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Synthesis and biological evaluation of (-)-dictyostatin and stereoisomers |
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| Authors: | Shin Youseung Fournier Jean-Hugues Brückner Arndt Madiraju Charitha Balachandran Raghavan Raccor Brianne S Edler Michael C Hamel Ernest Sikorski Rachel P Vogt Andreas Day Billy W Curran Dennis P |
| Affiliation: | a Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA b Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA c Department of Pharmacology, University of Pittsburgh, Pittsburgh, PA 15261, USA d Toxicology and Pharmacology Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute at Frederick, National Institutes of Health, Frederick, MD 21702, USA |
| Abstract: | 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. |
| Keywords: | Microtubule Macrolactone Paclitaxel Discodermolide |
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