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Synthesis

TOTAL SYNTHESES OF DICTYOSTATIN

Two methods, devised independently, could speed anticancer activity testing

by Stu Borman
July 12, 2004 | APPEARED IN VOLUME 82, ISSUE 28

The first total syntheses of the promising anticancer agent dictyostatin have been achieved by two groups working independently [Angew. Chem. Int. Ed., published online July 1, http://www3.interscience.wiley.com/cgi-bin/abstract/109086576/ and 109086575/]. About a half-dozen synthetic teams are believed to have been pursuing the compound.

The two studies--by Dennis P. Curran's group at the University of Pittsburgh and by Ian Paterson of Cambridge University and coworkers--should facilitate testing by making available greater quantities of dictyostatin, which has been accessible only in tiny amounts from natural sources.

Dictyostatin (shown) was isolated from a marine sponge a decade ago by George R. Pettit of Arizona State University, Tempe, and coworkers, who predicted its structure. "Though their stereostructure was incomplete, their connectivity was correct, and assigning even that was a real feat given the small sample," Curran says.

Later, a group led by marine natural products chemist Amy E. Wright of Harbor Branch Oceanographic Institution, Fort Pierce, Fla., isolated it again and determined its mechanism to be microtubule stabilization, similar to that of the anticancer agents paclitaxel and discodermolide.

Paterson's group, in collaboration with Wright, recently used nuclear magnetic resonance imaging and molecular modeling to deduce a revised structure of dictyostatin [Chem. Commun., 2004, 632]. "We felt the assignment should be revisited," Paterson says, "rather than taking a shot in the dark at synthesizing different stereoisomers."

Curran and Paterson found out that their groups had completed different dictyostatin total syntheses, and they agreed to joint publication. "What could have been a hair-raising race to the journal finish line turned out to be a very pleasant exchange," Curran says. "We have preliminary bio results back on our synthetic sample, and it is indeed exceptionally active."

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