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.

在我们对抗有丝分裂剂、微管组装抑制剂的研究过程中，我们发现了许多天然和合成化合物的抑制剂。它们的作用机制也已明确。本研究项目取得了以下成果：从黑曲霉球水提物中分离得到13元环肽Ustiloxins A-D，并确定了其结构。 Ustiloxins A-D 强烈抑制微管组装。 IC_<50>值为； A (0.7 uM)、B (2.8 uM)、C (4.4 uM)、D (6.6 uM)。竞争性结合分析表明，它们在微管蛋白上的结合位点与根瘤素/拟茎点蛋白的结合位点相同。通过乌斯蒂洛辛 D 的化学转化和全合成，尝试寻找乌斯蒂洛辛/拟茎点蛋白类抗生素与微管蛋白结合的最小结构。以考布他汀的 Aza 类似物作为秋水仙碱位点配体，研究该药物结合位点的功能。合成的一些化合物是微管组装的后抑制剂。本论文尝试合成具有强效抗有丝分裂活性的新型秋水仙碱位点配体curacin A的部分结构，阐明其立体化学和作用机制，并开发新的细胞毒药物。

项目成果

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。

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。”

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.Koiso et al.: "Ustiloxins, antimitotic cyclic peptides from false smut balls on rice panicles caused by Ustilaginoidea virens" J.Antibiotics. 47. 801-809

Y.Koiso 等人：“Ustiloxins，抗有丝分裂环肽，来自由黑粉菌引起的稻穗上的黑穗病球”J.Antibiotics。

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)