Conformation-activity relationships in polyketide natural products: a new perspective on the rational design of epothilone analogues.
Conformation-activity relationships in polyketide natural products: a new perspective on the rational design of epothilone analogues.
复制标题
聚酮化合物天然产物的构象-活性关系：埃坡霉素类似物合理设计的新视角。
DOI：
10.1021/ja028196l
复制
发表时间：
2003
影响因子：
15
通讯作者：
Zhou,Yiqing
中科院分区：
文献类型：
--
作者：
Taylor,RichardE;Chen,Yue;Beatty,Alicia;Myles,DavidC;Zhou,Yiqing
报道了埃博霉素C_（14）-甲基类似物B和D的合成。使用计算方法，X-射线晶体学和NMR研究的构象分析表明，在C14的立体化学的环氧化物区域的构象有显着的影响。生物测定表明，它们的生物活性存在显着差异。稳定构象异构体I的取代保留了显著的生物活性。相反，取代稳定构象II提供类似物没有可测量的细胞毒性。构象-活性关系强烈支持构象I作为埃坡霉素环氧化物区域的生物活性构象的重要性。该方法为合理设计具有生物活性的聚酮化合物提供了一个新的视角。
The syntheses of C14-methyl analogues of epothilone B and D are described. Conformational analysis using computational methods, X-ray crystallography, and NMR studies showed that the stereochemistry at C14 has a pronounced effect on the conformation of the epoxide region. Biological assays indicated significant differences in their biological activity. Substitution which stabilized conformer I retained significant biological activity. In contrast, substitution which stabilized conformer II provided analogues with no measurable cytotoxicity. The conformation−activity relationships strongly support the importance of conformer I as the bioactive conformation of the epoxide region of epothilone. The approach presented here offers a new perspective on rational design of modified biologically active polyketides.