Structure-activity relationships study of new microtubule stabilizing taccalonolides

Microtubule stabilizing drugs have an excellent utility in the treatment of adult solid malignancies. In the effort to find new microtubule stabilizing agents we evaluated tropical plants and identified a new class of microtubule stabilizers, the taccalonolides, from Tacca chantrieri. Recently, a number of new natural taccalonolides were isolated including one, designated taccalonolide AF, that retains microtubule stabilizing activity and has an IC50 value of 23 nM in Hela cells. This compound was the first to contain an epoxide group bridging C22–23, the only difference between AF and the major plant component taccalonolide A. This epoxide group results in a 230-fold increase in potency. A one-step epoxidation reaction was used to synthesize AF from A and AJ from B. AJ is highly potent with an IC50 value of 4.2 nM. To generate sufficient AJ for in vivo antitumor efficacy studies seven different hydrolysis reactions were evaluated to produce B from A. The reaction conditions were optimized and an 80% yield of B from A was achieved with one method. Additionally, a new taccalonolide AO was also obtained. This optimized hydrolysis reaction was applied to synthesize N from E and yielded an additional 4 new taccalonolides, AK, AL, AM, and AN. They are all microtubule active and provide additional information for SAR.