Synthesis of Stereochemically and Skeletally Diverse Fused Ring Systems from Functionalized <i>C</i>-Glycosides

Gerard, Baudouin; Lee, Maurice D.; Dandapani, Sivaraman; Duvall, Jeremy R.; Fitzgerald, Mark E.; Kesavan, Sarathy; Lowe, Jason T.; Marié, Jean-Charles; Pandya, Bhaumik A.; Suh, Beomseok; O’Shea, Morgan Welzel; Dombrowski, Michael T.; Hamann, Diane; Lemercier, Bérénice C.; Murillo, Tiffanie; Akella, Lakshmi B.; Foley, Michael A.; Marcaurelle, Lisa A.

doi:10.1021/jo4000916

Cited by 21 publications

(18 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Tetrahydroisoquinoline 10 , from a DOS library and shown in Table 1, is the most abundant scaffold (36 analogs) representing nearly 12% of all hits and including the most potent hit identified with an IC 50 value of 75 nM. Another interesting DOS scaffold (6 analogs) is the oxazocane typified by 17 (Gerard, et al, 2013). Several other DOS scaffolds registered as hits (Table S1) including benzooxathiazocines (Gerard, et al, 2011), monocyclic azetidine nitriles (Lowe, et al, 2012), and tricyclic pyridones (Marcaurelle, et al, 2009).…”

Section: Resultsmentioning

confidence: 99%

Target-Based Identification of Whole-Cell Active Inhibitors of Biotin Biosynthesis in Mycobacterium tuberculosis

Park

Casalena

Wilson

et al. 2015

Chemistry & Biology

View full text Add to dashboard Cite

SUMMARY Biotin biosynthesis is essential for survival and persistence of Mycobacterium tuberculosis (Mtb) in vivo. The aminotransferase BioA, which catalyzes the antepenultimate step in the biotin pathway, has been established as a promising target due to its vulnerability to chemical inhibition. We performed high-throughput screening (HTS) employing a fluorescence displacement assay and identified a diverse set of potent inhibitors including many diversity-oriented synthesis (DOS) scaffolds. To efficiently select only hits targeting biotin biosynthesis, we then deployed a whole-cell counter-screen in either biotin-free and biotin-containing medium against wild-type Mtb and in parallel with isogenic bioA Mtb strains that possess differential levels of BioA expression. This counter-screen proved crucial to filter out compounds whose whole-cell activity was off-target as well as identify hits with weak, but measurable whole-cell activity in BioA-depleted strains. Several of the most promising hits were co-crystallized with BioA to provide a framework for future structure-based drug design efforts.

show abstract

Section: Resultsmentioning

confidence: 99%

Target-Based Identification of Whole-Cell Active Inhibitors of Biotin Biosynthesis in Mycobacterium tuberculosis

Park

Casalena

Wilson

et al. 2015

Chemistry & Biology

View full text Add to dashboard Cite

show abstract

“…Confirmed hits with no cell toxicity were further tested for effects on apoB secretion in HepG2 cells. After completing the triaging process and reviewing existing SAR generated from the DOS collection, we identified a benzofuran scaffold [ 24 ] ( Fig. 1A ), which upregulated TRIB1 in both cell lines and was able to reduce apoB secretion in HepG2 cells >30%, thus mimicking the effects of TRIB1 cDNA overexpression [ 14 ].…”

Section: Resultsmentioning

confidence: 99%

“…To this end we developed a qRT-PCR screen to identify compounds that can upregulate TRIB1 expression. We chose to screen the Broad Institute small-molecule library that includes 100,000 novel compounds derived from diversity-oriented synthesis (DOS), a synthetic strategy to access complex and diverse compounds in an efficient manner [ 21 – 24 ]. The DOS compounds are enriched in sp 3 carbons and chiral centers leading to more 3-dimensionality compared to flat, achiral compounds often found in commercial libraries.…”

Section: Introductionmentioning

confidence: 99%

Modulators of Hepatic Lipoprotein Metabolism Identified in a Search for Small-Molecule Inducers of Tribbles Pseudokinase 1 Expression

et al. 2015

Self Cite

View full text Add to dashboard Cite

Recent genome wide association studies have linked tribbles pseudokinase 1 (TRIB1) to the risk of coronary artery disease (CAD). Based on the observations that increased expression of TRIB1 reduces secretion of VLDL and is associated with lower plasma levels of LDL cholesterol and triglycerides, higher plasma levels of HDL cholesterol and reduced risk for myocardial infarction, we carried out a high throughput phenotypic screen based on quantitative RT-PCR assay to identify compounds that induce TRIB1 expression in human HepG2 hepatoma cells. In a screen of a collection of diversity-oriented synthesis (DOS)-derived compounds, we identified a series of benzofuran-based compounds that upregulate TRIB1 expression and phenocopy the effects of TRIB1 cDNA overexpression, as they inhibit triglyceride synthesis and apoB secretion in cells. In addition, the compounds downregulate expression of MTTP and APOC3, key components of the lipoprotein assembly pathway. However, CRISPR-Cas9 induced chromosomal disruption of the TRIB1 locus in HepG2 cells, while confirming its regulatory role in lipoprotein metabolism, demonstrated that the effects of benzofurans persist in TRIB1-null cells indicating that TRIB1 is sufficient but not necessary to transmit the effects of the drug. Remarkably, active benzofurans, as well as natural products capable of TRIB1 upregulation, also modulate hepatic cell cholesterol metabolism by elevating the expression of LDLR transcript and LDL receptor protein, while reducing the levels of PCSK9 transcript and secreted PCSK9 protein and stimulating LDL uptake. The effects of benzofurans are not masked by cholesterol depletion and are independent of the SREBP-2 regulatory circuit, indicating that these compounds represent a novel class of chemically tractable small-molecule modulators that shift cellular lipoprotein metabolism in HepG2 cells from lipogenesis to scavenging.

show abstract

“…7 Beyond this, TRIB1 has recently been implicated in macrophage differentiation and diabetes. 8 Using a cell-based screen of ∼9 K compounds from a diversity oriented synthesis (DOS) screening collection, 9,10 we identified two classes of lead compounds, benzofurans and tricyclic glycals, which induce TRIB1 mRNA. In HepG2 cells, both classes of compounds exhibit time-and dose-dependent effects on TRIB1 expression.…”

Section: Introductionmentioning

confidence: 99%

Novel tricyclic glycal-basedTRIB1inducers that reprogram LDL metabolism in hepatic cells

et al. 2018

Self Cite

View full text Add to dashboard Cite

show abstract

Synthesis of Stereochemically and Skeletally Diverse Fused Ring Systems from Functionalized C-Glycosides

Cited by 21 publications

References 50 publications

Target-Based Identification of Whole-Cell Active Inhibitors of Biotin Biosynthesis in Mycobacterium tuberculosis

Target-Based Identification of Whole-Cell Active Inhibitors of Biotin Biosynthesis in Mycobacterium tuberculosis

Modulators of Hepatic Lipoprotein Metabolism Identified in a Search for Small-Molecule Inducers of Tribbles Pseudokinase 1 Expression

Novel tricyclic glycal-basedTRIB1inducers that reprogram LDL metabolism in hepatic cells

Contact Info

Product

Resources

About