Total Synthesis and Biological Evaluation of C16 Analogs of (−)-Dictyostatin

Jung, Won Hyuk; Harrison, Cristian L.; Shin, Youseung; Fournier, Jean Hugues; Balachandran, Raghavan; Raccor, Brianne S.; Sikorski, Rachel; Vogt, Andreas; Curran, Dennis P.; Day, Billy W.

doi:10.1021/jm061385k

Cited by 48 publications

(39 citation statements)

References 41 publications

(46 reference statements)

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“…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.…”

Section: Methodssupporting

confidence: 83%

“…Toxicity measurements and the MDEC values generated from this initial screen provided a rapid and economical assessment of the analogs' biological activities. As shown in Table 1, the 20-membered ring iso analogs of dictyostatin, 16-epi-isodictyostatin, 15Z,16-normethylisodictyostatin, and 16-epi-dictyostatin were inactive, yielding MDEC and EC 50 values Ͼ5 M. This led to the conclusions that the 22-membered ring of dictyostatin is essential for retention of biological activity and that if the C16 methyl group is present, it must be in the S configuration (Jung et al, 2007). 2E,15Z,16-Normethyldictyostatin analog was considerably less active than 15Z,16-normethyldictyostatin, proving that C2:3Z geometry is necessary for activity.…”

Section: Methodsmentioning

confidence: 99%

“…Dictyostatin was synthesized as described previously (Shin et al, 2004). The syntheses of the analogs are reported elsewhere Fukui et al, 2006;Jung et al, 2007). Tubulin was isolated to electrophoretic homogeneity from fresh bovine brain (Hamel and Lin, 1984).…”

Section: Methodsmentioning

confidence: 99%

“…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.…”

mentioning

confidence: 99%

“…Because discodermolide can be considered an open chain form of the macrolactone of dictyostatin, a 16-epi open chain methyl ester analog of the latter was included in our analysis. Finally, we made dictyostatin analogs containing a C15-C16 Z-alkene because discodermolide possesses a C13-C14 Z-alkene, which is missing in dictyostatin, and two 20-member macrolactone iso analogs Fukui et al, 2006;Jung et al, 2007).…”

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confidence: 99%

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

et al. 2007

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Compounds that bind to microtubules (MTs) and alter their dynamics are highly sought as a result of the clinical success of paclitaxel and docetaxel. The naturally occurring compound (Ϫ)-dictyostatin binds to MTs, causes cell cycle arrest in G 2 /M at nanomolar concentrations, and retains antiproliferative activity in paclitaxel-resistant cell lines, making dictyostatin an attractive candidate for development as an antineoplastic agent. In this study, we examined a series of dictyostatin analogs to probe biological and biochemical structure-activity relationships. We used a high-content multiparameter fluorescence-based cellular assay for MT morphology, chromatin condensation, mitotic arrest, and cellular toxicity to identify regions of dictyostatin that were essential for biological activity. Four analogs (6-epidictyostatin, 7-epi-dictyostatin, 16-normethyldictyostatin, and 15Z,16-normethyldictyostatin) retained low nanomolar activity in the cell-based assay and were chosen for analyses with isolated tubulin. All four compounds were potent inducers of MT assembly. Equilibrium binding constant (K i ) determinations using [14 C]epothilone B, which has a 3-fold higher affinity for the taxoid binding site than paclitaxel, indicated that 6-epidictyostatin and 7-epi-dictyostatin displaced Finally, we developed a set of quantitative structure-activity relationship equations correlating structures with antiproliferative activity. The equations accurately predicted biological activity and will help in the design of future analogs.

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Section: Methodssupporting

confidence: 83%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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

et al. 2007

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Porifera (Sponges)–5

Kornprobst

2014

Encyclopedia of Marine Natural Products

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A Highly Step‐Economical Synthesis of Dictyostatin

Bucher

Leighton

2013

Angewandte Chemie

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In 1994 Petit reported the isolation and anti-cancer activity of the marine sponge-derived macrolide dictyostatin. [1] Wright subsequently isolated a sample that allowed initial biological characterization of dictyostatin as a potent inducer of tubulin polymerization, [2] and that was used by Wright and Paterson to make a full structural assignment in 2004. [3] This assignment was confirmed soon thereafter by total syntheses by Paterson [4] and Curran, [5] and the material thus obtained facilitated more detailed characterization of dictyostatin's mechanism of action. [6,7] Total syntheses by Phillips [8] and Ramachandran, [9] formal syntheses by Micalizio [10] and Cossy, [11] a synthesis of C(9)-epi-dictyostatin by Gennari, [12] second generation syntheses by Paterson [13] and Curran, [14] and several fragment syntheses [15] followed these initial reports. In addition, the Paterson/Wright [16] and Curran/Day [17] teams have reported extensive SAR studies, while the Paterson/Díaz/ Jiménez-Barbero [18] and Curran/Snyder [19] teams have advanced models for the interaction of dictyostatin with the taxane binding site on -tubulin. Because dictyostatin and some of the prepared analogs are among the most potent microtubule-stabilizing agents characterized to date, there has been and continues to be intense interest in the possibility of advancing dictyostatin or an analog thereof into the clinic, a goal which might be facilitated by the development of a significantly more efficient and step-economical synthesis. As part of a larger program devoted to the development of new strategies and methods for the synthesis of complex and precious marine macrolides with high levels of step-economy, efficiency, and scalability, [20] we have developed and report herein a synthesis of dictyostatin that comprises just 14 steps in the longest linear sequence.Similarly to the previous syntheses of dictyostatin, our retrosynthesis disconnected the target into three roughly equally complex fragments, 1, 2, and 3 (Fig. 1A). It was in the synthesis of the fragments, and especially the C(12)-C(14) and C(20)-C(22) stereotriad-containing fragments 1 and 2 that we saw an opportunity for a streamlining of the synthesis. Ever since its introduction by Roush more than 20 years ago, what might be called the "Roche ester strategy" has reigned supreme for the synthesis of such stereotriads, [21] and indeed was employed in the Paterson, Curran, and Ramachandran syntheses, in most of the approaches reported by others, and in most of the syntheses of the related natural product discodermolide. [22] In this approach, the requisite enantiomer of the Roche ester is protected, reduced, and oxidized to the corresponding aldehyde, which is then subjected to diastereoselective crotylation, followed by several additional functional group manipulations (Fig. 1B). Thus, these stereotriad syntheses typically comprise at least 6-7 steps of which all Correspondence to: James L. Leighton, leighton@chem.columbia.edu. Supporting information for this article is ava...

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Total Synthesis and Biological Evaluation of C16 Analogs of (−)-Dictyostatin

Cited by 48 publications

References 41 publications

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

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

Porifera (Sponges)–5

A Highly Step‐Economical Synthesis of Dictyostatin

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