Total Synthesis of Bryostatin 1: A Short Route

Manaviazar, Soraya; Hale, Karl J.

doi:10.1002/anie.201101562

Cited by 30 publications

(14 citation statements)

References 31 publications

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“…In some of the earlier trials, the mode of delivery (a bolus at or close to the maximum tolerated dose or MTD) may have been the major problem, as myalgia was a serious side effect. In 2011, the Keck group reported the first complete total synthesis of bryostatin 1 [131], which was rapidly followed by a paper from Manaviazar and Hale with details of a shorter route to the same compound [132]. Later the same year, Trost et al published papers on the ring-expanded versions of bryostatins obtained by total synthesis, so the synthetic story of this class of macrocycles has not yet finished [133,134].…”

Section: Pipecolidepsin Stellatolide a And Irvalecmentioning

confidence: 99%

Drugs and Drug Candidates from Marine Sources: An Assessment of the Current “State of Play”

2016

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The potential of the marine environment to produce candidate compounds (structures) as leads to, or even direct drugs from, has been actively discussed for the last 50 or so years. Over this time frame, several compounds have led to drugs, usually in the area of cancer (due to funding sources). This review is designed to show where there have been successes, but also to show that in a number of disease areas, there are structures originally isolated from marine invertebrates and free-living microbes that have potential, but will need to be ?adopted? by pharmaceutical houses in order to maximize their potential.

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Section: Pipecolidepsin Stellatolide a And Irvalecmentioning

confidence: 99%

Drugs and Drug Candidates from Marine Sources: An Assessment of the Current “State of Play”

2016

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“…This situation is now changing. Recent advances in bryostatin chemistry are now making it possible to design bryostatin derivatives to address these issues [27][28][29][30].…”

Section: Introductionmentioning

confidence: 99%

Biological activity of the bryostatin analog Merle 23 on mouse epidermal cells and mouse skin

Kelsey

Cataisson

Chen

et al. 2016

Molecular Carcinogenesis

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Bryostatin 1, a complex macrocyclic lactone, is the subject of multiple clinical trials for cancer chemotherapy. Although bryostatin 1 biochemically functions like the classic mouse skin tumor promoter phorbol 12-myristate 13-acetate (PMA) to bind to and activate protein kinase C, paradoxically, it fails to induce many of the typical phorbol ester responses, including tumor promotion. Intense synthetic efforts are currently underway to develop simplified bryostatin analogs that preserve the critical functional features of bryostatin 1, including its lack of tumor promoting activity. The degree to which bryostatin analogs maintain the unique pattern of biological behavior of bryostatin 1 depends on the specific cellular system and the specific response. Merle 23 is a significantly simplified bryostatin analog that retains bryostatin like activity only to a limited extent. Here, we show that in mouse epidermal cells the activity of Merle 23 was either similar to bryostatin 1 or intermediate between bryostatin 1 and PMA, depending on the specific parameter examined. We then examined the hyperplastic and tumor promoting activity of Merle 23 on mouse skin. Merle 23 showed substantially reduced hyperplasia and was not tumor promoting at a dose comparable to that for PMA. These results suggest that there may be substantial flexibility in the design of bryostatin analogs that retain its lack of tumor promoting activity. © 2016 Wiley Periodicals, Inc.

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“…Synthetic organic chemistry has often been touted as the solution to the supply problem of sufficient amounts of bioactive compounds from marine invertebrates for drug development. However, the structural and stereochemical complexity of bioactive compounds remains a significant challenge in this regard [220,221]. Bryostatin-1 synthesis, for example, requires 60 steps [221].…”

Section: Chemical Synthesismentioning

confidence: 99%

“…However, the structural and stereochemical complexity of bioactive compounds remains a significant challenge in this regard [220,221]. Bryostatin-1 synthesis, for example, requires 60 steps [221]. There is thus some irony in the fact that the same complexity which results in a plethora of bioactivities, often with different modes of action, also results in synthetic pathways consisting of >40 chemical steps which are generally not considered short enough for realistic pharmaceutical exploitation.…”

Section: Chemical Synthesismentioning

confidence: 99%

The Phylum Bryozoa: From Biology to Biomedical Potential

et al. 2020

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Less than one percent of marine natural products characterized since 1963 have been obtained from the phylum Bryozoa which, therefore, still represents a huge reservoir for the discovery of bioactive metabolites with its ~6000 described species. The current review is designed to highlight how bryozoans use sophisticated chemical defenses against their numerous predators and competitors, and which can be harbored for medicinal uses. This review collates all currently available chemoecological data about bryozoans and lists potential applications/benefits for human health. The core of the current review relates to the potential of bryozoan metabolites in human diseases with particular attention to viral, brain, and parasitic diseases. It additionally weighs the pros and cons of total syntheses of some bryozoan metabolites versus the synthesis of non-natural analogues, and explores the hopes put into the development of biotechnological approaches to provide sustainable amounts of bryozoan metabolites without harming the natural environment.

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Total Synthesis of Bryostatin 1: A Short Route

Cited by 30 publications

References 31 publications

Drugs and Drug Candidates from Marine Sources: An Assessment of the Current “State of Play”

Drugs and Drug Candidates from Marine Sources: An Assessment of the Current “State of Play”

Biological activity of the bryostatin analog Merle 23 on mouse epidermal cells and mouse skin

The Phylum Bryozoa: From Biology to Biomedical Potential

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