Chemical & pharmaceutical bulletin最新文献

A direct dehydroxylative allylation reaction of benzylic alcohols with allylsilanes catalyzed by Brønsted acids in 1,1,1,3,3,3-hexafluoro-2-propanol was developed. A wide variety of secondary and tertiary benzylic alcohols are applicable to the reaction with various allyltrimethylsilanes, to provide the corresponding coupling products in high yields. Using this catalytic transformation, a concise and short-step synthesis of (±)-crucudiol was achieved.

Bioequivalence (BE) studies are essential for confirming therapeutic equivalence. However, current compendial dissolution tests do not necessarily provide a reliable prediction of clinical BE. We aimed to develop a biorelevant dissolution test that predicts clinical bioequivalence (BE). Three enteric-coated pellets of esomeprazole magnesium trihydrate (ECP-ESO), either clinically BE or non-BE (NBE), were evaluated. Dissolution tests were performed using the paddle method (pH 6.5 or 6.8, 25-100 rpm, 500 mL, 37°C). Biorelevant bicarbonate buffer (BCB) was used as a simulated intestinal fluid, with a floating lid applied to prevent CO₂ escape and maintain pH. Hydrodynamics that suppresses artifact cone formation (coning) were produced using an apex vessel (Apex-V). These biorelevant conditions were compared with the compendial phosphate buffer (PPB) and the round-bottom vessel (RB-V). RB-V is considered less biorelevant as it causes coning at the vessel bottom. When PPB and RB-V were used, BE and NBE formulations could not be distinguished. Substitution of RB-V with Apex-V eliminated coning but lacked discriminative power. This outcome was also observed with BCB and RB-V. Combining both BCB and Apex-V successfully differentiated between BE and NBE formulations, consistent with the clinical BE results. Dissolution testing using biorelevant BCB and Apex-V predicted the clinical BE/NBE of ECP-ESOs. The floating lid method enabled the practical use of BCB, while Apex-V prevented coning. This simple, yet biorelevant, dissolution test could help to predict clinical BE in formulation development.

Phoslactomycins and leustroducsins are highly functionalized polyketides. In this paper, we report the new synthetic method for the C1-C13 fragment. This method involves a Suzuki-Miyaura coupling reaction between the C3-C7 acetylene and C8-C13 iodoolefin, followed by construction of the lactone part. The C8-C9 diol is constructed by dihydroxylation in the late stage of the synthesis.

The clinical application of natural core streptavidin remains unrealized owing to its immunogenicity and interference from endogenous D-biotin. These limitations could be addressed using D-core streptavidin, the mirror-image form. Here, we evaluated the immunogenicity and biodistribution of D-core streptavidin in mice. Intraperitoneal administration of natural core streptavidin induced antibodies against streptavidin, whereas no antibody production was observed for D-core streptavidin. The protease assay indicated that proteolysis by cathepsin B differed between D-core streptavidin and the natural core form. The difference in degradation by cathepsin B in non-denatured conditions may contribute to the reduced immunogenicity of D-core streptavidin. Biodistribution studies revealed no significant differences between D-core and natural core streptavidins in tumor-bearing mice. These findings support the further development of D-core streptavidin in combination with L-biotin for in vivo applications.

Inhalation delivery of protein therapeutics has emerged as a promising non-invasive alternative to traditional injectable formulations that offers potential for both localized and systemic treatment of pulmonary diseases. This review comprehensively summarizes the current advances in inhalable protein formulations, with emphasis on design strategies, formulation technologies, barriers to effective delivery, and disease-specific applications. Key aspects include the role of particle size, surface charge, and protein engineering in optimizing lung deposition and cellular uptake, as well as techniques such as spray freeze drying and PEGylation to enhance protein stability. The review also explores novel therapeutic approaches that target cystic fibrosis, asthma, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, lung infections, and cancer, including the use of antibodies, nanobodies, exosomes, and albumin-based carriers. Clinical translation remains limited, but ongoing innovation in delivery systems and molecular design is thought to hold significant promise for expanding the therapeutic landscape of inhaled protein drugs.

Ziziphi Fructus (the fruit of Ziziphus jujuba Miller var. inermis Rehder; Japanese name "Taiso"), listed in the 18th edition of the Japanese Pharmacopoeia (JP18), is widely used in Kampo (Japanese traditional) medicine. However, a specific identification test for Ziziphi Fructus was not prescribed in JP18. Hence, in this study, we establish a TLC-based identification test for quality assurance of the crude drug Ziziphi Fructus. The HPLC experiments identified 3-O-cis-p-coumaroylalphitolic acid and 3-O-trans-p-coumaroylaliphitolic acid as suitable indicators. After developing the samples to a distance of 10 cm using ethyl acetate (EtOAc)/n-hexane/acetic acid (AcOH)/H₂O (60 : 40 : 2 : 1) as the TLC-developing solvent and UV light at 254 nm, two spots with an Rf value of approximately 0.4-0.6 were detected. Additionally, based on the TLC-based experiments, alphitolic and maslinic acids emerged as potential indicator components. Treatment of samples with EtOAc/n-hexane/AcOH (60 : 40 : 1) serving as the developing solvent, followed by exposure to dilute sulfuric acid solution, heat, and UV light at 365 nm, revealed two clear spots with Rf values of approximately 0.2-0.3. These findings potentially serve as a basis for the development of an identification test to identify Ziziphi Fructus.

Biologics represent a major advance in therapy, offering highly specific and potent treatment options for diseases previously difficult to manage; however, their administration routes are commonly limited to injection due to poor oral bioavailability, which can lead to patient inconvenience and adherence challenges. The pulmonary route offers a promising alternative, leveraging the lung's large absorptive surface area, thin alveolar-capillary barrier, rich vascularization, and avoidance of first-pass metabolism to enable both local and systemic delivery. Effective inhaled biologic therapies require harmonizing the drug's physicochemical properties with aerosol aerodynamic behavior and dissolution. The pharmacokinetic fate of inhaled biologics is further influenced by lung physiology, including airflow dynamics, airway structure, mucociliary clearance, and respiratory lining fluid composition. These factors present significant barriers to the stability, absorption, and retention of inhaled biologics. Extensive research efforts focus on optimizing formulations, inhalation devices, and excipients, alongside deepening the understanding of the biopharmaceutical characteristics of inhaled biologics. This review summarizes recent advances in inhalation systems of therapeutic peptides and proteins for systemic and local effects, emphasizing practical strategies to overcome key biopharmaceutical and physicochemical challenges, thus advancing the clinical potential of next-generation inhaled biologics.

This review highlights recent progress in transition metal-free reductive transformations using organic electron donors. According to previous reports, pyridine-derived super electron donors enable the selective reduction of nitrobenzenes to azobenzenes and phenazines, while also promoting the efficient desulfurization of thioacetals and thioethers under mild conditions. These transformations proceeded with a broad substrate scope and good functional group compatibility. Additionally, a sodium hydride (NaH)/1,10-phenanthroline system developed for radical-mediated C-C bond formation promoted the hydroarylation and hydroalkylation of styrenes with high anti-Markovnikov selectivities. Mechanistic studies suggested that the in situ-generated anilide anion acts as both an electron donor and a hydrogen source, supporting a radical-based reaction pathway. These works demonstrate the potential of organic electron donors for use as sustainable and practical alternatives to conventional transition metal-based reductive methods in organic synthesis.

The Hippo signaling pathway plays a central role in regulating cell growth, and dysregulation of its downstream effector Yes-associated protein (YAP) leads to tumorigenesis. Verteporfin (VP), a clinically approved drug, inhibits YAP-TEA domain (TEAD) complex formation, yet its binding mechanism remains unclear. In this study, we conducted a comprehensive in silico analysis of all 4 VP isomers within the context of the full-length YAP-TEAD complex. The complex structure was modeled using AlphaFold2 multimer, which provided sufficient accuracy for docking simulations despite incomplete experimental data on YAP. Docking calculations were performed against 2 grids, one centered on a predicted druggable pocket and the other on the YAP-TEAD interface. A total of 304 poses were generated, and the top-scoring 100 were clustered using protein-ligand interaction fingerprints. Clusters derived from the interface grid revealed strong interactions with residues critical for YAP-TEAD binding. Among the 4 isomers, Ia-2 consistently showed the most favorable binding free energies. Notably, Cluster 7 highlighted a unique Ia-2 binding mode involving simultaneous interactions with Met86 and Arg87, suggesting a competitive mechanism at the YAP-TEAD interface. These results suggest that structural chirality may influence binding stability and interaction patterns, and that the Ia-2 isomer is predicted to preferentially stabilize an inhibitory binding mode. This study provides the first systematic comparison of all VP isomers with full-length YAP and suggests that isolating Ia-2 from Visudyne may enhance anticancer efficacy. The findings further support the rational strategies for designing selective YAP-TEAD inhibitors.

A new depsidone, termed mollicellin Z2 (1), and three known mollicellins D, H, and I (2-4), were isolated from cultured Chaetomium brasiliense NBRC 6548 mycelia. The structure of 1 was determined from one dimensional (1D) and 2D-NMR and high resolution electron ionization (HREI)MS spectra. It is the first 4-desmethyl mollicellin analogue found to contain a C-7 prenyl group and is likely generated via a biosynthetic pathway that is distinct from those that produce the 27 known analogues. This is the first report of mollicellin derivatives with antibacterial activity against nontuberculous mycobacteria.