Recent developments in the chemistry and biology of epothilones

Epothilones (Epo's) are bacterial natural products which are potent inhibitors of human cancer cell proliferation in vitro and in vivo. Tumor growth inhibition is based on the stabilization of cellular microtubules and at least seven epothilone-derived agents are presently undergoing clinical evaluation in humans. While all of these compounds are closely related structurally to the natural product leads Epo A and B, our own work involves the design, synthesis, and biological evaluation of analogs with significantly altered structural features. The ultimate goal of these efforts is the stepwise creation of new ( and simplified) scaffolds for microtubule inhibition, bearing little or no obvious resemblance with the original epothilone structure. Such compounds would constitute new lead structures for anticancer drug discovery. In this paper we discuss the synthesis and biological properties of such hypermodified epothilone analogs, whose biological activity is within the same potency range as that of Epo A or B.