Total synthesis of (−)-dictyostatin, a microtubule-stabilising anticancer macrolide of marine sponge origin

Paterson, Ian; Britton, Robert; Delgado, Oscar; Gardner, Nicola M.; Meyer, Arnd; Naylor, Guy J.; Poullennec, Karine G.

doi:10.1016/j.tet.2010.01.083

Cited by 34 publications

(29 citation statements)

References 73 publications

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“…Dictyostatin was synthesized as a white solid (26mg, 0.49mmol) according to reported procedures [ 38 ] and purified by silica gel flash column chromatography (purity level > 95%, as determined by HPLC and NMR). All the spectral data (1H-NMR, 13C-NMR, HR-Mass) were identical to reported data [ 38 ].…”

Section: Methodsmentioning

confidence: 99%

Evaluation of the brain-penetrant microtubule-stabilizing agent, dictyostatin, in the PS19 tau transgenic mouse model of tauopathy

Makani

Zhang

Han

et al. 2016

acta neuropathol commun

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Neurodegenerative disorders referred to as tauopathies, which includes Alzheimer’s disease (AD), are characterized by insoluble deposits of the tau protein within neuron cell bodies and dendritic processes in the brain. Tau is normally associated with microtubules (MTs) in axons, where it provides MT stabilization and may modulate axonal transport. However, tau becomes hyperphosphorylated and dissociates from MTs in tauopathies, with evidence of reduced MT stability and defective axonal transport. This has led to the hypothesis that MT-stabilizing drugs may have potential for the treatment of tauopathies. Prior studies demonstrated that the brain-penetrant MT-stabilizing drug, epothilone D, had salutary effects in transgenic (Tg) mouse models of tauopathy, improving MT density and axonal transport, while reducing axonal dystrophy. Moreover, epothilone D enhanced cognitive performance and decreased hippocampal neuron loss, with evidence of reduced tau pathology. To date, epothilone D has been the only non-peptide small molecule MT-stabilizing agent to be evaluated in Tg tau mice. Herein, we demonstrate the efficacy of another small molecule brain-penetrant MT-stabilizing agent, dictyostatin, in the PS19 tau Tg mouse model. Although dictyostatin was poorly tolerated at once-weekly doses of 1 mg/kg or 0.3 mg/kg, likely due to gastrointestinal (GI) complications, a dictyostatin dose of 0.1 mg/kg was better tolerated, such that the majority of 6-month old PS19 mice, which harbor a moderate level of brain tau pathology, completed a 3-month dosing study without evidence of significant body weight loss. Importantly, as previously observed with epothilone D, the dictyostatin-treated PS19 mice displayed improved MT density and reduced axonal dystrophy, with a reduction of tau pathology and a trend toward increased hippocampal neuron survival relative to vehicle-treated PS19 mice. Thus, despite evidence of dose-limiting peripheral side effects, the observed positive brain outcomes in dictyostatin-treated aged PS19 mice reinforces the concept that MT-stabilizing compounds have significant potential for the treatment of tauopathies.

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Section: Methodsmentioning

confidence: 99%

Evaluation of the brain-penetrant microtubule-stabilizing agent, dictyostatin, in the PS19 tau transgenic mouse model of tauopathy

Makani

Zhang

Han

et al. 2016

acta neuropathol commun

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“…[7] The first synthetic preparations of the macrolide date back to 2004 when Paterson et al [8] and Curran et al [9] released their total syntheses of dictyostatin in consecutive articles in the same journal. Six years later, both research groups published revised total syntheses, the one from the Paterson group affording dictyostatin in a batch of 40 mg. [10,11] To date, three other total syntheses were presented by Phillips, [12] Ramachandran, [13] and Leighton. [14] In addition, the promising biological properties of dictyostatin fueled efforts in the preparation of analogues.…”

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confidence: 99%

Probing o‐Diphenylphosphanyl Benzoate (o‐DPPB)‐Directed CC Bond Formation: Total Synthesis of Dictyostatin

Wünsch

Breit

2014

Chemistry A European J

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Herein, we report a robust total synthesis of dictyostatin. This polyketide natural product has attracted much attention because of its impressive antiproliferative activity against several human cancer-cell lines. We accomplished its synthesis in a highly convergent manner from three fragments of equal complexity, which were prepared on multigram scale. The southern and northwestern subunits were constructed through application of our o-DPPB-directed hydroformylation and allylic substitution methodology, respectively. These methods generated the C6 and C14 stereocenters of dictyostatin with good diastereoselectivities and simultaneously allowed further elaboration of the fragments by Wittig olefination and Sharpless asymmetric epoxidation, respectively. The compelling performance of the hydroformylation and allylic substitution with regard to practicability, selectivity, and scale underline their value for the construction of propionate motifs.

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“…Finally, Luche reduction of the C9 ketone exploiting macrocyclic stereocontrol and desilylation of 135 delivered target molecule 119, which to our great satisfaction was identical in all respects to an authentic sample of dictyostatin. [56] After further optimisation, [60] this total synthesis enabled a sustainable supply of this precious microtubule-stabilising agent to facilitate further studies as a potential anticancer drug candidate and treatment for neurodegenerative diseases. These studies, along with that of other groups, [61] demonstrated that dictyostatin has a similar β-tubulin binding site to both Taxol and discodermolide, guiding the rational design of discodermolidedictyostatin hybrids.…”

Section: Dictyostatinmentioning

confidence: 99%

The Stereocontrolled Total Synthesis of Polyketide Natural Products: A Thirty-Year Journey

Stockdale

Lam

Anketell

et al. 2020

Bulletin of the Chemical Society of Japan

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The diverse and complex structures of polyketide natural products have stimulated the imagination of synthetic chemists for decades. Captivated by their often impressive biological activities and their dazzling array of stereochemically-rich motifs, we have been motivated to achieve their efficient and stereocontrolled total synthesis. This review captures snapshots from our thirty-year foray into the total synthesis of 18 polyketide natural products, detailing the unique challenges, discoveries and revelations made en route to eventual success. Notably, crucial to each of these campaigns was the judicious application of highly selective aldol reactions to iteratively configure the densely oxygenated stereoclusters that characterise this fascinating class of bioactive natural products.

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Total synthesis of (−)-dictyostatin, a microtubule-stabilising anticancer macrolide of marine sponge origin

Cited by 34 publications

References 73 publications

Evaluation of the brain-penetrant microtubule-stabilizing agent, dictyostatin, in the PS19 tau transgenic mouse model of tauopathy

Evaluation of the brain-penetrant microtubule-stabilizing agent, dictyostatin, in the PS19 tau transgenic mouse model of tauopathy

Probing o‐Diphenylphosphanyl Benzoate (o‐DPPB)‐Directed CC Bond Formation: Total Synthesis of Dictyostatin

The Stereocontrolled Total Synthesis of Polyketide Natural Products: A Thirty-Year Journey

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