Epothilone B and its Derivatives as Novel Antitumor Drugs

The chemotherapy of cancer strongly depends on the nature of the individual tumor under consideration. For instance, tumors located in hormone dependent organs such as the ovaries, breasts, etc. are treated with antihormons, e.g. anti-estrogens or anti-androgens, which retard the growth of the individual tissue and thus also that of the tumor enclosed. In the regular case, however, the drug is intended to kill already existing tumor cells by damaging their DNA (mostly after intercalation) or by interrupting their mitotic cycle.

This aim is most efficiently achieved by addressing the so-called microtubles. Microtubules are dynamic structures within the cell that play a critical role in many cellular processes, one of their most important functions being the formation of the mitotic spindle which controls the movement of the chromatids throughout the cell division. Microtubules are made up of many individual protein subunits known as α- and β-tubulin.

In the first step of the formation of microtubules, one α- and one β-subunit are joining to form heterodimers which polymerize to protofilaments. Subsequent aggregation of these protofilaments leads to microtubules which are in a mobile equilibrium with the smaller fragments. If this equilibrium is disturbed, the mitotic cycle is interrupted. Alkaloids such as colchicine or vinblastine have been known for a long time to prevent the aggregation of the protofilaments. With the advent of paclitaxel (taxol®), however, a new mode of interaction was discovered. Paclitaxel stabilizes the microtubules by inhibiting their disaggregation. However, despite its impressive biological profile and its wide application (annual sales of about 1 billion USD), paclitaxel has turned out to be far from ideal for several reasons, e.g. multidrug resistance, poor bioavailability, and several serious side effects. However, its mode of action was considered as unique among all cytostatic drugs, until, quite sensationally, Bollag and coworkers discovered in 1995 that natural compound called epothilone not only binds to microtubules in a paclitaxel-like manner, but that it was much more active! Surprisingly, epothilone was not a new compound at that time; it had been isolated and structurally elucidated as a secondary metabolite from the soil myxobacterium Sorangium cellulosum by Hofle and Reichenbach and their coworkers at GBF in Braunschweig as early as 1987. Unfortunately, the screening at that time had been focused on pesticidal activity only. Epothilone, which turned out to be a mixture of epothilone A und B, did show activity towards certain fungi, but was too toxic for any practical application. Another effect which was already detected at that time was the high cytotoxicity which, however, was not pursued any further. Epothilone thus shared the fate of Sleeping Beauty for about seven years, when, in the aftermath of the sensational success of paclitaxel, a general test for rapid detection of microtubule stabilizing substances. It was in parallel tests at Merck, Sharp, and Dohme, however, that the above-mentioned hit was scored on testing an extract from Sorangium cellulosum containing epothilone A and B. In the tubulin assay, epothilone A turned out to be as active as paclitaxel, epothilone B was fifty times more active. These results were confirmed afterwards by a group from the National Cancer Institute. Later, several other natural products were found with a similar microtubule stabilizing capability. Nevertheless, however, the main interest continues to be concentrated on the epothilones, in particular epothilone B because it promises to have some significant advantages over paclitaxel and the other compounds depicted. First of all, epothilone B is available in kg-quantities by fermentation. This is particularly important in considering that compounds 1-2 to 1-5 are all metabolites of marine organisms and can be isolated from the natural source only with great difficulty and in minute quantities. This excludes their practical applicability and limits the exploration of their bioprofile. Secondly, epothilone B is more soluble in water and has thus better galenic qualities than paclitaxel. Thirdly, it is still active on cells showing multidrug resistance. Fourthly, it exhibits similar toxicity towards various tumor cells (e.g. breast cancer, lung cancer), but acts more rapidly than paclitaxel does. Fifthly (and in our context most importantly), its molecular architecture is much simpler. This means that total synthesis of epothilone B and more potent unnatural derivatives is much more promising and practical than it is in the paclitaxel series. Meanwhile, the epothilone family comprises altogether six members which have all been isolated as metabolites from microbial sources.



Johann Mulzer. Monatshefte fur Chemie 131, 205–238 (2000)