Synthesis and biological evaluation of (-)-dictyostatin and stereoisomers.
Total syntheses of (-)-dictyostatin, 6,16-bis-epi-dictyostatin, 6,14,19-tris-epi-dictyostatin and a number of other isomers and analogs are reported. Three main fragments-top, middle and bottom-were first assembled and then joined by olefination or anionic addition reactions. After appending the two dienes at either end of the molecule, macrolactonization and deprotection completed the syntheses. The work proves both the relative and absolute configurations of (-)-dictyostatin. The compounds were evaluated by cell-based measurements of increased microtubule mass and antiproliferative activity, and in vitro tubulin polymerization assays as well as competitive assays with paclitaxel for its binding site on microtubules. These assays showed dictyostatin to be the most potent of the agents and further showed that the structural alterations caused from 20- to >1000-fold decreases in activity.
Shin
Youseung
Y
Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15261 USA.
Fournier
Jean-Hugues
JH
Brückner
Arndt
A
Madiraju
Charitha
C
Balachandran
Raghavan
R
Raccor
Brianne S
BS
Edler
Michael C
MC
Hamel
Ernest
E
Sikorski
Rachel P
RP
Vogt
Andreas
A
Day
Billy W
BW
Curran
Dennis P
DP