Conformational properties of epothilone
Conformational properties of epothilone
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DOI：
10.1021/jo991014u
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发表时间：
1999-09-17
影响因子：
3.6
通讯作者：
Zajicek, J
中科院分区：
文献类型：
--
作者：
Taylor, RE;Zajicek, J
埃博霉素是大环内酯类天然产物，由粘细菌纤维堆囊菌（Sorangium cellulosum）（So ce 90）产生，其模拟抗癌剂紫杉醇的生物活性。这些有趣的化合物已被证明结合微管蛋白，诱导微管聚合，并稳定微管动力学。埃坡霉素结构相对简单，加上其生物活性，使其成为全合成和类似物制备的一个令人兴奋的目标。到目前为止，只有有限的信息已报告关于埃坡霉素的构象在溶液中。我们已经使用了核磁共振研究和计算建模相结合，以调查这一令人兴奋的癌症化疗新铅的构象特性。一维和二维的H-1 NMR实验以及计算方法表明，埃坡霉素A更喜欢存在于两种构象中的CD 2Cl 2和DMSO/D2 O-埃坡霉素在有机和生物介质中的溶液构象的知识可以允许确定的空间排列的关键功能所需的微管蛋白结合和微管动态结构的稳定。此外，对埃坡霉素及其类似物构象特性的进一步了解可能有助于合理设计具有微管稳定特性的新化合物。
The epothilones are macrolide natural products, produced by myxobacterium Sorangium cellulosum (So ce 90), which mimic the biological activity of the anticancer agent Taxol. These interesting compounds have been shown to bind tubulin, induce microtubule polymerization, and stabilize microtubule dynamics. Coupled with its biological activity, epothilone's relatively simple structure has made it an exciting target for total synthesis and analogue preparation. To date, only limited information has been reported with regard to epothilone's conformation in solution. We have used a combination of NMR studies and computational modeling to investigate the conformational properties of this exciting new lead in cancer chemotherapy. One- and two-dimensional H-1 NMR experiments as well as computational methods suggest that the epothilone A prefers to exist in two conformations in both CD2Cl2 and DMSO/D2O-Knowledge of the solution conformation of epothilone in both organic and biological media may allow for the determination of the spatial arrangement of key functionality necessary for tubulin binding and the stabilization of microtubule dynamic structures. In addition, increased understanding of epothilone and its analogues' conformational properties may allow for the rational design of new compounds with microtubule-stabilizing properties.