Natural product-based drug discovery -: Epothilones as lead structures for the discovery of new anticancer agents

Epothilones are microtubule depolymerization inhibitors, which inhibit the growth of a broad range of human cancer cell lines in vitro with low nM or sub-nM IC(50)s. Unlike other cytotoxic anticancer agents, epothilones are also active in vitro against multidrug-resistant cell lines and they inhibit the growth of multidrug-resistant tumors in vivo. In order to further our understanding of the structural requirements for biological activity and, ultimately, to identify new microtubule-stabilizing agents with improved overall properties, we have investigated the biological activity of a variety of structurally modified epothilone analogs. This report will focus on two selected aspects of our SAR work, namely (1) the synthesis and biological characterization of a series of 12-aza epothilones and (2) analogs with a conformationally constrained side-chain. Several of these structures exhibit potent in vitro anti proliferative activity, and thus may be interesting candidates for further profiling in tumor models and perhaps for the development of improved clinical candidates.