site ligands to study the function of this drug-binding site. Some compounds synthesized were postent inhibitors of microtubule assembly.Synthesis of the partial structure of curacin A,a novel colchicine site ligand having potent antimitotic activity, were attempted to clarify its stereochemistry and action mechanism, and also to develope new cytotoxic agents.

在关于抗魔法剂的研究过程中，微管组装的抑制剂，我们发现了许多抑制剂作为天然和合成化合物。他们的动作机制也得到了澄清。在这项研究项目中，已经实现了以下内容。从虚假的Smut Balls（Ina-Kouji）的水提取物中分离出13元的环状肽A-D，并确定其结构。 USTILOXINS A-D强烈抑制微管组件。 IC_ <50>值为； a（0.7 um），b（2.8 um），c（4.4 um），d（6.6 um）。竞争性结合鉴定表明，它们在小管蛋白上的结合位点与根蛋白毒素/phomopsin的结合位点相同。发现乌斯特尔氧蛋白D的化学转化和combretastatin的全合成蛋白的化学转化，已尝试发现紫氧蛋白/phomopsin类抗生素与微管蛋白结合的最小结构的方法。合成的一些化合物是微管组装的邮政抑制剂。策素A的部分结构（一种具有有效抗染色性活性的新型秋水仙碱位点配体）的结构，以阐明其立体化学化学和动作机制，并取代新的细胞毒素。

项目成果

Nakada M.et al.: "The first total synthesis of the antitumor macrolide rhizoxin." Tetrahedron Lett.34. 1039-1042 (1993)

Nakada M.等人：“抗肿瘤大环内酯根毒素的首次全合成。”

R.Mutoh et al.: "Synthetivc approach toward the minimal active structure of phomopsin-ustiloxin class of antibiotics" Heterocycles. 41. 9-12 (1995)

R.Mutoh 等人：“拟茎点菌素-乌司洛辛类抗生素最小活性结构的合成方法”杂环。

Y.Li et al.: "Interaction of marine toxin dolastatin 10 with porcine brain tubulin. Competitive inhibition of rhizoxin and phomopsin A binding" Chemico-Bio Interactions. 93. 175-183 (1994)

Y.Li 等人：“海洋毒素多拉司他汀 10 与猪脑微管蛋白的相互作用。根瘤素和拟茎点菌素 A 结合的竞争性抑制”化学-生物相互作用。

Y.Li,他: "Interaction of a marine toxin dolastatin 10 with porcin 〜" Chemico-Bio.Interactions. 93. 175-183 (1994)

Y.Li 等人：“海洋毒素多拉司他汀 10 与猪的相互作用 ~”Chemico-Bio.Interactions 93. 175-183 (1994)

R.Mutoh et al.: "Synthetic approach toward the minimal active structure of phomopsin-ustiloxin class of antibiotics" Heterocycles. 41. 9-12 (1995)

R.Mutoh 等人：“拟茎点菌素-乌司洛辛类抗生素最小活性结构的合成方法”杂环。