The clinical success of paclitaxel (PT) in the treatment of ovarian and breast cancer strongly contributed to the assessment that tubulin is one of the best clinically validated targets in tumor therapy. However, one disadvantage with PT and other taxane analogues is their recognition by cellular efflux mechanisms, such as the p-glycoprotein (p-gp), which contribute to a loss of activity in cells overexpressing the multidrug-resistance (MDR) phenotype.
In 1995 Bollag et al. [1] reported that the natural product class of epothilones mimics the biological activity of PT with respect to its action on the tubulin system. Thus, the cell cycle is arrested in the G2/M phase and the cells are driven into mitotic catastrophe and/or apoptosis. In contrast to PT, epothilones possess the potential to overcome MDR in vitro and, most importantly, in vivo. [2][3][4][5] These findings stimulated intensive research activities in chemistry, pharmacology, and medicine.
Epothilones were first discovered by Reichenbach, HΓΆfle, and co-workers who characterized the compounds they had isolated from the myxobacterial strain Sorangium cellulosum. [6,7] They also described their cytotoxic potential in a patent application filed in 1991. [8] The first total syntheses of epothilone A were reported in 1996/1997 by the research groups of Danishefsky, Nicolaou, and Schinzer. [9][10][11] Since we had no access to the more potent compound epothilone B, from the start of our project we focused on total synthesis to evaluate the potential of this compound class. During our own investigations, the total syntheses of epothilones B and D were reported.