Conformational Properties of Epothilone
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- 作者：Richard E. Taylor and Jaroslav Zajicek
- 刊名：Journal of Organic Chemistry
- 出版年：1999
- 出版时间：September 17, 1999
- 年：1999
- 卷：64
- 期：19
- 页码：7224 - 7228
- 全文大小：144K
- 年卷期：v.64,no.19(September 17, 1999)
- ISSN：1520-6904
文摘
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 interestingcompounds have been shown to bind tubulin, induce microtubule polymerization, and stabilizemicrotubule dynamics. Coupled with its biological activity, epothilone's relatively simple structurehas made it an exciting target for total synthesis and analogue preparation. To date, only limitedinformation has been reported with regard to epothilone's conformation in solution. We have useda combination of NMR studies and computational modeling to investigate the conformationalproperties of this exciting new lead in cancer chemotherapy. One- and two-dimensional 1H NMRexperiments as well as computational methods suggest that the epothilone A prefers to exist intwo conformations in both CD2Cl2 and DMSO/D2O. Knowledge of the solution conformation ofepothilone in both organic and biological media may allow for the determination of the spatialarrangement of key functionality necessary for tubulin binding and the stabilization of microtubuledynamic 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.