Aggerholmseverinsen9936

The utility of low sample volume in vitro diagnostic (IVDr) proton nuclear magnetic resonance (1H NMR) spectroscopic experiments on blood plasma for information recovery from limited availability or high value samples was exemplified using plasma from patients with SARS-CoV-2 infection and normal controls. 1H NMR spectra were obtained using solvent-suppressed 1D, spin-echo (CPMG), and 2-dimensional J-resolved (JRES) spectroscopy using both 3 mm outer diameter SampleJet NMR tubes (100 μL plasma) and 5 mm SampleJet NMR tubes (300 μL plasma) under in vitro diagnostic conditions. We noted near identical diagnostic models in both standard and low volume IVDr lipoprotein analysis (measuring 112 lipoprotein parameters) with a comparison of the two tubes yielding R2 values ranging between 0.82 and 0.99 for the 40 paired lipoprotein parameters samples. Lipoprotein measurements for the 3 mm tubes were achieved without time penalty over the 5 mm tubes as defined by biomarker recovery for SARS-CoV-2. Overall, biomarker pattern recovery for the lipoproteins was extremely similar, but there were some small positive offsets in the linear equations for several variables due to small shimming artifacts, but there was minimal degradation of the biological information. For the standard untargeted 1D, CPMG, and JRES NMR experiments on the same samples, the reduced signal-to-noise was more constraining and required greater scanning times to achieve similar differential diagnostic performance (15 min per sample per experiment for 3 mm 1D and CPMG, compared to 4 min for the 5 mm tubes). We conclude that the 3 mm IVDr method is fit-for-purpose for quantitative lipoprotein measurements, allowing the preparation of smaller volumes for high value or limited volume samples that is common in clinical studies. If there are no analytical time constraints, the lower volume experiments are equally informative for untargeted profiling.Polyacylated trehaloses in Mycobacterium tuberculosis play important roles in pathogenesis and structural roles in the cell envelope, promoting the intracellular survival of the bacterium, and are potential targets for drug development. Herein, we describe a linear ion-trap multiple-stage mass spectrometric approach (LIT MS n ) with high-resolution mass spectrometry to the structural characterization of a glycolipid family that includes a 2,3-diacyltrehalose, 2,3,6-triacyltrehalose, 2,3,6,2',4'-petaacyltrehalose, and a novel 2,3,6,2'-tetraacyltrehalose (TetraAT) subfamily isolated from biofilm cultures of M. tuberculosis H37Rv. The LIT MS n spectra (n = 2, 3, or 4) provide structural information to unveil the location of the palmitoyl/stearoyl and one to four multiple methyl-branched fatty acyl substituents attached to the trehalose backbone, leading to the identification of hundreds of glycolipid species with many isomeric structures. We identified a new TetraAT subfamily whose structure has not been previously defined. We also developed a strategy for defining the structures of the multiple methyl-branched fatty acid substituents, leading to the identification of mycosanoic acid, mycolipenic acid, mycolipodienoic acid, mycolipanolic acid, and a new cyclopropyl-containing acid. The observation of the new TetraAT family, and the realization of the structural similarity between the various subfamilies, may have significant implications in the biosynthetic pathways of this glycolipid family.An efficient protocol for the synthesis of thioether directly from heteroarenes has been developed in the presence of visible light in a one-pot manner at room temperature. This method involves two sequential reactions in a single pot where the formation of the iodinated heteroarene is followed by a transition-metal-free C-S coupling reaction. A wide range of heteroarene and thiol partners (including aliphatic thiols) have been used for the synthesis of thioethers. NMR studies and DFT calculations revealed the presence of a halogen bond between the thiolate anion (halogen bond acceptor) and iodoheteroarene (halogen bond donor). This halogen bonded complex on photoexcitation facilitates the electron transfer from the thiolate anion to the iodoheteroarene at room temperature.Phosphorus-modified siliceous zeolites, or P-zeosils, catalyze the selective dehydration of biomass derivatives to platform chemicals such as p-xylene and 1,3-butadiene. Water generated during these reactions is a critical factor in catalytic activity, but the effects of hydrolysis on the structure, acidity, and distribution of the active sites are largely unknown. In this study, the P-sites in an all-silica self-pillared pentasil (P-SPP) with a low P-loading (Si/P = 27) were identified by solid-state 31P NMR using frequency-selective detection. This technique resolves overlapping signals for P-sites that are covalently bound to the solid phase, as well as oligomers confined in the zeolite but not attached to the zeolite. Dynamic Nuclear Polarization provides the sensitivity necessary to conduct 29Si-filtered 31P detection and 31P-31P correlation experiments. Imatinib The aforementioned techniques allow us to distinguish sites with P-O-Si linkages from those with P-O-P linkages. The spectra reveal a previously unappreciated diversity of P-sites, including evidence for surface-bound oligomers. In the dry P-zeosil, essentially all P-sites are anchored to the solid phase, including mononuclear sites and dinuclear sites containing the [Si-O-P-O-P-O-Si] motif. The fully-condensed sites evolve rapidly when exposed to humidity, even at room temperature. Partially hydrolyzed species have a wide range of acidities, inferred from their calculated LUMO energies. Initial cleavage of some P-O-Si linkages results in an evolving mixture of surface-bound mono- and oligonuclear P-sites with increased acidity. Subsequent P-O-P cleavage leads to a decrease in acidity as the P-sites are eventually converted to H3PO4. The ability to identify acidic sites in P-zeosils and to describe their structure and stability will play an important role in controlling the activity of microporous catalysts by regulating their water content.In the world plagued by the emergence of new diseases, it is essential that we accelerate the drug design process to develop new therapeutics against them. In recent years, deep learning-based methods have shown some success in ligand-based drug design. Yet, these methods face the problem of data scarcity while designing drugs against a novel target. In this work, the potential of deep learning and molecular modeling approaches was leveraged to develop a drug design pipeline, which can be useful for cases where there is limited or no availability of target-specific ligand datasets. Inhibitors of the homologues of the target protein were screened at the active site of the target protein to create an initial target-specific dataset. Transfer learning was used to learn the features of the target-specific dataset. A deep predictive model was utilized to predict the docking scores of newly designed molecules. Both these models were combined using reinforcement learning to design new chemical entities with an optimized docking score. The pipeline was validated by designing inhibitors against the human JAK2 protein, where none of the existing JAK2 inhibitors were used for training. The ability of the method to reproduce existing molecules from the validation dataset and design molecules with better binding energy demonstrates the potential of the proposed approach.Five new tyrosine derivatives (1-5), one new phenylacetic acid derivative (6), two new quinazolinone analogues (7 and 8), one new naphthalenedicarboxylic acid (9), and one new 3,4-dihydroisocoumarin derivative (10), together with seven known compounds, were isolated from the fungus Xylaria sp. FM1005, which was isolated from Sinularia densa (leather coral) collected in the offshore region of the Big Island, Hawaii. The structures of compounds 1-10 were elucidated by extensive analysis of NMR spectroscopy, HRESIMS, and ECD data. Due to their structure similarity to the antiplatelet drug tirofiban, compounds 1-5 together with 6 were investigated for their antithrombotic activities. Compounds 1 and 2 strongly inhibited the binding of fibrinogen to purified integrin IIIb/IIa in a dose-dependent manner with the IC50 values of 0.89 and 0.61 μM, respectively, and compounds 1 and 2 did not show any cytotoxicity against A2780 and HEK 293 at 40 μM.We report a two-step approach to bicyclic and monocyclic 5-(1-alkoxyalkylidene)tetronates starting from lactones/esters. The method features the use of thionolactones and thionoesters as activated forms of lactones/esters that allows the direct condensation with tetronates via one-pot enolate formation, nucleophilic addition, S-methylation, and DBU-promoted elimination. The value of the method was demonstrated by the stereoselective syntheses of two natural products 5,6-Z-fadyenolide (Z/E ratio = 61) and 9,10-methylenedioxy-5,6-Z-fadyenolide (Z/E ratio = 91).Low-temperature soft chemical synthesis routes to transition-metal nitrides are of interest as an alternative to conventional high-temperature ammonolysis reactions involving large volumes of chemotoxic NH3 gas. One such method is the reaction between metal oxides and NaNH2 at ca. 200 °C to yield the counterpart nitrides; however, there remains uncertainty regarding the reaction mechanism and product phase assemblage (in particular, noncrystalline components). Here, we extend the chemical tool box and mechanistic understanding of such reactions, demonstrating the nitridation of Fe3O4 by reaction with NaNH2 at 170-190 °C, via a pseudomorphic reaction. The more reduced Fe3O4 precursor enabled nitride formation at lower temperatures than the previously reported equivalent reaction with Fe2O3. The product phase assemblage, characterized by X-ray diffraction, thermogravimetric analysis, and 57Fe Mössbauer spectroscopy, comprised 49-59 mol % ε-Fe2+xN, accompanied by 29-39 mol % FeO1-xN x and 8-14 mol % γ″-FeN. The oxynitride phase was apparently noncrystalline in the recovered product but could be crystallized by heating at 180 °C. Although synthesis of transition-metal nitrides is achieved by reaction of the counterpart oxide with NaNH2, it is evident from this investigation that the product phase assemblage may be complex, which could prove a limitation if the objective is to produce a single-phase product with well-defined electrical, magnetic, or other physical properties for applications. However, the significant yield of the FeO1-xN x oxynitride phase identified in this study opens the possibility for the synthesis of metastable oxynitride phases in high yield, by reaction of a metal oxide substrate with NaNH2, with either careful control of H2O concentration in the system or postsynthetic hydrolysis and crystallization.3,4-Dimercaptophenylalanines and 2,3-dimercaptophenylalanines have been synthesized for the first time by nucleophilic substitution of a protected aminomalonate on 3,4- and 2,3-dimercaptobenzyl bromide derivatives. The dithiol functions were protected as thioketals, and the key precursors, diphenylthioketal-protected dimercaptobenzyl bromides, were synthesized via two distinct routes from either dihydroxy benzoates or toluene-3,4-dithiol. Racemic mixtures of the fully protected amino acids were separated by chiral HPLC into the corresponding enantiomers. The absolute configuration of both 3,4- and 2,3-analogues could be assigned based on X-ray crystallography and VCD/DFT measurements. Thioketal groups were deprotected upon reaction with mercury oxide and aqueous tetrafluoroboric acid followed by treatment with H2S gas under an argon atmosphere to obtain the corresponding dimercapto amino acids. The optically pure l-Fmoc-protected 3,4-analogue (S- enantiomer) was successfully incorporated into a decapeptide using standard solid-phase peptide synthesis.