Total Synthesis and Configurational Assignment of (−)‐Dictyostatin, a Microtubule‐Stabilizing Macrolide of Marine Sponge Origin

Paterson, Ian; Britton, Robert; Delgado, Oscar; Meyer, Arnd; Poullennec, Karine G.

doi:10.1002/ange.200460589

Cited by 27 publications

(23 citation statements)

References 29 publications

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“…Previously overshadowed by (+)-discodermolide, (−)-dictyostatin, a closely related compound, has recently gained attention as a potential anticancer agent. A decade after isolation, the complex structure was finally resolved (5), and two total syntheses (6, 7) provided enough sample for a detailed characterization (7, 8). Extensive structure activity relationship (SAR) studies have provided important information for the development of several (−)-dictyostatin analogs (9–11).…”

Section: Introductionmentioning

confidence: 99%

A Simplified Synthesis of Novel Dictyostatin Analogues with In Vitro Activity against Epothilone B–Resistant Cells and Antiangiogenic Activity in Zebrafish Embryos

Vollmer

Jiménez

Camarco

et al. 2011

Molecular Cancer Therapeutics

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The natural product (−)-dictyostatin is a microtubule stabilizing agent that potently inhibits the growth of human cancer cells including paclitaxel-resistant clones. Extensive structure-activity relationship studies have revealed several regions of the molecule that could be altered without loss of activity. The most potent synthetic dictyostatin analog described to date, 6-epi-dictyostatin, has in vivo antitumor activity against human breast cancer xenografts superior to paclitaxel. Despite their encouraging preclinical activities, the complex chemical structure of the dictyostatins presents a major obstacle in their development into novel antineoplastic therapies. We recently reported a streamlined synthesis of 16-desmethyl-25,26 dihydrodictyostatins and found several agents that compared with 6-epi-dictyostatin retained nanomolar activity in cellular microtubule bundling assays but showed cross-resistance to paclitaxel in cells with mutations in beta-tubulin. Extending these studies, we applied the new, highly convergent synthesis to generate 25,26-dihydrodictyostatin and 6-epi-25,26-dihydrodictyostatin. Both compounds were potent microtubule perturbing agents that induced mitotic arrest and microtubule assembly in vitro and in intact cells. In vitro radioligand binding studies showed that 25,26-dihydrodictyostatin and its C-6 epimer were able to displace [3H]paclitaxel and [14C]epothilone B from microtubules with potencies comparable to (−)-dictyostatin and discodermolide. Both compounds inhibited the growth of paclitaxel- and epothilone B-resistant cell lines at low nanomolar concentrations, synergized with paclitaxel in MDA-MB-231 human breast cancer cells, and had antiangiogenic activity in transgenic zebrafish larvae. The data identify 25,26-dihydrodictyostatin and 6-epi-25,26-dihydrodictyostatin as candidates for scale-up synthesis and further preclinical development.

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Section: Introductionmentioning

confidence: 99%

A Simplified Synthesis of Novel Dictyostatin Analogues with In Vitro Activity against Epothilone B–Resistant Cells and Antiangiogenic Activity in Zebrafish Embryos

Vollmer

Jiménez

Camarco

et al. 2011

Molecular Cancer Therapeutics

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“…Finally in 2004, its structure was elucidated from high-field NMR and computational analyses (Paterson et al, 2004b) and was independently verified by two full syntheses (Paterson et al, 2004a;Shin et al, 2004). The chemical structure of dictyostatin closely resembles that of discodermolide, and 10 of the 11 stereocenters in dictyostatin are shared with discodermolide.…”

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confidence: 95%

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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“…[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.…”

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confidence: 81%

A Highly Step‐Economical Synthesis of Dictyostatin

Bucher

Leighton

2013

Angew Chem Int Ed

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Total Synthesis and Configurational Assignment of (−)‐Dictyostatin, a Microtubule‐Stabilizing Macrolide of Marine Sponge Origin

Cited by 27 publications

References 29 publications

A Simplified Synthesis of Novel Dictyostatin Analogues with In Vitro Activity against Epothilone B–Resistant Cells and Antiangiogenic Activity in Zebrafish Embryos

A Simplified Synthesis of Novel Dictyostatin Analogues with In Vitro Activity against Epothilone B–Resistant Cells and Antiangiogenic Activity in Zebrafish Embryos

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

A Highly Step‐Economical Synthesis of Dictyostatin

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