Recent Synthesis and Discovery of Brefeldin A Analogs

Paek, Seung‐Mann

doi:10.3390/md16040133

Cited by 27 publications

(16 citation statements)

References 35 publications

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“…86 The recent synthesis and discovery of new brefeldin A analogs has been reviewed in detail. 87 Numerous analogues were synthesized to improve drug-like properties and various prodrug strategies were considered as well ( Fig. 5).…”

Section: Brefeldinsmentioning

confidence: 99%

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Natural products as modulators of eukaryotic protein secretion

Luesch

Paavilainen

2020

Nat. Prod. Rep.

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Covering: up to the end of 2019 Diverse natural product small molecules have allowed critical insights into processes that govern eukaryotic cells' ability to secrete cytosolically synthesized secretory proteins into their surroundings or to insert newly synthesized integral membrane proteins into the lipid bilayer of the endoplasmic reticulum. In addition, many components of the endoplasmic reticulum, required for protein homeostasis or other processes such as lipid metabolism or maintenance of calcium homeostasis, are being investigated for their potential in modulating human disease conditions such as cancer, neurodegenerative conditions and diabetes. In this review, we cover recent findings up to the end of 2019 on natural products that influence protein secretion or impact ER protein homeostasis, and serve as powerful chemical tools to understand protein flux through the mammalian secretory pathway and as leads for the discovery of new therapeutics.

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Section: Brefeldinsmentioning

confidence: 99%

“…5). 87 BFA is a classical tool compound used in cell biology studies as a secretion inhibitor because of its action on the Golgi apparatus and endosomes. 88,89 The elucidation of its mechanism of action led to the concept of interfacial inhibition as a way to stabilize protein-protein interactions (PPI) instead of inhibiting PPI 90 (Fig.…”

Section: Brefeldinsmentioning

confidence: 99%

Natural products as modulators of eukaryotic protein secretion

Luesch

Paavilainen

2020

Nat. Prod. Rep.

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“…To validate our drug repurposing findings, we chose to assess the anti-inflammatory properties of BFA and investigate a possible underlying mechanism of benefiting IBD patients. BFA has been widely studied for its antitumor, antifungal, and antiviral effects and apoptosis-inducing property 76 . BFA not only effectively inhibits protein trafficking from the endoplasmic reticulum (ER) to the Golgi apparatus 58 , but also blocks type I IFN production by impeding the translocation of STING to the ER-Golgi intermediate compartment 59 .…”

Section: Discussionmentioning

confidence: 99%

Microbial and genetic-based framework identifies drug targets in inflammatory bowel disease

Wang¹,

Guo²,

Gao³

et al. 2021

Theranostics

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Rationale: With increasing incidence and prevalence of inflammatory bowel disease (IBD), it has become one of the major public health threats, and there is an urgent need to develop new therapeutic agents. Although the pathogenesis of IBD is still unclear, previous research has provided evidence for complex interplays between genetic, immune, microbial, and environmental factors. Here, we constructed a gene-microbiota interaction-based framework to discover IBD biomarkers and therapeutics. Methods: We identified candidate biomarkers for IBD by analyzing the publicly available transcriptomic and microbiome data from IBD cohorts. Animal models of IBD and diarrhea were established. The inflammation-correlated microbial and genetic variants in gene knockout mice were identified by 16S rRNA sequences and PCR array. We performed bioinformatic analysis of microbiome functional prediction and drug repurposing. Our validation experiments with cells and animals confirmed anti-inflammatory properties of a drug candidate. Results: We identified the DNA-sensing enzyme cyclic GMP-AMP synthase (cGAS) as a potential biomarker for IBD in both patients and murine models. cGAS knockout mice were less susceptible to DSS-induced colitis. cGAS-associated gut microbiota and host genetic factors relating to IBD pathogenesis were also identified. Using a computational drug repurposing approach, we predicted 43 candidate drugs with high potency to reverse colitis-associated gene expression and validated that brefeldin-a mitigates inflammatory response in colitis mouse model and colon cancer cell lines. Conclusions: By integrating computational screening, microbiota interference, gene knockout techniques, and in vitro and in vivo validation, we built a framework for predicting biomarkers and host-microbe interaction targets and identifying repurposing drugs for IBD, which may be tested further for clinical application. This approach may also be a tool for repurposing drugs for treating other diseases.

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“…The unique biological profile of brefeldin A, C, and analogues has attracted a lot of interest in the synthetic organic chemistry community. The first synthesis of the racemic brefeldin A was reported by Corey and Wollenberg in 1976 followed by around 40 total and formal syntheses .…”

Section: Figurementioning

confidence: 99%

A Short Synthesis of (+)‐Brefeldin C through Enantioselective Radical Hydroalkynylation

Gnägi

Martz

Meyer

et al. 2019

Chemistry A European J

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Av ery conciset otal synthesis of (+ +)-brefeldin C starting from 2-furanylcyclopentene is described. This approach is based on an unprecedented enantioselective radical hydroalkynylation process to introduce the two cyclopentanes tereocenters in as ingle step. The use of a furan substituent allows ah igh trans diastereoselectivity to be achieved duringt he radicalp rocess and it contains the four carbona toms C1-C4 of the natural product in an oxidation state closely relatedt ot he one of the target molecule. The eight-step synthesis requires six product purifications and it provides (+ +)-brefeldin Ci n1 8% overall yield.[**] Ap revious versiono ft his manuscript has been deposited on ap reprint server (https://doi.org/10.26434/chemrxiv.8397731.v1)Supporting information and the ORCID identification number(s) for the author(s) of this articlecan be found under: https://doi.

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Recent Synthesis and Discovery of Brefeldin A Analogs

Cited by 27 publications

References 35 publications

Natural products as modulators of eukaryotic protein secretion

Natural products as modulators of eukaryotic protein secretion

Microbial and genetic-based framework identifies drug targets in inflammatory bowel disease

A Short Synthesis of (+)‐Brefeldin C through Enantioselective Radical Hydroalkynylation

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