Synthesis and Biological Evaluation of 12,13-Cyclopropyl and 12,13-Cyclobutyl Epothilones

An unambiguous chemical synthesis and biological evaluation of the title compounds revealed their comparable potencies to natural epothilone A (1) against tumor cell lines, shedding further light on structure–activity relationships within the epothilone class. The picture shows a superposition of molecular models of 1 and 12,13-cyclopropyl epothilone A (2) (C atoms in magenta and white, respectively) in the tubulin binding site. A water molecule hydrogen-bonded to 1 (H atoms in magenta) is displaced upon binding of 2 (H atoms in white) which makes hydrophobic interactions with the side chain of Leu 273.