Epothilones analogues

Fig. 7 Scheme of the structures of epothilone analogues studied in [36], the chemical differences between them, and the effect of these modifications in the free energy of binding to their site in microtubules at 35°C. Taken from [36]... 

A convergent strategy was chosen, which allows the introduction of modifications at nearly every position of the macrolactone. During the research more than 350 active epothilone analogues were synthesized and it was found that the side chains at C-15 and C-6 are responsible for the tolerability and efficacy. ... 

Precursor-directed biosynthesis has also been utilized in the biosynthesis of rapa-mycin analogues [95,96]. In addition, a partial epothilone pathway that consists of the last four modules, expressed in E. coli, was shown to process an exogenously fed synthetic precursor that mimics the natural substrate of the pathway entry point into epothilone C [97]. This result suggests that this system is set up to accept nonnatural precursors for the production of epothilone analogues. 

Buey RM, Diaz JF, Andreu JM, et al. Interaction of epothilone analogues with the paclitaxel binding site relationship between binding affinity, microtubule stabilization, and cytotoxicity. Chem Biol 2004 11 225-236. 

Employing the above combinatorial strategy as well as conventional solution-based approaches, researchers around the world have synthesized hundreds of epothilone analogues. Their screening has established a strong foundation for an SAR profile. As summarized in Scheme 26, these studies reveal the inherent molecular... 

Scheme 43 Allylic substitutirai in the preparation of a metabolically stable Epothilone analogue...

The synthetic approach to epothilone analogues is an example of extensive structural modification of the lead from nature. This approach, rather than simple peripheral derivatization of existing leads, is characterized by the replacement of... 

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