CHAPTER 3: Epothilones

Epothilones A and B are naturally occurring microtubule stabilizers with nanomolar or even sub-nanomolar activity against human cancer cells in vitro and potent in vivo antitumor activity against multidrug-resistant tumors. Over the last decade, ten epothilonetype agents have entered clinical trials in humans; of these, the epothilone B lactam ixabepilone (BMS-247550; Ixempra^®) was approved by the FDA for breast cancer treatment in 2007. Numerous synthetic and semisynthetic analogs of epothilones have been prepared and their in vitro and (in selected cases) in vivo biological activity has been determined, producing a wealth of SAR information on this compound family. This chapter will provide a brief summary of the in vitro and in vivo biological properties of epothilone B (Epo B). The major part of the discussion will then be organized around those epothilone analogs that have entered clinical development. For each analog the underlying synthetic chemistry and the most important preclinical features will be reviewed, together with the properties of some important related structures.