Epothilone biological effects

The basic biology and pharmacology of Epo B (as the most potent and most widely studied natural epothilone) have been summarized in several previous review articles.As indicated in Section 1.1, the biological effects of the compound are based on its ability to bind to microtubules and alter the intrinsic stabihty and dynamic properties of these supramolecular structures. In cell-free in vitro systems, this is demonstrated by the prevention of Ca - or cold-induced depolymerization of preformed microtubule polymers as well as by the promotion of tubuhn polymerization (to form microtubule-like polymers) in the absence of either microtubule-associated proteins (MAPs) and/or guanosine triphosphate (GTP), at temperatures significantly below 37 °C, and in the presence of The latter... 

Epothilones A, B and E (4,5 and 6) (Fig. 2) are representative members of a new class of bacterially derived natural products which exhibit potent biological activity. Isolated by Hofle and coworkers [6] from a soil sample collected near the Zambesi river, the compounds have provided a great deal of excitement in the scientific community due to their potent cytotoxicity against a number of multiple drug-resistant tumor cell lines and because of the mechanism by which they exert this effect. Like Taxol [7], the epothilones promote the combination of a- and 3-tubulin subunits and stabilize the resulting microtubule structures. This mode of action inhibits the cell division process and is, therefore, an attractive strategy for cancer chemotherapy [7,8]. 

Fig. 23 Bridging biological space. The overlap of epothilone B (cyan carbons) and PTX (green carbons) models derived from EC reveal shared anchors between the exchangeable nucleotide site through H227 and the truncated B9-B10 loop of the beta tubulin site. Perhaps rigidifying this vector across the site is of greater importance to the MT stabilizing effect than picking up interactions within the deep hydrophobic pocket...

The potent biological activity of the epothilones rendered them hot targets for synthesis teams and it is significant that the first three syntheses of epothilone A (33) used RCM to form the macrocycle. This served to highlight the confidence of the synthetic community, with what was then a relatively new tool. However, despite the effective cyclizations, the absence of any significant selectivity for the desired (Z) -olefin geometry represented a major issue at a late stage of the synthesis [19a-cj. 

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