Synthesis of the methanesulfonates of α-(4-chlorophenyl)-α-[1-(2-chlorophenyl)emenyl]-1H-1,2,4-triazole-1-ethanol and α-[1-(2-chlorophenyl)ethenyl]-α-(2,4-difluorophenyl)-1H-1,2,4-triazole-1-ethanol,alpha styryl carbinol antifungal agents

The methanesulfonates of (α-(4-chlorophenyl)-α-[1-(2-chlorophenyl)ethenyl]-1H-1,2,4-triazole-1-ethanol and α-[1-(2-chlorophenyl)ethenyl]-α-(2,4-difluorophenyl)-1H-1,2,4-triazole-1-ethanol ( 1a, b ) are orally effective α-styryl carbinol derivatives developed for the treatment and prevention of systemic fungal infections. Practical new processes amenable for the large-scale production of these compounds are described. Of note is the selection of dichlorostyrene as a convenient precursor of the styryl portion, modification of a sensitive Grignard addition into a realistic preparative reaction and the use of 1,2,4-triazole simultaneously as a base transfer agent and nucleophile.     

Green chemistry and sustainability metrics in the pharmaceutical manufacturing sector

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Local immune cell contributions to fracture healing in aged individuals – A novel role for interleukin 22

With increasing age, the risk of bone fractures increases while regenerative capacity decreases. This variation in healing potential appears to be linked to adaptive immunity, but the underlying mechanism is still unknown. This study sheds light on immunoaging/inflammaging, which impacts regenerative processes in aging individuals. In an aged preclinical model system, different levels of immunoaging were analyzed to identify key factors that connect immunoaged/inflammaged conditions with bone formation after long bone fracture. Immunological facets, progenitor cells, the microbiome, and confounders were monitored locally at the injury site and systemically in relation to healing outcomes in 12-month-old mice with distinct individual levels of immunoaging. Bone tissue formation during healing was delayed in the immunoaged group and could be associated with significant changes in cytokine levels. A prolonged and amplified pro-inflammatory reaction was caused by upregulated immune cell activation markers, increased chemokine receptor availability and a lack of inhibitory signaling. In immunoaged mice, interleukin-22 was identified as a core cell signaling protein that played a central role in delayed healing. Therapeutic neutralization of IL-22 reversed this specific immunoaging-related disturbed healing. Immunoaging was found to be an influencing factor of decreased regenerative capacity in aged individuals. Furthermore, a novel therapeutic strategy of neutralizing IL-22 may successfully rejuvenate healing in individuals with advanced immune experiences.Subject terms: Trauma, Mechanisms of disease, Interleukins, Osteoimmunology     

Metal-Free Twofold Electrochemical C−H Amination of Activated Arenes: Application to Medicinally Relevant Precursor Synthesis

The efficient production of many medicinally or synthetically important starting materials suffers from wasteful or toxic precursors for the synthesis. In particular, the aromatic non-protected primary amine function represents a versatile synthetic precursor, but its synthesis typically requires toxic oxidizing agents and transition metal catalysts. The twofold electrochemical amination of activated benzene derivatives via Zincke intermediates provides an alternative sustainable strategy for the formation of new C−N bonds of high synthetic value. As a proof of concept, we use our approach to generate a benzoxazinone scaffold that gained attention as a starting structure against castrate-resistant prostate cancer. Further improvement of the structure led to significantly increased cancer cell line toxicity. Thus, exploiting environmentally benign electrooxidation, we present a new versatile and powerful method based on direct C−H activation that is applicable for example the production of medicinally relevant compounds.     

Investigations of the Vicarious C‐Aminations of 5,7‐Dinitrobenzotriazole and 4,6‐Dinitrobenzotriazol‐3‐ium‐1‐oxide and Their Energetic Properties

This combined experimental and theoretical study details the vicarious nucleophilic substitution by amination of 5,7‐dinitrobenzotriazol ( 1 ) and 4,6‐dinitrobenzotriazole‐3‐ium‐1‐oxide ( 4 ) with trimethylhydrazinium iodide to afford the new corresponding one‐ and two‐time aminated compounds and investigations of its mechanism by EPR spectroscopy. The preferred position for the first amination is computed by spin density population and verified by X‐ray crystallography. The zwitterionic structure of 4 is investigated in solution by ¹H NMR spectroscopy and in solid state by X‐ray diffraction. Furthermore, the crystal structure of 1 is presented. The energetic behavior of the aminated products as well as the starting materials 1 and 4 was investigated, regarding sensitivities and performance.     

Inverse colloidal crystal membranes for hydrophobic interaction membrane chromatography

A collaborative study on the robustness and portability of a capillary electrophoresis‐mass spectrometry method for peptide mapping was performed by an international team, consisting of 13 independent laboratories from academia and industry. All participants used the same batch of samples, reagents and coated capillaries to run their assays, whereas they utilized the capillary electrophoresis‐mass spectrometry equipment available in their laboratories. The equipment used varied in model, type and instrument manufacturer. Furthermore, different types of sheath‐flow capillary electrophoresis–mass spectrometry interfaces were used. Migration time, peak height and peak area of ten representative target peptides of trypsin‐digested bovine serum albumin were determined by every laboratory on two consecutive days. The data were critically evaluated to identify outliers and final values for means, repeatability (precision within a laboratory) and reproducibility (precision between laboratories) were established. For relative migration time the repeatability was between 0.05 and 0.18% RSD and the reproducibility between 0.14 and 1.3% RSD. For relative peak area repeatability and reproducibility values obtained were 3–12 and 9–29% RSD, respectively. These results demonstrate that capillary electrophoresis‐mass spectrometry is robust enough to allow a method transfer across multiple laboratories and should promote a more widespread use of peptide mapping and other capillary electrophoresis‐mass spectrometry applications in biopharmaceutical analysis and related fields.     

Solid-State Photocyclodimerization of 1-Thiocoumarin (= 2H-1-Benzothiopyran-2-one)

Irradiation (λ > 390 nm) of 2H-1-benzothiopyran-2-one ( 1 ) in the solid state affords selectively 6aα,6bα,12bα,12cα -tetrahydrocyclobuta[1,2-c:4,3-c′]bis[1]benzothiopyran -6,7-dione ( 2 ), the head-to-head (HH) cis-cisoid-cis-dimer, while irradiation of 1 in the solid state using shorter wavelengths (λ > 340 nm) affords a mixture of all four cis-fused tricyclic dimers 2 – 5 . These results represent a novel wavelength effect in solid-state photochemistry.     

A Combined Spectroscopic and Theoretical Study on a Ruthenium Complex Featuring a π-Extended dppz Ligand for Light-Driven Accumulation of Multiple Reducing Equivalents

The design of photoactive systems capable of storing and relaying multiple electrons is highly demanded in the field of artificial photosynthesis, where transformations of interest rely on multielectronic redox processes. The photophysical properties of the ruthenium photosensitizer [(bpy)₂Ru( oxim-dppqp )]²⁺ ( Ru ), storing two electrons coupled to two protons on the π-extended oxim-dppqp ligand under light-driven conditions, are investigated by means of excitation wavelength-dependent resonance Raman and transient absorption spectroscopies, in combination with time-dependent density functional theory; the results are discussed in comparison to the parent [(bpy)₂Ru(dppz)]²⁺ and [(bpy)₂Ru( oxo-dppqp )]²⁺ complexes. In addition, this study provides in-depth insights on the impact of protonation or of accumulation of multiple reducing equivalents on the reactive excited states.