scholarly journals Modulating NHC catalysis with fluorine

2013 ◽  
Vol 9 ◽  
pp. 2812-2820 ◽  
Author(s):  
Yannick P Rey ◽  
Ryan Gilmour
Keyword(s):  
Small Molecule ◽  
Heterocyclic Carbenes ◽  
Fluorine Substitution ◽  
X Ray ◽  
Catalytically Active ◽  
Triazolium Salts

Fluorination often confers a range of advantages in modulating the conformation and reactivity of small molecule organocatalysts. By strategically introducing fluorine substituents, as part of a β-fluoroamine motif, in a triazolium pre-catalyst, it was possible to modulate the behaviour of the corresponding N-heterocyclic carbene (NHC) with minimal steric alterations to the catalyst core. In this study, the effect of hydrogen to fluorine substitution was evaluated as part of a molecular editing study. X-ray crystallographic analyses of a number of derivatives are presented and the conformations are discussed. Upon deprotonation, the fluorinated triazolium salts generate catalytically active N-heterocyclic carbenes, which can then participate in the enantioselective Steglich rearrangement of oxazolyl carbonates to C-carboxyazlactones (e.r. up to 87.0:13.0).

Recent Development of Small Molecule Glutaminase Inhibitors

2018 ◽  
Vol 18 (6) ◽  
pp. 432-443 ◽  
Author(s):  
Minsoo Song ◽  
Soong-Hyun Kim ◽  
Chun Young Im ◽  
Hee-Jong Hwang
Keyword(s):  
Small Molecule ◽  
Cell Metabolism ◽  
Phase 1 ◽  
Vital Role ◽  
Glutamine Metabolism ◽  
Inhibition Mechanism ◽  
Tumor Cell Growth ◽  
X Ray ◽  
New Class ◽  
Preclinical And Clinical Studies

Glutaminase (GLS), which is responsible for the conversion of glutamine to glutamate, plays a vital role in up-regulating cell metabolism for tumor cell growth and is considered to be a valuable therapeutic target for cancer treatment. Based on this important function of glutaminase in cancer, several GLS inhibitors have been developed in both academia and industry. Most importantly, Calithera Biosciences Inc. is actively developing the glutaminase inhibitor CB-839 for the treatment of various cancers, and it is currently being evaluated in phase 1 and 2 clinical trials. In this review, recent efforts to develop small molecule glutaminase inhibitors that target glutamine metabolism in both preclinical and clinical studies are discussed. In particular, more emphasis is placed on CB-839 because it is the only small molecule GLS inhibitor being studied in a clinical setting. The inhibition mechanism is also discussed based on X-ray structure studies of thiadiazole derivatives present in glutaminase inhibitor BPTES. Finally, recent medicinal chemistry efforts to develop a new class of GLS inhibitors are described in the hopes of providing useful information for the next generation of GLS inhibitors.

scholarly journals Backbonding contributions to small molecule chemisorption in a metal–organic framework with open copper(i) centers

2021 ◽  
Author(s):  
Gregory M. Su ◽  
Han Wang ◽  
Brandon R. Barnett ◽  
Jeffrey R. Long ◽  
David Prendergast ◽  
...  
Keyword(s):  
Fine Structure ◽  
Small Molecule ◽  
Metal Organic Framework ◽  
X Ray ◽  
Metal Site ◽  
Absorption Fine ◽  
Metal Organic ◽  
X Ray Absorption ◽  
Organic Framework

In situ near edge X-ray absorption fine structure spectroscopy directly probes unoccupied states associated with backbonding interactions between the open metal site in a metal–organic framework and various small molecule guests.

scholarly journals A small molecule compound with an indole moiety inhibits the main protease of SARS-CoV-2 and blocks virus replication

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Shin-ichiro Hattori ◽  
Nobuyo Higashi-Kuwata ◽  
Hironori Hayashi ◽  
Srinivasa Rao Allu ◽  
Jakka Raghavaiah ◽  
...  
Keyword(s):  
Small Molecule ◽  
Covalent Bond ◽  
Amino Acid Residues ◽  
X Ray ◽  
Viral Breakthrough ◽  
Main Protease ◽  
Small Molecule Compound ◽  
Polar Interactions ◽  
High Concentrations

AbstractExcept remdesivir, no specific antivirals for SARS-CoV-2 infection are currently available. Here, we characterize two small-molecule-compounds, named GRL-1720 and 5h, containing an indoline and indole moiety, respectively, which target the SARS-CoV-2 main protease (Mpro). We use VeroE6 cell-based assays with RNA-qPCR, cytopathic assays, and immunocytochemistry and show both compounds to block the infectivity of SARS-CoV-2 with EC50 values of 15 ± 4 and 4.2 ± 0.7 μM for GRL-1720 and 5h, respectively. Remdesivir permitted viral breakthrough at high concentrations; however, compound 5h completely blocks SARS-CoV-2 infection in vitro without viral breakthrough or detectable cytotoxicity. Combination of 5h and remdesivir exhibits synergism against SARS-CoV-2. Additional X-ray structural analysis show that 5h forms a covalent bond with Mpro and makes polar interactions with multiple active site amino acid residues. The present data suggest that 5h might serve as a lead Mpro inhibitor for the development of therapeutics for SARS-CoV-2 infection.

scholarly journals A Personal History of Using Crystals and Crystallography to Understand Biology and Advanced Drug Discovery

Crystals ◽  
2020 ◽  
Vol 10 (8) ◽  
pp. 676
Author(s):  
Tom L. Blundell
Keyword(s):  
Growth Factors ◽  
Drug Discovery ◽  
Cell Surface ◽  
Small Molecule ◽  
Personal History ◽  
X Ray ◽  
Surface Receptors ◽  
The Past ◽  
Industry Collaboration ◽  
History Of

Over the past 60 years, the use of crystals to define structures of complexes using X-ray analysis has contributed to the discovery of new medicines in a very significant way. This has been in understanding not only small-molecule inhibitors of proteins, such as enzymes, but also protein or peptide hormones or growth factors that bind to cell surface receptors. Experimental structures from crystallography have also been exploited in software to allow prediction of structures of important targets based on knowledge of homologues. Crystals and crystallography continue to contribute to drug design and provide a successful example of academia–industry collaboration.

scholarly journals Structural and functional conservation of the programmed −1 ribosomal frameshift signal of SARS-CoV-2

2020 ◽  
Author(s):  
Jamie A. Kelly ◽  
Alexandra N. Olson ◽  
Krishna Neupane ◽  
Sneha Munshi ◽  
Josue San Emeterio ◽  
...  
Keyword(s):  
Molecular Mechanism ◽  
Small Molecule ◽  
Ribosomal Frameshift ◽  
Short Term ◽  
X Ray ◽  
Functional Conservation ◽  
Lead Compounds ◽  
X Ray Scattering ◽  
The World ◽  
Functional Analyses

Abstract17 years after the SARS-CoV epidemic, the world is facing the COVID-19 pandemic. COVID-19 is caused by a coronavirus named SARS-CoV-2. Given the most optimistic projections estimating that it will take over a year to develop a vaccine, the best short-term strategy may lie in identifying virus-specific targets for small molecule interventions. All coronaviruses utilize a molecular mechanism called −1 PRF to control the relative expression of their proteins. Prior analyses of SARS-CoV revealed that it employs a structurally unique three-stemmed mRNA pseudoknot to stimulate high rates of −1 PRF, and that it also harbors a −1 PRF attenuation element. Altering −1 PRF activity negatively impacts virus replication, suggesting that this molecular mechanism may be therapeutically targeted. Here we present a comparative analysis of the original SARS-CoV and SARS-CoV-2 frameshift signals. Structural and functional analyses revealed that both elements promote similar rates of −1 PRF and that silent coding mutations in the slippery sites and in all three stems of the pseudoknot strongly ablated −1 PRF activity. The upstream attenuator hairpin activity has also been functionally retained. Small-angle x-ray scattering indicated that the pseudoknots in SARS-CoV and SARS-CoV-2 had the same conformation. Finally, a small molecule previously shown to bind the SARS-CoV pseudoknot and inhibit −1 PRF was similarly effective against −1 PRF in SARS-CoV-2, suggesting that such frameshift inhibitors may provide promising lead compounds to counter the current pandemic.

N-Heterocyclic carbenes from ylides of indolyl-imidazolium, azaindolyl-imidazolium, and indolyl-triazolium salts, and their borane adducts

Tetrahedron ◽  
2014 ◽  
Vol 70 (45) ◽  
pp. 8672-8680 ◽  
Author(s):  
Nazar Pidlypnyi ◽  
Sebastian Wolf ◽  
Ming Liu ◽  
Kari Rissanen ◽  
Martin Nieger ◽  
...  
Keyword(s):  
Heterocyclic Carbenes ◽  
Triazolium Salts

Unambiguous determination of molecular packing in crystalline donor domains of small molecule solution processed solar cell devices using routine X-ray diffraction techniques

2014 ◽  
Vol 2 (10) ◽  
pp. 3536 ◽  
Author(s):  
Aurélien Viterisi ◽  
Núria F. Montcada ◽  
Challuri Vijay Kumar ◽  
Francesc Gispert-Guirado ◽  
Eddy Martin ◽  
...  
Keyword(s):  
Solar Cell ◽  
Small Molecule ◽  
Molecular Packing ◽  
X Ray Diffraction ◽  
Solution Processed ◽  
X Ray ◽  
Unambiguous Determination

scholarly journals Solution X-Ray Absorption Spectroscopy (XAS) for Analysis of Catalytically Active Species in Reactions with Ethylene by Homogeneous (Imido)vanadium(V) Complexes—Al Cocatalyst Systems

Catalysts ◽  
2019 ◽  
Vol 9 (12) ◽  
pp. 1016 ◽  
Author(s):  
Kotohiro Nomura
Keyword(s):  
Active Species ◽  
Oxidation States ◽  
Donor Ligands ◽  
Ethylene Dimerization ◽  
Edge Structure ◽  
Donor Ligand ◽  
X Ray ◽  
Catalytically Active ◽  
Type V ◽  
X Ray Absorption

Solution V K-edge XANES (X-ray absorption near edge structure) and EXAFS (extended X-ray absorption fine structure) analysis of vanadium(V) complexes containing both imido ligands and anionic ancillary donor ligands (L) of type, V(NR)(L)X2 (R = Ar, Ad (1-adamantyl); Ar = 2,6-Me2C6H3; X = Cl, Me, L = 2-(ArNCH2)C5H4N, OAr, WCA-NHC, and 2-(2’-benzimidazolyl)pyridine; WCA-NHC = anionic NHCs containing weak coordinating B(C6F5)3), which catalyze ethylene dimerization and/or polymerization in the presence of Al cocatalysts, has been explored. Different catalytically actives species with different oxidation states were formed depending upon the Al cocatalyst (MAO, Me2AlCl, AliBu3, etc.) and the anionic ancillary donor ligand employed. The method is useful for obtainment of the direct information of the active species (oxidation state, basic framework around the centered metal) in solution, and for better understanding in catalysis mechanism and organometallic as well as coordination chemistry.

scholarly journals Experiences with CCD detectors on a home X-ray source

1999 ◽  
Vol 55 (10) ◽  
pp. 1669-1671 ◽  
Author(s):  
Steven W. Muchmore
Keyword(s):  
Small Molecule ◽  
High Intensity ◽  
Detection System ◽  
Large Molecule ◽  
Short Exposure ◽  
X Ray Diffraction ◽  
X Ray ◽  
Image Plate ◽  
Ccd Detector ◽  
Ccd Detectors

Charged-coupled device (CCD) detectors have been widely accepted as detectors for collecting X-ray diffraction images. The CCD detector offers a sensitive detection system well suited for diffraction analysis and, compared with other detectors on the market, a relatively rapid system for read-out of the collected image. The two predominant markets for the CCD detector have been those in which relatively short exposure times are used,i.e.small-molecule X-ray diffraction and large-molecule crystallography at high-intensity synchrotron sources. CCD detectors have not been commonly used on rotating-anode X-ray sources for large-molecule crystallography. Comparison of the performance of the CCD detectors with commercially available image-plate detectors shows that the CCD detectors function in a similar fashion to image-plate-based detectors.

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