QSAR epothilones

At the end of the equilibration protocol, a 3D-QSAR equation with a good correlation (r = 0.81) and a low root mean square deviation (rmsd 0.85) on the estimated interaction energies were derived. The predictive power of the model was evaluated with a test set of 11 taxanes and epothilones, obtaining a prediction coefficient of 0.78. 

Fig. 8 Overlap of the three pharmacophores representing the interactions found for paclitaxel in the 1JFF structure (A), epothilone A in the NMR-derived structure (B), and epothilone A in the QSAR model from Botta and co-workers (C), respectively. Blue C7-OH (epothilones) oxetane ring (paclitaxel) red C13 carbon (epothilones) phenyl ring (paclitaxel) yellow Cl carbonyl oxygen (epothilones) Cl carbonyl oxygen (paclitaxel) purple thiazole ring (epothilone) C3 benzamide (paclitaxel). (3-tubulin monomer is represented as a green cartoon and residues involved in hydrogen bonds are in orange (hydrogens are omitted for sake of clarity)...

With the established synthetic routes in hand, many of the more obvious derivatives have been synthesized in order to obtain a quantitative structure-activity relationship (QSAR) and to maybe enhance the activitiy and pharmacological profile of epothilones. These derivatives also include epothilone E (2e, Scheme 13), which is emphasized because it also is an active natural derivative, hydroxylated at C21. 

Manetti F, Forli S, Maccari L, et al. 3D QSAR studies of the interaction between (3-tubulin and microtubule stabilizing antimitotic agents (MSAA). A combined pharmacophore generation and pseudoreceptor modeling approach applied to taxanes and epothilones. II Farmaco 2003 58 357-361... 

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