Action mechanism and molecular design of biologically active enediyne compounds

生物活性烯二炔化合物的作用机制及分子设计

• 批准号: 07408033
• 负责人: SUGIURA Yukio
• 金额: $ 4.74万
• 依托单位: KYOTO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 1995
• 资助国家: 日本
• 起止时间: 1995 至 1997
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07408033/
• 关键词: Antitumor antibiotic; DNA cleavage; Radical formation; Enediyne; Dynemicin; C-1027; Esperamicin; Molecular design; 抗生物質; DNA設計; DNA認識; 抗癌活性; 作用発現機構

The enediyne antibiotics possess unprecedented chemical structure, potent anticancer activity, and a fascinating mode of bioligical action.In order to clarify the action mechanism of a new enediyne antibiotic C-1027 isolated in Japan, we investigated the C-1027 chromophore-d (GTATC)_2 interaction mode by high resolution NMR method. The NMR results clearly indicate both intercalation and minor groove binding modes with the enediyne chromophore. In the NOESY spectra, the disruption of the sequential connectivities of the base and sugar protons strongly supports intercalative binding at the T_4-A_5 step. The NMR observation is also consistent with intercalation of the benzoxazolinate at the (T_4・A_3)-(A_5・T_2) step. The complex model shows that the DNA oligomer remains in a B-form conformation, although minor groove width (6.04*) are somewhat widened by the occupation of the bulky chromophore. On the other hand, we designed and synthesized 9-membered masked enediyne analogues with DNA intercalator and/or sugar moiety. These new compounds gave high DNA cleaving activity and sequence-specific cleavage. In particular, the sugar attached enediyne analogues are of great promise in respect of antitumor activity and bio-targeting.

烯二炔抗生素具有前所未有的化学结构、强大的抗癌活性和令人着迷的生物作用模式。为了阐明日本分离的新型烯二炔抗生素C-1027的作用机制，我们研究了C-1027发色团-d（GTATC） )_2 高分辨率 NMR 方法的相互作用模式 NMR 结果清楚地表明了 NOESY 中与烯二炔发色团的嵌入和小沟结合模式。从光谱中可以看出，碱基和糖质子连续连接的破坏强烈支持了 T_4-A_5 步骤中的插入结合。NMR 观察结果也与 (T_4·A_3)-(A_5·T_2) 步骤中苯并恶唑啉的插入一致。复杂模型表明，DNA 寡聚物仍保持 B 型构象，尽管小凹槽宽度 (6.04*) 由于大体积的占据而有所加宽。另一方面，我们设计并合成了具有 DNA 嵌入剂和/或糖部分的 9 元掩蔽烯二炔类似物，这些新化合物具有高 DNA 切割活性和序列特异性切割。在抗肿瘤活性和生物靶向方面具有巨大前景。

项目成果

T.Takahashi: "Synthesis of Nine-membered,Masked Enediyne Analogues with DNA Intercalators" Angew.Chem.Int.Ed.Engl.36. 1524-1526 (1997)

T.Takahashi：“用 DNA 嵌入剂合成九元掩蔽烯二炔类似物”Angew.Chem.Int.Ed.Engl.36。

Takahashi, T..et al.: "Synthesis of nine-membered, masked enediyne analogues with DNA intercalators" Angew.Chem.Int.Ed.Engl.36. 1524-1526 (1997)

Takahashi, T..et al.：“用 DNA 嵌入剂合成九元掩蔽烯二炔类似物”Angew.Chem.Int.Ed.Engl.36。

Y.Okuno: "Interaction of C-1027 chromophore with d (GTATAC)_2 : A binding model based on NMR experiments" J.Am.Chem.Soc.118・19. 4729-4730 (1996)

Y.Okuno：“C-1027发色团与d(GTATAC)_2的相互作用：基于NMR实验的结合模型”J.Am.Chem.Soc.118・19(1996)。