Synthesis of Denosomin–Vitamin D₃ Hybrids and Evaluation of Their Anti-Alzheimer’s Disease Activities

As an extension of previously conducted studies on developing an anti-Alzheimer’s disease agent, denosomin (1-deoxy-24-norsominone, an artificial inducer of neurite elongation), derivatives were designed and synthesized based on the hypothesis that our denosomin would exhibit axonal extension activity via a 1,25D₃-membrane-associated, rapid response steroid-binding protein (1,25D₃-MARRS) pathway. The biological assay revealed that the hybridization of characteristic δ-lactone in denosomin and the triene moiety in VD₃ was effective to enhance the nerve re-extension activity in amyloid β (Aβ)-damaged neurons

Kinetic Study and Model-Based Design Space Determination for a Drug Substance Flow Synthesis Using an Amination Reaction via Nucleophilic Aromatic Substitution

A kinetic study and model-based design space determination for drug substance flow synthesis using an amination reaction are presented. A flow experiment was conducted to synthesize 3-fluoro-4-morpholinobenzonitrile from 3,4-difluorobenzonitrile, morpholine, and diazabicycloundecene. Concentrations, residence time, temperature, and reactor inner diameter were varied to gather the kinetic data. A set of equations was defined to describe the mass and energy balances, and the developed model could reproduce the experimental profiles with high accuracy. By incorporating the Reynolds number into the pre-exponential factor, the developed one-dimensional model could account for performance variations in different inner diameter conditions. The model was then used to identify the design space, considering yield, temperature, productivity, and environment. The study also evaluated the process robustness given pulse disturbances, which could help identify the required sensor monitoring. Finally, a method for facilitating regulatory processes was proposed. The presented model-based approach can aid in producing high-quality pharmaceuticals in an efficient, sustainable, and cost-effective way by utilizing digital power

Spectroscopic and Thermodynamic Characterization of the Metal-Binding Sites in the LH1–RC Complex from Thermophilic Photosynthetic Bacterium Thermochromatium tepidum

The light-harvesting 1 reaction center (LH1–RC) complex from thermophilic photosynthetic bacterium Thermochromatium (Tch.) tepidum exhibits enhanced thermostability and an unusual LH1 <i>Q_y</i> transition, both induced by Ca²⁺ binding. In this study, metal-binding sites and metal–protein interactions in the LH1–RC complexes from wild-type (B915) and biosynthetically Sr²⁺-substituted (B888) Tch. tepidum were investigated by isothermal titration calorimetry (ITC), atomic absorption (AA), and attenuated total reflection (ATR) Fourier transform infrared (FTIR) spectroscopies. The ITC measurements revealed stoichiometric ratios of approximately 1:1 for binding of Ca²⁺, Sr²⁺, or Ba²⁺ to the LH1 αβ-subunit, indicating the presence of 16 binding sites in both B915 and B888. The AA analysis provided direct evidence for Ca²⁺ and Sr²⁺ binding to B915 and B888, respectively, in their purified states. Metal-binding experiments supported that Ca²⁺ and Sr²⁺ (or Ba²⁺) competitively associate with the binding sites in both species. The ATR-FTIR difference spectra upon Ca²⁺ depletion and Sr²⁺ substitution demonstrated that dissociation and binding of Ca²⁺ are predominantly responsible for metal-dependent conformational changes of B915 and B888. The present results are largely compatible with the recent structural evidence that another binding site for Sr²⁺ (or Ba²⁺) exists in the vicinity of the Ca²⁺-binding site, a part of which is shared in both metal-binding sites