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

Wender, Paul A.; Hardman, Clayton; Ho, Stephen; Jeffreys, Matthew S.; Maclaren, Jana K.; Quiroz, Ryan V.; Ryckbosch, Steven M.; Shimizu, Akira; Sloane, Jack L.; Stevens, Matthew C.

doi:10.1126/science.aan7969

Cited by 89 publications

(102 citation statements)

References 74 publications

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“…1d) from two synthetically accessible building blocks ( Fig. 1d) 44 . This study provided a synthetic supply (>2 g) of bryostatin 1 that is required to support synthesis studies.…”

Section: Resultsmentioning

confidence: 99%

“…Aquaculture and engineered biosynthesis have been explored, but the former encountered capitalization and yield problems and the latter difficulties in cultivation of the symbiotic bacterium necessary for production of bryostatin 1 43 . Recently, we reported a solution to this supply problem, a scalable synthesis of bryostatin 1, that has afforded sustainable access to gram scale quantities of the natural product as needed to ensure further research and its continued clinical evaluation 44 . Additionally as reported herein, our chemical synthesis also serves as a platform for accessing bryostatin analogs and the exploration of structure-function relationships, thereby enabling the design and synthesis of potentially more accessible, more efficacious and better tolerated bryostatin-inspired leads.…”

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confidence: 99%

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Synthesis and evaluation of designed PKC modulators for enhanced cancer immunotherapy

Hardman

Shimizu

et al. 2020

Nat Commun

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Bryostatin 1 is a marine natural product under investigation for HIV/AIDS eradication, the treatment of neurological disorders, and enhanced CAR T/NK cell immunotherapy. Despite its promising activity, bryostatin 1 is neither evolved nor optimized for the treatment of human disease. Here we report the design, synthesis, and biological evaluation of several close-in analogs of bryostatin 1. Using a function-oriented synthesis approach, we synthesize a series of bryostatin analogs designed to maintain affinity for bryostatin's target protein kinase C (PKC) while enabling exploration of their divergent biological functions. Our latestage diversification strategy provides efficient access to a library of bryostatin analogs, which per our design retain affinity for PKC but exhibit variable PKC translocation kinetics. We further demonstrate that select analogs potently increase cell surface expression of CD22, a promising CAR T cell target for the treatment of leukemias, highlighting the clinical potential of bryostatin analogs for enhancing targeted immunotherapies.

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“…1d) from two synthetically accessible building blocks ( Fig. 1d) 44 . This study provided a synthetic supply (>2 g) of bryostatin 1 that is required to support synthesis studies.…”

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Synthesis and evaluation of designed PKC modulators for enhanced cancer immunotherapy

Hardman

Shimizu

et al. 2020

Nat Commun

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“…Scheme11. Convergent synthesis of bryostatin 1, Wender (2017). MMPP = magnesium monoperoxyphthalate,2 ,2-DMP = 2,2-dimethoxypropane, TBDPSCl = tert-butyl(chloro)diphenylsilane, PPTS = pyridinium p-toluenesulfonate, NaHMDS = sodium bis(trimethylsilyl)amide.…”

Section: Bryostatin 1( Wender2 017)mentioning

confidence: 99%

Empowering Synthesis of Complex Natural Products

Hernandez

Šarlah

2019

Chemistry A European J

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Synthesis of natural products remains a daring task. Their richly diverse and intricate structures often encompass a large degree of unsaturation, contain fused and/or bridged rings, or possess numerous stereogenic centers. Thus, their preparation requires significant synthetic overhead, detracting from their overall practicality as well as hampering the ability of medicinal chemists to synthesize derivatives for pharmaceutical optimization and structure‐activity relationship studies. The purpose of this Minireview is to showcase recent examples of efficient total syntheses. Emphasis was not given to the evaluation of ideality or economies (quality), but rather to the practicality (quality with quantity).

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“…Attempts to resolve these issues have proven to be either ineffective or prohibitively costly (Mendola, 2003). Syntheses of several bryostatins have been reported (Keck, Poudel, Cummins, Rudra, & Covel, 2010; Lu, Woo, & Krische, 2011; Manaviazar & Hale, 2011; Wender & Schrier, 2011), and a recent “scalable” total synthesis of bryostatin-1 has recently been accomplished (Wender et al, 2017). Bryostatin analogs (termed “bryologs”) show promise (DeChristopher, Fan, Felsher, & Wender, 2012; Staveness et al, 2016; Wender et al, 2011), however, a simplified and effective replacement for bryostatin-1 has yet to be developed.…”

Section: Introductionmentioning

confidence: 99%

Chemoenzymatic Dissection of Polyketide β-Branching in the Bryostatin Pathway

Slocum

Lowell

Tripathi

et al. 2018

Methods in Enzymology

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β-Branching is an expansion upon canonical polyketide synthase extension that allows for the installation of diverse chemical moieties in several natural products. Several of these moieties are unique among natural products, including the two vinyl methylesters found in the core structure of bryostatins. This family of molecules is derived from an obligate bacterial symbiont of a sessile marine bryozoan, Bugula neritina. Within this family, bryostatin 1 has been investigated as an anticancer, neuroprotective, and immunomodulatory compound. We have turned to the biosynthetic gene cluster within the bacterial symbiont to investigate the biosynthesis of bryostatins. Recent sequencing efforts resulted in the annotation of two missing genes: bryT and bryU. Using novel chemoenzymatic techniques, we have validated these as the missing enoyl-CoA hydratase and donor acyl carrier protein, essential components of the β-branching cassette of the bryostatin pathway. Together, this cassette installs the vinyl methylester moieties essential to the activity of bryostatins.

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

Cited by 89 publications

References 74 publications

Synthesis and evaluation of designed PKC modulators for enhanced cancer immunotherapy

Synthesis and evaluation of designed PKC modulators for enhanced cancer immunotherapy

Empowering Synthesis of Complex Natural Products

Chemoenzymatic Dissection of Polyketide β-Branching in the Bryostatin Pathway

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