Synthesis and biological evaluation of (−)-dictyostatin and stereoisomers

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.

Cell-Based and Biochemical Structure-Activity Analyses of Analogs of the Microtubule Stabilizer Dictyostatin

“…For toxicity determinations, cell densities were measured as the number of Hoechst 33342-stained nuclei per imaging field. The toxicity measurements in HeLa cells were consistent with those reported for other human cancer cell lines, where the toxicity measure used was a decrease in absorbance at 490 nm after cells treated with drug were exposed to 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium and N-methylphenazine methylsulfate (Jung et al, 2007;Shin et al, 2007). Toxicity measurements and the MDEC values generated from this initial screen provided a rapid and economical assessment of the analogs' biological activities.…”

“…A few analogs of dictyostatin and their relative potencies against several cancer cell lines have been reported by others . We have synthesized several analogs in attempts to study the SAR of the dictyostatin scaffold (Fukui et al, 2006;Jung et al, 2007;Shin et al, 2007). From this collection of existing dictyostatin analogs, we chose several of them based on the structural differences between dictyostatin and discodermolide for detailed biological SAR studies (Fig.…”

Streamlined Syntheses of (−)-Dictyostatin, 16-Desmethyl-25,26-dihydrodictyostatin, and 6-epi-16-Desmethyl-25,26-dihydrodictyostatin

“…The original syntheses have been refined and improved,8 new total syntheses by Phillips9 and Ramachandran10 have appeared, and partial syntheses of key fragments have provided additional new options 11. Building on these foundations, our group12 and Paterson’s13 have made an assortment of analogs and stereoisomers of dictyostatin either by modifications of existing synthetic routes or by introducing new routes. A clear outline of the dictyostatin SAR has emerged,14 and several potent analogs with potential advantages over dictyostatin itself have been identified.…”

(+)-Sorangicin A: evolution of a viable synthetic strategy

“…Towards this end, treatment of seco-acid 138 with Mukaiyama reagent 141 and NaHCO 3 in CH 2 Cl 2 indeed furnished macrolactone 142 , albeit contaminated with minor amounts of other geometric isomers that proved difficult to remove. Recalling that the Yonemitsu modification of the Yamaguchi conditions, 98 involving direct introduction of DMAP at room temperature without preformation of the mixed anhydride, had successfully been employed by the Curran group in their total synthesis of (−)-dictyostatin possessing a Z , E -dienoacid, 99 we explored this tactic. Unfortunately, these conditions led to significant isomerization.…”