Chemical & pharmaceutical bulletin最新文献

Building on our previously reported techniques, we developed a concise and highly stereoselective synthesis method for β,β-disubstituted α,β-unsaturated esters. This synthesis comprises 3 reactions: the aldol reaction of acetic ester derivatives with ketones, the acetylation of tert-alcohols, and an elimination reaction utilizing 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). During the acetylation process, acetic anhydride and 4-dimethylaminopyridine (DMAP) facilitated the smooth acetylation of bulky tert-alcohols; however, employing DBU as a base reduced the yields. Additionally, the removal of excess DMAP effectively suppressed the formation of unwanted byproducts during the elimination step.

Sucroferric oxyhydroxide is a phosphate binder for the treatment of hyperphosphatemia in patients with chronic kidney disease undergoing dialysis. This study aimed to determine the effects of tablet size, shape, and tensile strength on disintegration time and friability of sucroferric oxyhydroxide-containing mini-tablets. A linear relationship between the disintegration time and tensile strength was observed across all mini-tablets, except for those with smaller tablets (diameters: <1.8 mm). However, the relationship between friability and tensile strength was not significantly correlated under linear or exponential approximations. Explaining friability solely based on tensile strength was challenging, indicating the role of tablet shape. To visualize the effects of mini-tablet shapes and tensile strength on their disintegration time and friability, response aspects were analyzed. The response surface analysis revealed that the disintegration time was not affected by the tablet shape. The friability of the mini-tablets with a cup depth/diameter of 0.209 was lower (<0.2) than that of tablets with other cup depth/diameter across all tested ranges of tensile strength (1-6). A cup depth/diameter of 0.2 was identified as optimal for minimizing the friability of mini-tablets and can be implemented in commercial production without issues. In conclusion, tablet shape should be carefully considered during the development of mini-tablets to ensure low friability.

Current methods for evaluating the photostability of pharmaceutical drugs typically separate the irradiation step from the analytical process, making it challenging to observe real-time photodegradation during irradiation. The use of HPLC equipped with UV and/or MS detectors, which are commonly used for quantitative analysis, requires considerable time to establish optimal conditions, and employs organic solvents, which are harmful to both the environment and the analyst. The aim of this study is to investigate the effectiveness of isothermal differential scanning calorimetry (DSC) equipped with a UV probe (photo-DSC) for evaluating the photostability of pharmaceutical drugs in the solid state. The response to light irradiation varies for different drugs, with some drugs exhibiting a thermal history showing endothermic behavior. To confirm the results of the endothermic reaction in photo-DSC, the percentage of the drug remaining after photo-irradiation was quantified using HPLC. Drugs that exhibited endothermic peaks consistently showed a decrease in residuals due to the photolysis reaction. In this study, we highlight the effectiveness of photo-DSC in evaluating the susceptibility of different drugs to photodegradation.

Enhancing the solubility of poorly water-soluble oral small-molecule drugs remains a critical challenge in the pharmaceutical industry, particularly during the early stages of drug development when selecting solubilized formulation technologies. This difficulty largely stems from the absence of objective indicators for comparing formulations. This study aimed to establish the selection indicators for solubilized formulation technologies based on applicable formulation preparation among amorphous solid dispersion (ASD), cyclodextrin (CD), lipid-based formulation (LBF), and nanocrystal (NC), utilizing the overall molecular properties, such as molecular weight, melting point (T_m), Log P, and polar surface area (PSA) in the marketed oral drugs employing solubilized formulation technologies. Single-property plots of the selected properties revealed the regions of higher or lower frequency in the selected molecular properties. The multiple property plot with T_m and the combined property of normalized Log P and PSA identified a specific area as the optimal range for selecting ASD, LBF, and NC, while excluding CD. These findings are expected to function as guide indicators that enable the rational selection of formulation technologies and serve as a foundational approach to accelerating development timelines based on molecular properties available during the early stages of drug development.

Structural transformation changes the activity of biological reactions. Neurotransmitter aralkylamines, such as phenethylamine, tyramine, dopamine, tryptamine, serotonin, and histamine, absorb aerial CO₂, and heteronuclear multiple bond connectivity (HMBC) correlations between the carbon derived from CO₂ and the α-hydrogen of the several amines were confirmed in the D₂O solution. The isolation of methyl carbamate from phenethylamine and CO₂ in water with TMSCHN₂ also supported the formation of covalently bound carbamic acid in the amine aqueous solution containing CO₂. Therefore, it is suggested that CO₂ produced in the body would react with neurotransmitter amines to form covalently bound carbamic acid, which might affect biological reactions.

Efficient cytosolic delivery of functional proteins such as therapeutic antibodies remains a major challenge in drug development. In this study, we sought to optimize the cytosolic delivery peptide Mel-V8G12, a melittin derivative, through structure-guided design and functional screening of its amino acid substitutions. Among seven derivatives, VG-6, featuring A10L, T11E, and S18K substitutions demonstrated superior cytosolic delivery efficiency compared with the parental Mel-V8G12, while maintaining low cytotoxicity. Notably, VG-6 exhibited enhanced membrane-lytic activity toward neutral lipid membranes, yet did not increase cellular toxicity, suggesting a delivery mechanism distinct from conventional pH-responsive endosomolytic peptides. Mechanistic studies revealed that, in contrast to Mel-V8G12 which predominantly utilizes actin-mediated endocytosis, VG-6 additionally engages caveolae-mediated endocytosis, contributing to its enhanced cytosolic delivery. Furthermore, VG-6 enabled successful cytosolic delivery of functional Cre recombinase and immunoglobulin G (IgG), facilitating biological activity and subcellular targeting. These findings suggest that VG-6 is a promising tool for intracellular delivery of protein therapeutics via a unique membrane-interacting and endocytic pathway.

The phytochemical investigation of the rainforest plant Croton argyratus (Euphorbiaceae) led to the isolation of two halimane-type diterpenes, crotargyolides A (1) and B (2), with an uncommon γ-lactone ring at C-5 and C-9, together with a crotofolane-type diterpene, 3-hydroxylated crotofolin C (3, crokocrotogenoid A), and the known clerodane diterpenes, junceic acid (4) and epoxyjunceic acid (5). The structures of the newly isolated compounds were elucidated by various NMR techniques, high resolution (HR)MS analysis, and electronic circular dichroism (ECD) spectroscopy. The proposed biosynthetic pathway of 1 from 4 was discussed. Crotargyolide A (1) and known compounds 4 and 5 were evaluated for antiproliferative activity and displayed no growth inhibitory effect toward all tested tumor cell lines.

5'-O-Triethylsilyl-2'-deoxy-5-azacytidine (5'-O-TesDAC) is a prodrug developed to counteract deamination by cytidine deaminase and spontaneous hydrolytic cleavage of the triazine ring. In this study, we have evaluated the physical properties of the crystal forms to determine the optimal crystal form for solid pharmaceutical development. Therefore, the crystalline morphology of 5'-O-TesDAC was assessed using terahertz spectroscopy, in addition to conventional methods (thermal analysis, powder X-ray diffraction, IR absorption spectroscopy and dynamic vapor sorption). Terahertz spectroscopy has the feature of being able to sensitively capture structural changes between lattices and molecules because the absorptions of the terahertz region correspond to those of skeletal vibrations, intermolecular vibrations, and/or lattice vibrations. For this reason, in the evaluation of crystal polymorphism, terahertz spectroscopy was considered to complement methods that have conventionally been used. Furthermore, the metastable state evaluated in this study rapidly transitions to hemihydrate at relative humidity (RH) above 10%, so it could not be measured using attenuated total reflectance-Fourier transform IR (ATR-FTIR), which is performed under atmosphere, whereas terahertz spectroscopy allowed measurements with the sample chamber exposed to dry air easily. The chemical stability was evaluated through a stability test that measured the amount of the main degradation product of each crystalline form using HPLC. As a result, four crystalline forms of 5'-O-TesDAC were identified. The characterization of 5'-O-TesDAC in this study provides valuable information for optimizing the manufacturing parameters of the formulation and selecting appropriate packaging materials for pharmaceutical development.

Silica powder is an essential pharmaceutical ingredient, which in some combinations with drugs, causes chemical instability of the drug adsorbed on it. NMR measurements have been used to determine the drug adsorption state; however, the relationship between drug chemical stability and NMR relaxation, one of the NMR processes, is yet to be thoroughly studied. This work investigated the relationship between the chemical stability of itraconazole (ITZ)-adsorbed silica and its NMR relaxation. NMR can specifically observe ¹H nuclei, and this feature was exploited to study only the T₁ relaxation of these nuclei in the drug, excluding the silica signal composed of Si and O. ITZ, a poorly water-soluble model drug, was physically adsorbed on nonporous silica (Aerosil 200, AER), and mesoporous silica (Sylysia 320), and the ¹H T₁ relaxation was measured before storage using the time domain (TD)-NMR technique. The amount of ITZ degradant adsorbed in the silicas was also measured after storage at humidified conditions. Then, the relationship between the degradant amount of ITZ-adsorbed silica after storage and the T₁ relaxation rate (1/T₁) before storage was investigated. The ITZ-adsorbed silicas showed a positive correlation between the degradant amount and the 1/T₁ value. ITZ-adsorbed AER showed a strong positive correlation (R² = 0.751). Thus, the 1/T₁ value may be an efficient parameter to determine the chemical stability of ITZ adsorbed on nonporous silica. The 1/T₁ value measurement by TD-NMR could provide new insight for evaluating the chemical stability of solid dosage forms containing silica.

N-Glycosylated RNA (glycoRNA) has been identified on the cell surface, and 3-(3-amino-3-carboxypropyl)uridine has been reported as a conjugation site of N-glycans on RNA. Although the association of glycoRNAs with various diseases has been reported, their biosynthetic mechanisms and biological roles remain unexplored. Here, we report the preparation of two species of N-glycan-conjugated 3-(3-amino-3-carboxypropyl)uridine as the minimal units of glycoRNA. Our synthesized glycoRNA unit would contribute to future biochemical research on glycoRNAs.