Total Synthesis of Bryostatin 9

Wender, Paul A.; Schrier, Adam J.

doi:10.1021/ja203034k

Cited by 116 publications

(54 citation statements)

References 69 publications

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“…Currently, seven total syntheses of bryostatins 7, 2, 3, 16, 1, and 9 have been reported by the groups of Masamune,79 Evans,80 Yamamura,81 Trost,82 Keck,83 Wender,84 and Krische 85. The initial routes were completed in 79–89 steps, with the most recent route towards bryostatin 7 by Krische and co‐workers in 2011 being the most efficient with a total step count of 36 (longest linear sequence: 20 steps).…”

Section: Natural Product Derived Fragments In Drug Discoverymentioning

confidence: 99%

Capturing Biological Activity in Natural Product Fragments by Chemical Synthesis

2016

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Natural products have had an immense influence on science and have directly led to the introduction of many drugs. Organic chemistry, and its unique ability to tailor natural products through synthesis, provides an extraordinary approach to unlock the full potential of natural products. In this Review, an approach based on natural product derived fragments is presented that can successfully address some of the current challenges in drug discovery. These fragments often display significantly reduced molecular weights, reduced structural complexity, a reduced number of synthetic steps, while retaining or even improving key biological parameters such as potency or selectivity. Examples from various stages of the drug development process up to the clinic are presented. In addition, this process can be leveraged by recent developments such as genome mining, antibody–drug conjugates, and computational approaches. All these concepts have the potential to identify the next generation of drug candidates inspired by natural products.

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Section: Natural Product Derived Fragments In Drug Discoverymentioning

confidence: 99%

Capturing Biological Activity in Natural Product Fragments by Chemical Synthesis

2016

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“…Bryostatins have recently risen to renewed prominence due to their effect on reducing the synaptic loss and plaque formation associated with Alzheimer’s disease in animal models, 96 and the development of efficient synthetic routes for potent bryostatin analogs. 97–99 …”

Section: Individual Domains Of Pkcmentioning

confidence: 99%

Dynamics and Membrane Interactions of Protein Kinase C

Igumenova

2015

Biochemistry

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Protein Kinase C (PKC) is a family of Ser/Thr kinases that regulate a multitude of cellular processes through participation in the phosphoinositide signaling pathway. Significant research efforts have been directed at understanding the structure, function, and regulatory modes of the enzyme since its discovery and identification as the first receptor for tumor-promoting phorbol esters. The activation of PKC involves a transition from the cytosolic auto-inhibited latent form to the membrane-associated active form. The membrane recruitment step is accompanied by the conformational rearrangement of the enzyme, which relieves auto-inhibitory interactions and thereby enables PKC to phosphorylate its targets. The multi-domain structure and intrinsic flexibility of PKC present remarkable challenges and opportunities for the biophysical and structural biology studies of this class of enzymes and their interactions with membranes – the major focus of this Current Topics article. I will highlight the recent advances in the field, outline the current challenges, and identify areas where biophysics and structural biology approaches can provide insight into the isoenzyme-specific regulation of PKC activity.

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“…Cleavage of the sterically congested but more electron-rich C16/C17 alkene in 14 provided a second test of our plan. Gratifyingly, a stoichiometric ozonolysis reaction resulted in chemoselective cleavage of the C16/C17 alkene to afford aldehyde 15 in 93% yield (25). …”

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confidence: 99%

Scalable synthesis of bryostatin 1 and analogs, adjuvant leads against latent HIV

Wender

Hardman

et al. 2017

Science

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100

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Bryostatin 1 is an exceedingly scarce marine-derived natural product that is in clinical development directed at HIV/AIDS eradication, cancer immunotherapy, and the treatment of Alzheimer’s disease. Despite this unique portfolio of indications, its availability has been limited and variable, thus impeding research and clinical studies. Here, we report a total synthesis of bryostatin 1 that proceeds in 29 total steps (19 in the longest linear sequence, >80% average yield per step), collectively produces grams of material, and can be scaled to meet clinical needs (~20 grams per year). This practical solution to the bryostatin supply problem also opens broad, facile, and efficient access to derivatives and potentially superior analogs.

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Total Synthesis of Bryostatin 9

Abstract: The total synthesis of bryostatin 9 was accomplished using a uniquely step economical and convergent Prins-driven macrocyclization strategy. At 25 linear and 42 total steps, this is currently the most concise and convergent (5 steps post fragment coupling) synthesis of a potent bryostatin.

Cited by 116 publications

References 69 publications

Capturing Biological Activity in Natural Product Fragments by Chemical Synthesis

Capturing Biological Activity in Natural Product Fragments by Chemical Synthesis

Dynamics and Membrane Interactions of Protein Kinase C

Scalable synthesis of bryostatin 1 and analogs, adjuvant leads against latent HIV

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