19926-50-2Relevant articles and documents
Homogeneous Catalysts Supported on Soluble Polymers: Biphasic Suzuki-Miyaura Coupling of Aryl Chlorides Using Phase-Tagged Palladium-Phosphine Catalysts
An Der Heiden, Markus,Plenio, Herbert
, p. 1789 - 1797 (2004)
The Suzuki-Miyaura coupling of aryl chlorides and PhB(OH)2 under biphasic conditions (DMSO/heptane) can be performed in almost quantitative yields over several cycles by means of polymeric Pd catalysts with soluble polyethylene glycol phase tags. Three sterically demanding and electron-rich phosphines 1-CH2Br,4-CH2P(1-Ad) 2-C6H4, and 2-PCy2,2′ -OH-biphenyl, and 2-PtBu2,2′-OH-biphenyl were covalently bonded to 2000 Dalton MeOPEG-OH. The catalysts, which were formed in situ from Na2[PdCl4], the respective polymeric phosphine, KF/K 3PO4, and PhB(OH)2, efficiently couple aryl chlorides at 80°C at 0.5 mol% loading, resulting in a > 90% yield of the respective biphenyl derivatives. The use of polar phase tags allows the efficient recovery of palladium-phosphine catalysts by simple phase separation of the catalyst-containing DMSO solution and the product-containing n-heptane phase. The high activity (TOF) of the catalyst remains almost constant over more than five reaction cycles, which involve the catalytic reaction, separation of the product phase from the catalyst phase, and addition of new reactants to initiate the next cycle. The Buchwald type biphenyl phosphines form the most active Pd catalysts, which are 1.3-2.8 times more active than catalysts derived from diadamantyl-benzylphosphine, but appear to be less robust in the recycling experiments. There is no apparent leaching of the catalyst into the heptane solution ( 0.05%), as evidenced by spectrophotometric measurements, and contamination of the product with Pd is avoided.
Identification and Optimization of Novel Small-Molecule Cas9 Inhibitors by Cell-Based High-Throughput Screening
Lee, Sang-Woo,Tran, Kim Tai,Vazquez-Uribe, Ruben,Gotfredsen, Charlotte Held,Clausen, Mads Hartvig,Mendez, Blanca Lopez,Montoya, Guillermo,Bach, Anders,Sommer, Morten Otto Alexander
, p. 3266 - 3305 (2022/02/23)
CRISPR/Cas9 has revolutionized several areas of life science; however, methods to control the Cas9 activity are needed for both scientific and therapeutic applications. Anti-CRISPR proteins are known to inhibit the CRISPR/Cas adaptive immunity; however, in vivo delivery of such proteins is problematic. Instead, small-molecule Cas9 inhibitors could serve as useful tools due to their permeable, proteolytically stable, and non-immunogenic nature. Here, we identified a small-molecule ligand with anti-CRISPR/Cas9 activity through a high-throughput screening utilizing an Escherichia coli selection system. Extensive structure-activity relationship studies, which involved a deconstruction-reconstruction strategy, resulted in a range of analogues with significant improvements in the inhibitory activity. Based on NMR and electrophoretic mobility shift assays, we propose that the inhibitory action of these compounds likely results from direct binding to apo-Cas9, preventing Cas9:gRNA complex formation. These molecules may find use as Cas9 modulators in various applications.
1,2,4-Triazole-3-thione compounds with a 4-ethyl alkyl/aryl sulfide substituent are broad-spectrum metallo-β-lactamase inhibitors with re-sensitization activity
Becker, Katja,Benvenuti, Manuela,Bossis, Guillaume,Conde, Pierre-Alexis,Crowder, Michael W.,Dillenberger, Melissa,Docquier, Jean-Denis,Gavara, Laurent,Hernandez, Jean-Fran?ois,Legru, Alice,Mangani, Stefano,Pozzi, Cecilia,Sannio, Filomena,Tassone, Giusy,Thomas, Caitlyn A.,Verdirosa, Federica
supporting information, (2021/10/12)
Metallo-β-lactamases (MBLs) are important contributors of Gram-negative bacteria resistance to β-lactam antibiotics. MBLs are highly worrying because of their carbapenemase activity, their rapid spread in major human opportunistic pathogens while no clinically useful inhibitor is available yet. In this context, we are exploring the potential of compounds based on the 1,2,4-triazole-3-thione scaffold as an original ligand of the di-zinc active sites of MBLs, and diversely substituted at its positions 4 and 5. Here, we present a new series of compounds substituted at the 4-position by a thioether-containing alkyl chain with a carboxylic and/or an aryl group at its extremity. Several compounds showed broad-spectrum inhibition with Ki values in the μM to sub-μM range against VIM-type enzymes, NDM-1 and IMP-1. The presence of the sulfur and of the aryl group was important for the inhibitory activity and the binding mode of a few compounds in VIM-2 was revealed by X-ray crystallography. Importantly, in vitro antibacterial susceptibility assays showed that several inhibitors were able to potentiate the activity of meropenem on Klebsiella pneumoniae clinical isolates producing VIM-1 or VIM-4, with a potentiation effect of up to 16-fold. Finally, a selected compound was found to only moderately inhibit the di-zinc human glyoxalase II, and several showed no or only moderate toxicity toward several human cells, thus favourably completing a promising behaviour.
Structure-activity relationship studies for the development of inhibitors of murine adipose triglyceride lipase (ATGL)
Breinbauer, Rolf,Doler, Carina,Fuchs, Elisabeth,Grabner, Gernot F.,Mayer, Nicole,Melcher, Michaela-Christina,Migglautsch, Anna K.,Romauch, Matthias,Schweiger, Martina,Zechner, Rudolf,Zimmermann, Robert
supporting information, (2020/07/13)
High serum fatty acid (FA) levels are causally linked to the development of insulin resistance, which eventually progresses to type 2 diabetes and non-alcoholic fatty liver disease (NAFLD) generalized in the term metabolic syndrome. Adipose triglyceride lipase (ATGL) is the initial enzyme in the hydrolysis of intracellular triacylglycerol (TG) stores, liberating fatty acids that are released from adipocytes into the circulation. Hence, ATGL-specific inhibitors have the potential to lower circulating FA concentrations, and counteract the development of insulin resistance and NAFLD. In this article, we report about structure–activity relationship (SAR) studies of small molecule inhibitors of murine ATGL which led to the development of Atglistatin. Atglistatin is a specific inhibitor of murine ATGL, which has proven useful for the validation of ATGL as a potential drug target.
