Rethinking the Role of Natural Products: Function‐Oriented Synthesis, Bryostatin, and Bryologs

Wender, Paul A.; Donnelly, Alison C.; Loy, Brian A.; Near, Katherine E.; Staveness, Daryl

doi:10.1002/9783527676545.ch14

Cited by 19 publications

(36 citation statements)

References 167 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The success of NP simplification (truncation) andDTS strategies led to the developmento famore general concept-FOS, as proposed by Wender and co-workersi n2 008. [181] The FOS concept combined the ideas of TOS, the NP truncation strategy, and DTS. The key principle behind FOS is that "the functiono f ab iologically active lead structure can be emulated, tuned, or even improved by replacement with simplerscaffolds designed to incorporate the activity-defining structuralf eatures of the lead compounds."…”

Section: Function-orienteds Ynthesis (Fos)mentioning

confidence: 99%

See 1 more Smart Citation

The Symbiotic Relationship Between Drug Discovery and Organic Chemistry

Grygorenko

Volochnyuk

Ryabukhin

et al. 2019

Chemistry A European J

135

123

View full text Add to dashboard Cite

All pharmaceutical products contain organic molecules; the source may be a natural product or a fully synthetic molecule, or a combination of both. Thus, it follows that organic chemistry underpins both existing and upcoming pharmaceutical products. The reverse relationship has also affected organic synthesis, changing its landscape towards increasingly complex targets. This Review article sets out to give a concise appraisal of this symbiotic relationship between organic chemistry and drug discovery, along with a discussion of the design concepts and highlighting key milestones along the journey. In particular, criteria for a high‐quality compound library design enabling efficient virtual navigation of chemical space, as well as rise and fall of concepts for its synthetic exploration (such as combinatorial chemistry; diversity‐, biology‐, lead‐, or fragment‐oriented syntheses; and DNA‐encoded libraries) are critically surveyed.

show abstract

Section: Function-orienteds Ynthesis (Fos)mentioning

confidence: 99%

“…FOS applications were reviewedr ecently; [181,182,183] hence, only selected examples are given below.I np articular,e nediyne drugs were designed aroundd ynemicin A, which was isolated from Micromonospora chersina in the mid-1980s. This NP has Scheme5.To tal synthesiso fEpoBand its analogues (KI = key intermediate).…”

Section: Function-orienteds Ynthesis (Fos)mentioning

confidence: 99%

The Symbiotic Relationship Between Drug Discovery and Organic Chemistry

Grygorenko

Volochnyuk

Ryabukhin

et al. 2019

Chemistry A European J

135

123

View full text Add to dashboard Cite

show abstract

“…Because different isoforms are associated with different therapeutic indications, access to isoform-selective PKC modulators enables the development of more therapeutically relevant, disease-specific leads (5, 6, 52, 53). This work opens sustainable research access to bryostatin 1 as well as more synthetically accessible analogs that are proving to be more effective and better tolerated in comparative studies with cells, disease models in animals, and ex vivo samples taken from HIV-positive patients (27, 54). …”

mentioning

confidence: 99%

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

Wender

Hardman

et al. 2017

Science

Self Cite

100

View full text Add to dashboard Cite

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.

show abstract

“…This work should be read in conjunction with two excellent reviews published by Wender et al (2014Wender et al ( , 2015, that demonstrated the ability, using modern synthetic techniques, to produce very active bryostatin variants, with an example being the third generation analog (Figure 3; 10). As a result of having readily available bryostatin 1, Wender and collaborators have now demonstrated that this bryostatin 1 and subtle variations such as SUW 133 (Figure 3; 11), can release latent HIV from cell depots in patients (Albert et al, 2017;Marsden et al, 2017).…”

Section: Chemical Syntheses Of Bryostatins and Structural Variationsmentioning

confidence: 99%

“…It should be emphasized that bryostatin 1 is still one of the most potent biological agents tested in antitumor clinical trials, and as mentioned earlier, though the material used in trials sponsored by the NCI, initially came by isolation from massive shallow-water collections off the coast of California, such efforts are no longer necessary. Since synthetic bryostatin 1 and derivatives are now available on a reasonable scale (Wender et al, 2014(Wender et al, , 2015 with these new synthetic techniques, coupled to the ability to make modifications easily, then the biological activities of this class of compounds will definitely increase. As an example, recently there were reports of activity against HIV virus that has been "sequestered" in dendritic cells (Albert et al, 2017;Marsden et al, 2017).…”

Section: The Current Status Of Bryostatinsmentioning

confidence: 99%

“From Large-Scale Collections to the Potential Use of Genomic Techniques for Supply of Drug Candidates”

Newman¹

2018

Front. Mar. Sci.

View full text Add to dashboard Cite

The initial sources of marine-derived compounds that on a small scale exhibited interesting biological activities, were often confined to collection levels ranging from <100 grams to a kilogram. Then if significant interest was shown, collections on a larger scale were made of the nominal source organism. Due to many reasons, including but not limited to realization of the environmental harm that can occur, and in some cases, has occurred, over the last 15 plus years, the paradigm moved to semi-synthesis, total synthesis (sometimes of simpler versions) and the use of genomic techniques both to identify the "source" and then to utilize the data in due course. In this short review, examples of how ideas have changed will range from the early days with the arabinose-containing nucleosides, the sourcing and use of didemnins and their derivatives, work with bryostatins, ecteinascidins and halichondrins, and then demonstrate how molecules derived from dolastatins are now used as "warheads." In most cases the varying methods used will be discussed, albeit in brief in some cases, with the aim of demonstrating how various techniques were used to optimize these compounds and their derivatives. The review finishes with comments as to the current and future involvement of microbes as sources of these and other agents.

show abstract

Rethinking the Role of Natural Products: Function‐Oriented Synthesis, Bryostatin, and Bryologs

Cited by 19 publications

References 167 publications

The Symbiotic Relationship Between Drug Discovery and Organic Chemistry

The Symbiotic Relationship Between Drug Discovery and Organic Chemistry

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

“From Large-Scale Collections to the Potential Use of Genomic Techniques for Supply of Drug Candidates”

Contact Info

Product

Resources

About