Design, synthesis, and biological properties of highly potent epothilone B analogues.

Owing to their potent cytotoxicity against tumor cells, including taxol (paclitaxel)-resistant cell lines, the epothilones (for example, epothilone A (1) and epothilone B (2)) continue to be the focus of intense chemical, biological, and clinical research efforts around the world. 3] Following the findings that cyclopropane-, methylsulfanylthiazole-, and pyridine-containing epothilone B derivatives (e.g. 3 and 5,) exhibit outstanding biological profiles as potential antitumor agents, we directed our attention toward the synthesis and evaluation of a small designed library of epothilone B analogues whose members are characterized by such structural motifs. Herein we report the details of these synthetic and biological investigations, which culminated in the discovery of 12,13-cis-cyclopropane methylsulfanyl epothilone B (4) as an extremely potent epothilone B analogue. The design of the present focused epothilone library was based on the current knowledge of structure–activity relationships (SAR), specifically the facts that: 1) epothilone B (2) is considerably more potent than epothilone A (1), 2) a methylsulfanyl replacement for the methyl group on the thiazole moiety enhances the potency, 3) a heterocycle (e.g. pyridine) replacement for the thiazole ring needs to maintain the proper position (adjacent to the point of