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Mcintyre Hewitt posted an update 6 months ago
Aspergillus fumigatus is a pathogenic fungus infecting the respiratory system and responsible for a variety of life-threatening lung diseases. A fucose-binding lectin named FleA which has a controversial role in A. fumigatus pathogenesis was recently identified. New chemical probes with high affinity and enzymatic stability are needed to explore the role of FleA in the infection process. In this study, we developed potent FleA antagonists based on optimized and non-hydrolysable thiofucoside ligands. We first synthesized a set of monovalent sugars showing micromolar affinity for FleA by isothermal titration calorimetry. The most potent derivative was co-crystallized with FleA to gain insights into the binding mode in operation. Its chemical multimerization on a cyclodextrin scaffold led to an hexavalent compound with a significantly enhanced binding affinity (Kd = 223 ± 21 nM) thanks to a chelate binding mode. The compound could probe the role of bronchial epithelial cells in a FleA-mediated response to tissue invasion.Presented herein is the discovery that bismuth(iii) trifluoromethanesulfonate (Bi(OTf)3) is an effective catalyst for the activation of glycosyl bromides and glycosyl chlorides. The key objective for the development of this methodology is to employ only one promoter in the lowest possible amount and to avoid using any additive/co-catalyst/acid scavenger except molecular sieves. Bi(OTf)3 works well in promoting the glycosidation of differentially protected glucosyl, galactosyl, and mannosyl halides with many classes of glycosyl acceptors. Most reactions complete within 1 h in the presence of only 35% of green and light-stable Bi(OTf)3 catalyst.Targeted fluorescent molecular probes are useful for cell microscopy, diagnostics, and biological imaging. An emerging discovery paradigm is to screen libraries of fluorescent molecules and identify hit compounds with interesting targeting properties. KD025 molecular weight However, a current limitation with this approach is the lack of fluorescent molecular scaffolds that can produce libraries of probe candidates with three dimensional globular shape, chiral centers, and constrained conformation. This study evaluated a new probe scaffold called squaraine figure-eight (SF8), a self-threaded molecular architecture that is comprised of an encapsulated deep-red fluorescent squaraine dye, surrounding tetralactam macrocycle, and peripheral loops. Easy synthetic variation of the loops produced four chiral isomeric SF8 probes, with the same log P values. Cell microscopy showed that subtle changes in the loop structure led to significant differences in intracellular targeting. Most notably, a comparison of enantiomeric probes revealed a large difference in mitochondrial accumulation, very likely due to differences in affinity for a chiral biomarker within the organelle. A tangible outcome of the research is a probe candidate that can be (a) developed further as a bright and photostable, deep-red fluorescent probe for mitochondrial imaging, and (b) used as a molecular tool to identify the mitochondrial biomarker for selective targeting. It will be straightforward to expand the SF8 probe chemical space and produce structurally diverse probe libraries with high potential for selective targeting of a wide range of biomarkers.A green and efficient approach for the synthesis of selenium-substituted iminoisobenzofuran using 2-vinylbenzamides and diselenides in a continuous electrochemical microreactor has been developed. This strategy enabled the preparation of a series of iminoisobenzofuran derivatives in moderate to good yields under metal-free and oxidant-free conditions. The application of the electrochemical flow system successfully overcomes the difficulty of process control in traditional electrochemistry and achieves efficient transformation of electricity. Moreover, the continuous-flow system combined with electrosynthesis overcomes the difficulty in realizing a scale-up reaction in conventional batch-type electrolysis.Herein, we report an efficient protocol for the synthesis of selenated tetracyclic indoloazulenes. The reaction of diorganyl diselenides with molecular iodine in dichloromethane leads to the in situ formation of organo selenenyl iodide. The synthesis of selenylated tetracyclic indoloazulenes through intramolecular cascade cyclization has been achieved via organo selenenyl iodide and bisindole at room temperature under metal-free conditions in good yields. All compounds were fully characterized by the FT-IR, HRMS, and 1H, 13C and 77Se NMR spectral data.We report here that a series of bridged O,O-ketal fused spiro piperidone-cyclopropane derivatives 3 can be constructed with excellent yields and good diastereoselectivity by the one-pot reaction of 1-acylcyclopropanecarboxamides 1 with electron-deficient alkene 2a (EWG = CHO) via the domino process involving annulation/intermolecular electrophilic addition/intramolecular cyclization. Furthermore, reactions of 1 with 2b/2c (EWG = CN, COOMe), leading to spiro piperidone-cyclopropane derivatives 4 or 5 by base catalyst selection, were also presented.A visible-light-mediated tandem cyanoalkylsulfonylation/cyclization of alkynoates with cycloketone oxime compounds for the preparation of 3-cyanoalkylsulfonylcoumarins via SO2 insertion is reported. The difunctionalization of carbon-carbon triple bonds includes a radical mechanism and involves the formation of an iminyl radical, ring-opening of the cycloketone, insertion of SO2, addition of the sulfonyl radical to carbon-carbon triple bonds, ipso-cyclization and ester migration.A rhodium-catalyzed denitrogenative formal (3 + 3) transannulation of 1,2,3-thiadiazoles with alk-2-enals is achieved, producing 2,3-dihydrothiopyran-4-ones in moderate to excellent yields. An inverse KIE of 0.49 is obtained, suggesting the reversibility of the oxidative addition of thioacyl Rh(i) carbenes to alk-2-enals. The late-stage structural modifications of steroid compounds are realized. Moreover, our studies show that thioacyl carbenes have different reactivities to those of α-oxo and α-imino carbenes, and highlight the importance of heteroatoms in deciding the reactivities of heterovinyl carbenes.
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