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.

NMR的结果清楚地表明插入和较小的凹槽结合模式与Enediyne发色团。在Noesy光谱中，碱基和糖质子的顺序连通性的破坏在T_4-A_5步骤上强烈支持互算结合。 NMR观察也与在（T_4・A_3） - （A_5 ・ t_2）步骤（t_4・A_3）处的苯唑唑酯插入一致。该复杂模型表明，DNA低聚物保留在B形构象中，尽管较小的凹槽宽度（6.04*）是由于笨重的发色团的占用而宽度的。另一方面，我们设计和合成了9元的蒙面iOsporlyne类似物，并使用了DNA插入量和/或糖部分。这些新化合物具有高DNA切割活性和序列特异性裂解。特别是，糖附着的就业类似物在抗肿瘤活性和生物靶向方面具有很大的希望。

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。

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)。

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。