Microtubule-stabilizing activity

The total synthesis of Epothilone B 4, the first natural product (with Epothilone A) to show the same microtubule-stabilizing activity as paclitaxel (Taxol ), has attracted a great deal of attention since that activity was first reported in 1995. The total synthesis of 4 devised J. Org. Chem. 2008, 73, 9675) by Gary E. Keck of the University of Utah was based in large part on the stereoselective allyl stannane additions (e.g. 1 + 2 3) that his group originated. 

Hood KA, West LM, Rouwe B, Northcote PT, Berridge MV, Wakefield SJ, Miller JH. Peloruside A, a novel antimitotic agent with pacfitaxel-like microtubule-stabilizing activity. Cancer Res. 2002 62 3356-3360. 

Field, J.J., Singh, A.J., Kanakkanthara, A., Halafihi, T, Northcote, P.T., and Miller, J.H. (2009) Microtubule-stabilizing activity of zampanobde, a potent macrolide isolated from the Tongan marine sponge Cacospongia mycofijiensis. J, Med, Chem., 52, 7328-7332. 

Chemical Synthesis and Biological Studies of the Epothilones - Microtubule Stabilizing Agents with Enhanced Activity Against Multidrug-Resistant Cell Lines and Tumors. 

Epothilones A-E (3, 17, 48-50, Fig. 12) were isolated by Hofle and Reichen-bach and co-workers from the myxobacterium Sorangium cellulosum [80, 81]. After initial selection for their antifungal activity, the epothilones were soon shown to possess significant cytotoxicity against mammalian cells, epothilone B being the most active one [82]. Their mode of action was shown to be microtubule stabilization in a fashion very similar to that of... 

Epothilones are naturally occurring cytotoxic macrolides, which were initially isolated from a mycobacterium. Their antitumor activity is similar to that of the clinically established taxoids (Taxol, Taxotere), by interrupting the dynamic mechanism of microtubule assembly/disassembly via microtubule stabilization. In contrast to taxoids, epothilones are remarkably efficient against multidrug resistant cells. 

Kowalski RJ, Giannakakous P et al (1997) Activities of the microtubule-stabilizing agents epothilones A and B with purified tubulin and in cells resistant to paclitaxel (Taxol). J Biol Chem 272 2534-2541... 

The third chapter describes a comprehensive study of the mechanisms of activity of microtubules stabilizing drugs. Thermodynamic, kinetic, structural and functional data on microtubules stabilizing drugs are discussed in an interdisciplinary manner to generate a time-resolved picture of the interaction of the drugs with different tubulin forms. 

After the identification of the paclitaxel mechanism of action, several additional microtubule stabilizing agents were discovered from natural sources (Chart 9). Among them, epothilones (12-15) are the most studied and characterized. Epothilones A and B (12,13) were first isolated by Hofle and coworkers [54] from a myxobacterium (Sorangium cellulosum strain 90) in 1993, while their activity in stabilizing microtubule similarly to paclitaxel was reported for the first time by Bollag and co-workers in 1995 [55], Experiments with radio-labeled paclitaxel... 

This type of tubulin activity has so far been exclusively found in the four above-mentioned natural products and some derivatives, although far more then 140000 synthetic compounds and extracts have been tested. Of these four compounds, epothilones appear to be the best candidates. They are equally or even more active, e.g. up to 35 000 times better then Taxol in resistant cell lines [2]. They also have better cytotoxic potential connected to the tubulin activity, as not all microtubule stabilizers lead to sufficient cell death, and they allow extensive derivatization much faster then Taxol or discodermolide [3, 4]. Also, improvements in the applicability to patients compared to the sparingly soluble Taxol arc expected, eliminating some of the severe side effects connected to the latter drug. Since the binding sites of Taxol and epothilones overlap, epitope comparisons and models of binding... 

A large part of the early SAR work on epothilones has focused on modifications of the epoxide moiety at positions 12/13 of the macrolactone ring. These studies have demonstrateded that the presence of the epoxide ring is not an indispensible prerequisite for efficient microtubule stabilization and potent antiproliferative activity. Thus, Epo C (10) and D (11) (Figure 1-1) are virtually equipotent inducers of tubulin polymerization as Epo A and B, respectively. They are also potent inhibitors... 

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