Stereochemical determination of dictyostatin, a novel microtubule-stabilising macrolide from the marine sponge Corallistidae sp.Electronic supplementary information (ESI) available: copies of 1D and 2D NMR spectra, tables of spectral data and calculated torsion angles. See http://www.rsc.org/suppdata/cc/b3/b316390c/

Paterson, Ian; Britton, Robert; Delgado, Oscar; Wright, Amy E.

doi:10.1039/b316390c

Cited by 87 publications

(69 citation statements)

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“…The observed NOE data for the bound state are very similar to those described above for discodermolide in water. Now, however, the NOE data are in agreement with a half-chair conformation for the www.chemeurj.org six-membered ring orientation, due to the weakness of the H2-H5 cross-peak, as well as the relative changes in the intensities of the key NOEs from the CH 3 25 and CH 3 26 signals. Thus, there is a conformational selection process regarding the shape of the six-membered ring.…”

Section: Nmr Tr-noesy Studies Of Discodermolide and Dictyostatin In Tsupporting

confidence: 53%

The Bound Conformation of Microtubule‐Stabilizing Agents: NMR Insights into the Bioactive 3D Structure of Discodermolide and Dictyostatin

Canales

Matesanz

Gardner

et al. 2008

Chemistry A European J

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Section: Nmr Tr-noesy Studies Of Discodermolide and Dictyostatin In Tsupporting

confidence: 53%

The Bound Conformation of Microtubule‐Stabilizing Agents: NMR Insights into the Bioactive 3D Structure of Discodermolide and Dictyostatin

Canales

Matesanz

Gardner

et al. 2008

Chemistry A European J

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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: 66%

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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“…4 Displaying a Taxol-like mechanism of action by binding to tubulin and inducing microtubule assembly, dictyostatin inhibits human cancer cell proliferation at nanomolar concentrations (ED 50 0.38 nM, P338 leukemia cells). 5 Importantly, both discodermolide and dictyostatin retain activity against multi-drug resistant celllines as they do not bind to P-glycoprotein, a principal mediator of taxane resistance. 6 With the withdrawal of discodermolide from clinical development in 2005, 7 interest in dictyostatin has increased, particularly as the natural supply is extremely scarce.…”

Section: Introductionmentioning

confidence: 99%