Mild and Efficient Heterogeneous Hydrogenation of Nitroarenes Facilitated by a Pyrolytically Activated Dinuclear Ni(II)-Ce(III) Diimine Complex.

We communicate the assembly of a solid, Ce-promoted Ni-based composite that was applied as catalyst for the hydrogenation of nitroarenes to afford the corresponding organic amines. The catalytically active material described herein was obtained through pyrolysis of a SiO2-pellet-supported bimetallic Ni-Ce complex that was readily synthesized prior to use from a MeO-functionalized salen congener, Ni(OAc)2·4 H2O, and Ce(NO3)3·6 H2O. Rewardingly, the requisite ligand for the pertinent solution phase precursor was accessible upon straightforward and time-saving imine condensation of ortho-vanillin with 1,3-diamino-2,2'-dimethylpropane. The introduced catalytic protocol is operationally simple in that the whole reaction set-up is quickly put together on the bench without the need of cumbersome handling in a glovebox or related containment systems. Moreover, the advantageous geometry and compact-sized nature of the used pellets renders the catalyst separation and recycling exceptionally easy.

Plasma Metabolomic Profiling Reveals Four Possibly Disrupted Mechanisms in Systemic Sclerosis.

Systemic sclerosis (SSc) is a rare systemic autoimmune disorder marked by high morbidity and increased risk of mortality. Our study aimed to analyze metabolomic profiles of plasma from SSc patients by using targeted and untargeted metabolomics approaches. Furthermore, we aimed to detect biochemical mechanisms relevant to the pathophysiology of SSc. Experiments were performed using high-performance liquid chromatography coupled to mass spectrometry technology. The investigation of plasma samples from SSc patients (n = 52) compared to a control group (n = 48) allowed us to identify four different dysfunctional metabolic mechanisms, which can be assigned to the kynurenine pathway, the urea cycle, lipid metabolism, and the gut microbiome. These significantly altered metabolic pathways are associated with inflammation, vascular damage, fibrosis, and gut dysbiosis and might be relevant for the pathophysiology of SSc. Further studies are needed to explore the role of these metabolomic networks as possible therapeutic targets of SSc.

Comparison of one-phase and two-phase extraction methods for porcine tissue lipidomics applying a fast and reliable tentative annotation workflow.

Lipidomics has great potential for the discovery of biomarkers, elucidation of metabolic processes and identifying dysregulations in complex biological systems. Concerning biofluids like plasma or cerebrospinal fluid, several studies for the comparison of lipid extraction solvents have already been conducted. With respect to tissues, which can differ significantly in terms of dry matter content and composition, only few studies are available. The proper selection of an extraction method that covers the complexity and individuality of different tissues is challenging. The goal of this work was to provide a systematic overview on the potential of different extraction methods for a broad applicability. This study covers six different extraction procedures and four different reconstitution solvents applied to ten different porcine tissues. To get an overview of the individual lipid profiles, a workflow was developed for a fast and reliable tentative lipid annotation. Therefore, several machine learning tools were utilized, like the prediction of collision cross sections to support the tentative lipid identification in case of untargeted lipidomics. In terms of data evaluation, unsupervised (e.g. principal component analysis) and supervised (e.g. partial least square - discriminant analysis) methods were applied to visualize and subsequently interpret all generated information. Furthermore, the influence of the tissue composition on the extraction performance was investigated. It could be shown that the ten porcine tissues can be distinguished based on their lipid profile with the applied workflow and that the methyl-tert-butyl ether (MTBE) based extraction method (two-phase) showed the best overall performance for the 16 examined lipid species. With this method the highest number of features (428 in lung tissue) could be annotated. Upcoming one-phase extractions also showed a high potential concerning total number of extracted lipids. Methanol/MTBE/chloroform (MMC) extracted slightly less lipids (393 in lung and liver) than MTBE but turned out to be the best one-phase extraction method. Additionally, the numbers of extracted lipids obtained by isopropanol/water 90:10 (IPA90) (399 in stomach) and by isopropanol/methanol/chloroform (IMC) (395 in stomach) were similar to those of the modified Folch method (402 in stomach). One-phase extractions can therefore clearly be seen as preferable when a high throughput is needed.

Large-Scale Evaluation of Collision Cross Sections to Investigate Blood-Brain Barrier Permeation of Drugs.

Successful drug administration to the central nervous system requires accurate adjustment of the drugs' molecular properties. Therefore, structure-derived descriptors of potential brain therapeutic agents are essential for an early evaluation of pharmacokinetics during drug development. The collision cross section (CCS) of molecules was recently introduced as a novel measurable parameter to describe blood-brain barrier (BBB) permeation. This descriptor combines molecular information about mass, structure, volume, branching and flexibility. As these chemical properties are known to influence cerebral pharmacokinetics, CCS determination of new drug candidates may provide important additional spatial information to support existing models of BBB penetration of drugs. Besides measuring CCS, calculation is also possible; but however, the reliability of computed CCS values for an evaluation of BBB permeation has not yet been fully investigated. In this work, prediction tools based on machine learning were used to compute CCS values of a large number of compounds listed in drug libraries as negative or positive with respect to brain penetration (BBB+ and BBB- compounds). Statistical evaluation of computed CCS and several other descriptors could prove the high value of CCS. Further, CCS-deduced maximum molecular size of BBB+ drugs matched the dimensions of BBB pores. A threshold for transcellular penetration and possible permeation through pore-like openings of cellular tight-junctions is suggested. In sum, CCS evaluation with modern in silico tools shows high potential for its use in the drug development process.

Changes in Plasma Phospholipid Metabolism Are Associated with Clinical Manifestations of Systemic Sclerosis.

Systemic sclerosis (SSc) is an autoimmune disease with fibrosis of the skin and/or internal organs, causing a decrease in quality of life and survival. There is no causative therapy, and the pathophysiology of the SSc remains unclear. Studies showed that lipid metabolism was relevant for autoimmune diseases, but little is known about the role of lipids in SSc. In the present study, we sought to explore the phospholipid profile of SSc by using the lipidomics approach. We also aimed to analyze lipidomics results for different clinical manifestations of SSc. Experiments were performed using high-performance liquid chromatography coupled to mass spectrometry for the lipidomic profiling of plasma samples from patients with SSc. Our study showed, for the first time, significant changes in the level of phospholipids such as plasmalogens and sphingomyelins from the plasma of SSc patients as compared to controls. Phosphatidylcholine plasmalogens species and sphingomyelins were significantly increased in SSc patients as compared to controls. Our results also demonstrated a significant association of changes in the metabolism of phospholipids (phosphatidylcholine and phosphatidylethanolamine plasmalogens species and sphingomyelins) with different clinical manifestations of SSc. Further lipidomic studies might lead to the detection of lipids as new biomarkers or therapeutic targets of SSc.

Enantioselective α-Chlorination Reactions of in Situ Generated C1 Ammonium Enolates under Base-Free Conditions.

The asymmetric α-chlorination of activated aryl acetic acid esters can be carried out with high levels of enantioselectivities utilizing commercially available isothiourea catalysts under base-free conditions. The reaction, which proceeds via the in situ formation of chiral C1 ammonium enolates, is best carried out under cryogenic conditions combined with a direct trapping of the activated α-chlorinated ester derivative to prevent epimerization, thus allowing for enantioselectivities of up to e.r. 99:1.

Enantiospecific deoxyfluorination of cyclic α-OH-ß-ketoesters.

We herein report the deoxyfluorination of cyclic α-hydroxy-ß-ketoesters using diethylaminosulfur trifluoride (DAST). The reaction proceeds with excellent levels of stereospecificity, giving the configurationally inverted α-fluoro-ß-ketoesters in high yields under operationally simple conditions.