Epothilones anticancer agents

The bis(isopinocampheyl)borane reagents described in the sections on enantioselective additions have found extensive use in the total synthesis of complex, bioactive natural products. A synthesis of the potent anticancer agent epothilone... 

The specific strategy used by Nicolaou and co-workers in their synthesis of the anticancer agent epothilone A19 was alkene metathesis20 (Scheme 3). This gave cyclization to 16-membered ring compounds while simultaneously cleaving the product from the resin. The alkene functionality formed in this key step was ultimately transformed into the epoxide group of the natural product. 

An example that illustrates the potential of this catalytic C-C bond-forming process to build up key structural subunits of natural products is shown in Scheme 2. The reaction of acetophenone with aldehyde 18 in the presence of 8 mol% catalyst 1 affords the aldol adduct 19 in 70% yield and 93% ee, which is subsequently transformed into 20, a key intermediate of the anticancer agent epothilone A [8b]. Similarly, Scheme 3, the aldol reaction of hydroxyacetylfuran 21 with valeralde-hyde in the presence of 5 mol% catalyst 3 produces syn diol 23 with high efficiency [10d]. Further chemical elaboration of 23 leads to 24, a key intermediate in the synthesis of (+)-boronolide, a folk medicine with emetic and anti-malaria activity. 

Epothilone A, a promising anticancer agent, was first isolated from soil bacteria collected from the banks of the Zambezi River in South Africa. 

The Suzuki cross-coupling reactions have been explored in the synthesis of drugs and related compounds on the laboratory scale but none have been explored on an industrial scale. A few examples given below are AT II antagonist losartan, a COX-2 selective inhibitor, rofecoxib, a highly potent HMG-CoA reductase inhibitor, NK-104, and anticancer agents epothilones A-B. 

A recent example of the power of this technique when applied to natural products is the development of an efficient method for scale-up produchon of epothilone D (Figure 8.6), which entered clinical trials as a potential anticancer agent but has now been disconhnued in favor of a congener, 9,10-didehydroepothilone D. Epothilone D was the most active of the epothilone series isolated from the myxobacte-rium, Sorangium cellulosum, and is the des-epoxy precursor... 

Hofle, G., Reichenbach, H. Epothilone, a myxobacterial metabolite with promising antimmor activity. In Anticancer Agents from Natural Products (Cragg, G. M., Kingston, D. G. I., Newman, D. J., Eds). Taylor and Francis Boca Raton, FL, 2005, pp. 413 50. 

Epothilones A and B are promising anticancer agents that bind to microtubules in the cell in the same way that paclitaxel (Taxol) does and are more potent.410 Paclitaxel was obtained first from the bark of the Pacific yew (Taxus brevifolia).4n Widespread extraction of the compound from this source could have wiped out the species. Fortunately, it can now be extracted from the needles of more common yews or produced in tissue culture. (See Sec II.C on tissue culture.) Forskolin is a diterpene, from the roots of Coleus forskohlii, that lowers blood pressure.412 Him-bacine, from an Australian pine tree, offers a potential treatment for Alzheimer s disease.413 Combretastatin, from the bark of the African bush willow, Combretum caffrum, cuts the flow of blood to tumors, causing 95% of the cancer cells to die in 24 h, but does not harm healthy blood vessels.414... 

Macrolide antibiotics with l-(2-methylthiazol-4-yl)propen-2-yl substitutent, Epothilones AD, and their thiazole-modified analogs as novel anticancer agents 99PAC2019. 

Meng et have recently reported a total synthesis of the promising anticancer agents epothilones A and B using alkylboranes coupling reaction as shown in Scheme 10. 

Testament to the urgency of finding new anticancer agents and the skill of synthetic chemists, in late 1996 the first total synthesis of epothilone A was accomplished by Danishefsky and co-woikeis at Columbia University, followed shortly by independent total syntheses from the Nicolaou and Schinzer laboratories. Since then, over twenty additional and often highly insightful and creative routes to these agents have been reported by these and other synthetic chemists from around the world. Taken collectively, these accomplishments embody a particularly accurate barometer of the current state of chemical synthesis, as the epothilones have served as a... 

Olefin metathesis has proved to be such a powerful tool for synthesis that the 2005 Nobel Prize in Chemistry was awarded to Chauvin, Grubbs, and Shrock for their work in this area. Uses include its application to several syntheses of anticancer agents in the epothilone family by Danishefsky, Nicolaou, Shinzer, Sinha, and others, as in the example shown here. 

Ogura H, Nishida CR, Hoch UR, Perera R, Dawson JH, Ortiz de Montellano PR (2004) Epok, a cytochrome P450 involved in biosynthesis of the anticancer agents epothilones a and B. Substrate-mediated rescue of a P450 enzyme. Biochemistry 43 14712-14721... 

Epothilone is a highly potent anticancer agent. In their synthesis of highly potent epothilone analogs [51], Altmaim and coworkers reported that alkene precursor 61 was stereoselectively epoxidized with ketone ent-42 to give compounds 62a,b (Scheme 3.22). It appears that the epoxidation is compatible with several functional groups such as the benzimidazole in 61, and the existing ketone in the macrocycle did not appear to interfere with the epoxidation [51, 52]. 

Ixabepilone is currently being marketed by Bristol-Myers Squibb under the trade name Ixempra. Several other analogs of the epothilones are currently undergoing clinical trials for treatment of many different forms of cancer. The next decade is likely to witness several epothilone analogs emerge as new anticancer agents. 

Hofle G, Rechcaibach H (2005) Epothilone, a Myxobacterial Metabolite with Promising Antitumor Activity. In Cragg GM, Kingston DGI, Newman DG (eds) Anticancer agents frran natural products. Taylor Francis, Boca Raton, FL, pp 413-450... 

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