{"id":604,"date":"2017-02-09T00:59:38","date_gmt":"2017-02-09T05:59:38","guid":{"rendered":"http:\/\/www.bocsci.com\/blog\/?p=604"},"modified":"2017-02-09T00:59:38","modified_gmt":"2017-02-09T05:59:38","slug":"epothilone-b-and-its-derivatives-as-novel-antitumor-drugs","status":"publish","type":"post","link":"https:\/\/www.bocsci.com\/blog\/epothilone-b-and-its-derivatives-as-novel-antitumor-drugs\/","title":{"rendered":"Epothilone B and its Derivatives as Novel Antitumor Drugs"},"content":{"rendered":"

The chemotherapy of cancer<\/a> strongly depends on the nature of the\u00a0individual tumor under consideration. For instance, tumors located in hormone\u00a0dependent organs such as the ovaries, breasts, etc. are treated with antihormons,\u00a0e.g. anti-estrogens or anti-androgens, which retard the growth of the individual\u00a0tissue and thus also that of the tumor enclosed. In the regular case, however, the\u00a0drug is intended to kill already existing tumor cells by damaging their DNA (mostly\u00a0after intercalation) or by interrupting their mitotic cycle.<\/p>\n

This aim is most efficiently achieved by addressing the so-called microtubles. Microtubules<\/a> are dynamic structures within the cell that play a critical\u00a0role in many cellular processes, one of their most important functions being the\u00a0formation of the mitotic spindle which controls the movement of the chromatids\u00a0throughout the cell division. Microtubules are made up of many individual protein\u00a0subunits known as \u03b1- and \u03b2-tubulin.<\/p>\n

In the first step of the formation of microtubules, one \u03b1- and one \u03b2-subunit are\u00a0joining to form heterodimers which polymerize to protofilaments. Subsequent\u00a0aggregation of these protofilaments leads to microtubules which are in a mobile\u00a0equilibrium with the smaller fragments. If this equilibrium is disturbed, the mitotic\u00a0cycle is interrupted. Alkaloids such as colchicine or vinblastine have been known\u00a0for a long time to prevent the aggregation of the protofilaments. With the advent of\u00a0paclitaxel<\/a> (taxol\u00ae), however, a new mode of interaction was\u00a0discovered. Paclitaxel stabilizes the microtubules by inhibiting their disaggregation. However, despite its impressive biological profile and its wide application\u00a0(annual sales of about 1 billion USD), paclitaxel has turned out to be far from ideal\u00a0for several reasons, e.g. multidrug resistance, poor bioavailability, and several\u00a0serious side effects. However, its mode of action was considered as unique among\u00a0all cytostatic drugs, until, quite sensationally, Bollag and coworkers discovered in\u00a01995 that natural compound called epothilone not only binds to microtubules\u00a0in a paclitaxel-like manner, but that it was much more active! Surprisingly,\u00a0epothilone was not a new compound at that time; it had been isolated and\u00a0structurally elucidated as a secondary metabolite from the soil myxobacterium\u00a0Sorangium cellulosum by Hofle and Reichenbach and their coworkers at GBF in\u00a0Braunschweig as early as 1987. Unfortunately, the screening at that time had\u00a0been focused on pesticidal activity only. Epothilone, which turned out to be a\u00a0mixture of epothilone A und B, did show activity towards\u00a0certain fungi, but was too toxic for any practical application. Another effect which\u00a0was already detected at that time was the high cytotoxicity which, however, was\u00a0not pursued any further. Epothilone thus shared the fate of Sleeping Beauty for\u00a0about seven years, when, in the aftermath of the sensational success of paclitaxel, a\u00a0general test for rapid detection of microtubule stabilizing substances. It was in parallel tests at Merck, Sharp, and Dohme,\u00a0however, that the above-mentioned hit was scored on testing an extract from\u00a0Sorangium cellulosum containing epothilone A<\/a> and B. In the tubulin assay,\u00a0epothilone A turned out to be as active as paclitaxel, epothilone B<\/a> was fifty times\u00a0more active. These results were confirmed afterwards by a group from the National\u00a0Cancer Institute. Later, several other natural products were found\u00a0with a similar microtubule stabilizing capability. Nevertheless,\u00a0however, the main interest continues to be concentrated on the epothilones, in\u00a0particular epothilone B because it promises to have some significant advantages\u00a0over paclitaxel and the other compounds depicted. First of all,\u00a0epothilone B is available in kg-quantities by fermentation. This is particularly\u00a0important in considering that compounds 1-2 to 1-5 are all metabolites of marine\u00a0organisms and can be isolated from the natural source only with great difficulty and\u00a0in minute quantities. This excludes their practical applicability and limits the\u00a0exploration of their bioprofile. Secondly, epothilone B is more soluble in water and\u00a0has thus better galenic qualities than paclitaxel. Thirdly, it is still active on cells\u00a0showing multidrug resistance. Fourthly, it exhibits similar toxicity towards various\u00a0tumor cells (e.g. breast cancer, lung cancer), but acts more rapidly than paclitaxel\u00a0does. Fifthly (and in our context most importantly), its molecular architecture is\u00a0much simpler. This means that total synthesis of epothilone B and more potent\u00a0unnatural derivatives is much more promising and practical than it is in the\u00a0paclitaxel series. Meanwhile, the epothilone family comprises altogether six\u00a0members which have all been isolated as\u00a0metabolites from microbial sources.<\/p>\n

 <\/p>\n

Reference:<\/p>\n

Johann Mulzer. Monatshefte fur Chemie 131, 205\u2013238 (2000)<\/p>\n","protected":false},"excerpt":{"rendered":"

The chemotherapy of cancer strongly depends on the nature of the\u00a0individual tumor under consideration. For instance, tumors located in hormone\u00a0dependent organs such as the ovaries, breasts, etc. are treated with […]<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":[],"categories":[181],"tags":[393],"_links":{"self":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts\/604"}],"collection":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/comments?post=604"}],"version-history":[{"count":1,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts\/604\/revisions"}],"predecessor-version":[{"id":605,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts\/604\/revisions\/605"}],"wp:attachment":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/media?parent=604"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/categories?post=604"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/tags?post=604"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}