Action mechanism and molecular design of biologically active enediyne compounds

依地因抗生物学可能不存在未预先确定的化学结构、潜在的抗生物活性和一种模糊的模式。在日本，我们根据高分辨率核磁共振方法研究了C-1027交互模式。核磁共振结果清楚地表明了与艾尼替恩变色灯的两种干扰和小沟槽结合模式。在NOESY的特殊情况下，破坏了base和糖protons在T_4-A_5步骤中的连续联系，这是一个强有力的支持。核磁共振观测在（T_4·A_3）-（A_5·T_2）步骤中也是一致的。一个复杂的模型显示，DNA聚合物残留在B形结构中，即使是较小的地面宽度（6.04*）是由大量变色器的占用所需要的。在另一方面，我们设计并合成了9个成员的掩蔽剂模拟与DNA调节器和/或糖动力学。这些新的化合物提供了更高的DNA清除活动和序列特定清除。在特定的，糖附着的Enediyne模拟是对拮抗活性和生物目标的尊重的一个很好的承诺。

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.