Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Total synthesis of bryostatin 1.

ABSTRACT: Bryostatin 1 is a marine natural product that is a very promising lead compound because of the potent biological activity it displays against a variety of human disease states. We describe herein the first total synthesis of this agent. The synthetic route adopted is a highly convergent one in which the preformed, heavily functionalized pyran rings A and C are united by "pyran annulation", the TMSOTf-promoted reaction between a hydroxyallylsilane appended to the A-ring fragment and an aldehyde contained in the C-ring fragment, with concomitant formation of the B ring. Further elaborations of the resulting very highly functionalized intermediate include macrolactonization and selective cleavage of just one of five ester linkages present.

SUBMITTER: Keck GE

PROVIDER: S-EPMC3030632 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Total synthesis of bryostatin 1.

Keck Gary E GE Poudel Yam B YB Cummins Thomas J TJ Rudra Arnab A Covel Jonathan A JA

Journal of the American Chemical Society 20101222 4

Bryostatin 1 is a marine natural product that is a very promising lead compound because of the potent biological activity it displays against a variety of human disease states. We describe herein the first total synthesis of this agent. The synthetic route adopted is a highly convergent one in which the preformed, heavily functionalized pyran rings A and C are united by "pyran annulation", the TMSOTf-promoted reaction between a hydroxyallylsilane appended to the A-ring fragment and an aldehyde c ...[more]

PMID: 21175177

Similar Datasets

Total synthesis of bryostatin 9.

Project description: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 synthesis of a potent bryostatin.

| S-EPMC3129979 | biostudies-literature

Total synthesis of bryostatin 16 using atom-economical and chemoselective approaches.

Project description:Of the concepts used to improve the efficiency of organic syntheses, two have been especially effective: atom economy (the use of routes in which most of the atoms present in the reactants also end up in the product) and chemoselectivity (the use of reactions that take place only at desired positions in a molecule). Synthesis of complex natural products is the most demanding arena in which to explore such principles. The bryostatin family of compounds are especially interesting targets, because they combine structural complexity with promising biological activity. Furthermore, synthetic routes to some bryostatins have already been reported, providing a benchmark against which new syntheses can be measured. Here we report a concise total synthesis of bryostatin 16 (1), a parent structure from which almost all other bryostatins could in principle be accessed. Application of atom-economical and chemoselective reactions currently under development provides ready access to polyhydropyran motifs in the molecule, which are common structural features of many other natural products. The most notable transformations are two transition-metal-catalysed reactions. The first is a palladium-catalysed reaction of two different alkynes to form a large ring. The product of this step is then converted into a dihydropyran (the 'C ring' of bryostatins) in the second key reaction, which is catalysed by a gold compound. Analogues of bryostatin that do not exist in nature could be readily made by following this route, which might allow the biological activity of bryostatins to be fine-tuned.

| S-EPMC2728752 | biostudies-literature

Total synthesis of bryostatin 7 via C-C bond-forming hydrogenation.

Project description:The marine macrolide bryostatin 7 is prepared in 20 steps (longest linear sequence) and 36 total steps with five C-C bonds formed using hydrogenative methods. This approach represents the most concise synthesis of any bryostatin reported, to date.

| S-EPMC3164899 | biostudies-literature

Total synthesis of bryostatin 16 using a Pd-catalyzed diyne coupling as macrocyclization method and synthesis of C20-epi-bryostatin 7 as a potent anticancer agent.

Project description:Asymmetric total synthesis of bryostatin 16 was achieved in 26 steps in the longest linear sequence and in 39 total steps from aldehyde 10. A Pd-catalyzed alkyne-alkyne coupling was employed for the first time as a macrocyclization method in a natural product synthesis. A route to convert bryostatin 16 to a new family of bryostatin analogues was developed. Toward this end, 20-epi-bryostatin 7 was synthesized from a bryostatin 16-like intermediate; the key step involves a Re-catalyzed epoxidation/ring-opening reaction. Preliminary biological studies indicated that this new analogue exhibits nanomolar anti-cancer activity against several cancer cell lines.

| S-EPMC2993185 | biostudies-literature

Synthesis and Biological Evaluation of Fluorescent Bryostatin Analogues.

Project description:To investigate the cellular distribution of tumor-promoting vs. non-tumor-promoting bryostatin analogues, we synthesized fluorescently labeled variants of two bryostatin derivatives that have previously shown either phorbol ester-like or bryostatin-like biological activity in U937 leukemia cells. These new fluorescent analogues both displayed high affinity for protein kinase?C (PKC) binding and retained the basic properties of the parent unlabeled compounds in U937 assays. The fluorescent compounds showed similar patterns of intracellular distribution in cells, however; this argues against an existing hypothesis that various patterns of intracellular distribution are responsible for differences in biological activity. Upon further characterization, the fluorescent compounds revealed a slow rate of cellular uptake; correspondingly, they showed reduced activity for cellular responses that were only transient upon treatment with phorbol ester or bryostatin?1.

| S-EPMC6980389 | biostudies-literature

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

Project description: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.

| S-EPMC5714505 | biostudies-literature

Design, synthesis, and evaluation of potent bryostatin analogs that modulate PKC translocation selectivity.

Project description:Modern methods for the identification of therapeutic leads include chemical or virtual screening of compound libraries. Nature's library represents a vast and diverse source of leads, often exhibiting exquisite biological activities. However, the advancement of natural product leads into the clinic is often impeded by their scarcity, complexity, and nonoptimal properties or efficacy as well as the challenges associated with their synthesis or modification. Function-oriented synthesis represents a strategy to address these issues through the design of simpler and therefore synthetically more accessible analogs that incorporate the activity-determining features of the natural product leads. This study illustrates the application of this strategy to the design and synthesis of functional analogs of the bryostatin marine natural products. It is specifically directed at exploring the activity-determining role of bryostatin A-ring functionality on PKC affinity and selectivity. The resultant functional analogs, which were prepared by a flexible, modular synthetic strategy, exhibit excellent affinity to PKC and differential isoform selectivity. These and related studies provide the basic information needed for the design of simplified and thus synthetically more accessible functional analogs that target PKC isoforms, major targets of therapeutic interest.

| S-EPMC3084132 | biostudies-literature

Synthesis and Biological Evaluation of Several Bryostatin Analogues Bearing a Diacylglycerol Lactone C-Ring.

Project description:As an initial step in designing a simplified bryostatin hybrid molecule, three bryostatin analogues bearing a diacylglycerol lactone-based C-ring, which possessed the requisite pharmacophores for binding to protein kinase C (PKC) together with a modified bryostatin-like A- and B-ring region, were synthesized and evaluated. Merle 46 and Merle 47 exhibited binding affinity to PKC alpha with Ki values of 7000 ± 990 and 4940 ± 470 nM, respectively. Reinstallation of the trans-olefin and gem-dimethyl group present in bryostatin 1 in Merle 48 resulted in improved binding affinity, 363 ± 42 nM. While Merle 46 and 47 were only marginally active biologically, Merle 48 showed sufficient activity on the U937 cells to confirm that it was PMA-like for growth and attachment, as predicted by the substitution pattern of its A- and B-rings.

| S-EPMC6957265 | biostudies-literature

Concise synthesis of the bryostatin A-ring via consecutive C-C bond forming transfer hydrogenations.

Project description:Under the conditions of C-C bond forming transfer hydrogenation, 1,3-propanediol 1 engages in double asymmetric carbonyl allylation to furnish the C(2)-symmetric diol 2. Double ozonolysis of 2 followed by TBS protection delivers aldehyde 3, which is subject to catalyst directed carbonyl reverse prenylation via transfer hydrogenation to deliver neopentyl alcohol 4 and, ultimately, the bryostatin A-ring 7. Through use of two consecutive C-C bond forming transfer hydrogenations, the Evans' bryostatin A-ring 7 is prepared in less than half the manipulations previously reported.

| S-EPMC2727624 | biostudies-literature

Total synthesis of (+)-dactylolide.

Project description:[reaction: see text] The development of an approach leading to the total synthesis of dactylolide is described. The key features of this route include a catalytic asymmetric allylation, a diastereoselective pyran annulation, and a Horner-Wadsworth-Emmons macrocyclization.

| S-EPMC1480405 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data