Second-generation epothilones: discovery of fludelone and its extraordinary antitumor properties

Herein, we describe the development of the second generation of epothilone derivatives, which possess impressive preclinical antitumor properties. In particular, we focus on the discovery and biological evaluation of a trifluoromethyl-9,10-dehydroepothilone derivative, termed fludelone, to which we gained access through diverted total synthesis. This review serves to highlight the role of natural product-based research combined with the power of chemical synthesis in the discovery and development of valuable drug candidates.