Structure and Function of Antitumor Ligand-Protein Complex Natural Products

抗肿瘤配体-蛋白质复合物天然产物的结构与功能

• 批准号: 11308022
• 负责人: HIRAMA Masahiro
• 金额: $ 24.74万
• 依托单位: Tohoku University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11308022/
• 关键词: Protein Complex; C-1027; Antitumor Antibiotic; Chromophore; Apoprotein; benzyne; biradical; ESR; 抗腫瘍性; 抗生物質; エンジイン; 9員環; リガンド

A number of extremely potent enediyne antitumor antibiotics have been isolated from culture filtrates of Streptomyces species. Although these antibiotics are believed to generate p-benzyne-type biradicals through cycloaromatization, no direct EPR measurements of carbon radical species generated from enediyne antibiotics have been reported. A chromoprotein antibiotic, C-1027, which is powder of a 1 : 1 complex composed of a carrier apoprotein and a DNA cleaving enediyne chromophore, shows a steady EPR spectrum at room temperature. We characterized three paramagnetic species existing in C1027 antibiotic by EPR spectroscopy. These radical species are supplied constantly by dynamic processes through hydrogen abstraction by p-benzyne type biradical from the apoprotein. The present results provide strong evidence for equilibration between the enediyne and p-benzyne form, as well as a chemical mechanism of deterioration leading to self-inactivation of the C-1027 antibiotic.

已从链霉菌属菌种的培养滤液中分离出许多极有效的烯二炔抗肿瘤抗生素。尽管这些抗生素被认为通过环芳构化产生对苯炔型双自由基，但尚未报道对烯二炔抗生素产生的碳自由基种类进行直接EPR测量。色蛋白抗生素C-1027是由载体脱辅基蛋白和DNA切割烯二炔发色团组成的1:1复合物粉末，在室温下显示出稳定的EPR谱。我们通过 EPR 光谱表征了 C1027 抗生素中存在的三种顺磁性物质。这些自由基种类通过动态过程通过对苯炔型双自由基从脱辅基蛋白中夺取氢来不断地提供。目前的结果为烯二炔和对苯炔形式之间的平衡以及导致 C-1027 抗生素自我失活的化学劣化机制提供了强有力的证据。

项目成果

平間正博: "エンジイン化合物の合成-K.I.君の物語"現代化学増刊. 36. 128-143 (2000)

Masahiro Hirama：“烯二炔化合物的合成 - K.I. 的故事”现代化学特别版。36. 128-143 (2000)。

S.Kobayashi: "Investigation of the Total Synthesis of N1999-A2 : Implication of Stereochemistry."J.Am.Chem.Soc.. (in press).

S.Kobayashi：“N1999-A2 全合成的研究：立体化学的意义”。J.Am.Chem.Soc.（正在出版）。

T.Sasaki: "Synthetic Studies toward C-1027 Chromophore : Construction of a Highly Unsaturated Macro cycle"Tetrahedron Lett.. 42. 5299-5303 (2001)

T.Sasaki：“C-1027 发色团的合成研究：高度不饱和宏观循环的构建”Tetrahedron Lett.. 42. 5299-5303 (2001)

F.Yoshimura et al.: "Synthetic Study of Kedarcidin Chromophore : Atropselective Construction of the Ansamacrolide"Tetrahedron Lett.. 40. 8281-8285 (1999)

F.Yoshimura 等人：“Kedarcidin 生色团的合成研究：Ansmacrolide 的阻转选择性构建”Tetrahedron Lett.. 40. 8281-8285 (1999)

K.Takahashi: "Concise Synthesis of the Nephthoate Conponent of N1999-A2"Synlett. 71-72 (1999)

K.Takahashi：“N1999-A2 萘甲酸酯成分的简明合成”Synlett。