The Chemistry, Biology, and Clinical Development of Epothilones–A 30‐Year Retrospective

ABSTRACT The epothilones are a family of natural products from myxobacteria, whose major representatives epothilone A and B were first isolated in 1987 at the Gesellschaft für Biotechnologische Forschung in Germany. Their discovery was never published, however, until they were found to be microtubule‐stabilizing agents at Merck Research Laboratories in the US in 1995, and thus, to possess a taxol‐like mode of action. Within a short period of time, this finding turned epothilones into widely pursued targets for total synthesis and lead structures for anticancer drug discovery, with several major pharmaceutical companies becoming involved in the hunt for epothilone‐derived anticancer drugs. These efforts eventually led to two approved drugs for breast cancer treatment, out of a total of 9 epothilone‐type structures that entered clinical trials. In this review, I will summarize some of the key aspects of the (semi)synthetic chemistry of epothilones that have transpired from a wealth of synthetic work on natural epothilones and the synthesis of a multitude of analogs. Particular emphasis is placed on those compounds that have entered clinical trials. In addition, I will also discuss the development history of these compounds, including some non‐scientific aspects that are perhaps less known and appreciated in the scientific community.