Conformational preferences of natural and C3-modified epothilones in aqueous solution

M ErdΓ©lyi, B Pfeiffer, K Hauenstein, J Fohrer, J Gertsch, KH Altmann & T Carlomagno

Journal of Medicinal Chemistry 51, 1469–1473 (2008)

The conformational properties of the microtubule-stabilizing agent epothilone A (1a) and its 3-deoxy and 3-deoxy-2,3-didehydro derivatives 2 and 3 have been investigated in aqueous solution by a combination of NMR spectroscopic methods, Monte Carlo conformational searches, and NAMFIS calculations. The tubulin-bound conformation of epothilone A (1a), as previously proposed on the basis of solution NMR data, was found to represent a significant fraction of the ensemble of conformations present for the free ligands in aqueous solution.