Conformational properties of epothilone

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.