Chemical & pharmaceutical bulletin最新文献

{"title":"Foreword.","authors":"Kazunori Kadota","doi":"10.1248/cpb.c26-ctf7401","DOIUrl":"https://doi.org/10.1248/cpb.c26-ctf7401","url":null,"abstract":"","PeriodicalId":9773,"journal":{"name":"Chemical & pharmaceutical bulletin","volume":"74 1","pages":"16-17"},"PeriodicalIF":1.3,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145899265","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, Synthesis, and Biological Evaluation of Potent Cognition-Improved Compounds Targeting AMPA Receptor Based on CX717.","authors":"Xiuhua Zeng, Yaowen Cui, Li Song, Lin Pan, Haoxin Xiong, Zhiwei Shen, Jinlong Cai, Tingting Chen, Tao Peng, Shouguo Zhang, Shuchen Liu, Lin Wang, Jing Xu","doi":"10.1248/cpb.c26-00122","DOIUrl":"https://doi.org/10.1248/cpb.c26-00122","url":null,"abstract":"<p><p>Aiming to develop safe and efficient cognitive enhancers, this study reports the design, synthesis, and biological evaluation of novel α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor modulators derived from the lead compound CX717. Twenty-four derivatives were designed, synthesized, and characterized by ¹H-NMR, ¹³C-NMR, and high resolution MS (HR-MS). Molecular docking studies indicated that, compared to CX717, the compounds exhibited lower binding energy to the AMPA receptor. Cognition-improved activity was evaluated by passive avoidance, active avoidance, novel object recognition, and novel place recognition tests in mice. The results demonstrated that nine compounds significantly enhanced cognitive function in mice, with compounds B7 and C3 showing efficacy superior to CX717 in vivo. Furthermore, B7 and C3 alleviated serum oxidative stress, enhanced hippocampal glutamate transport efficiency, and reduced serum pro-inflammatory cytokine levels in scopolamine-treated mice. Subacute toxicity studies revealed favorable safety profiles for both compounds. Molecular dynamics simulations supported stable binding of B7 and C3 to the AMPA receptor, consistent with the structural modification strategy. Surface plasmon resonance (SPR) analysis demonstrated that B7 and C3 bound directly to the GluR2 protein with moderate affinity, with C3 showing higher affinity than B7. Patch-clamp experiments further showed that B7 and C3 positively modulated AMPA receptor-mediated currents, supporting their positive allosteric modulator (PAM)-like activity. The membrane permeability assay suggested that B7 and C3 had higher passive membrane permeability than CX717 in vitro. In conclusion, B7 and C3 demonstrated superior cognition-improved activity and safety compared to CX717, highlighting their potential as candidates for treating cognitive disorders.</p>","PeriodicalId":9773,"journal":{"name":"Chemical & pharmaceutical bulletin","volume":"74 6","pages":"513-528"},"PeriodicalIF":1.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148343970","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation of the Effect of the Introduction of Disubstituted Amino Acids Aib on the Lipid Membrane into Amphipathic Helical Peptides K9L9.","authors":"Hiina Danno, Akiko Asano, Mitsunobu Doi, Takuma Kato","doi":"10.1248/cpb.c26-00197","DOIUrl":"https://doi.org/10.1248/cpb.c26-00197","url":null,"abstract":"<p><p>Cell-penetrating peptides (CPPs) have attracted considerable attention as carriers that facilitate the intracellular delivery of biomacromolecules. In this study, the amphipathic antimicrobial peptide K9L9 was used as a model, and a series of peptides incorporating the non-proteinogenic amino acid α-aminoisobutyric acid (Aib) were designed and synthesized to investigate the relationship between peptide structure, membrane interaction, and cellular uptake behavior. Circular dichroism analysis revealed that K9L9 adopted a β-sheet-like conformation in an aqueous solution, whereas the Aib-containing peptide formed a stable α-helical structure. In liposome leakage assays, peptides containing two Aib residues exhibited enhanced membrane-disruptive activity, whereas the peptide containing four Aib residues exhibited reduced activity. Furthermore, intracellular delivery studies using fluorescein isothiocyanate-dextran (FITC-dextran) demonstrated that delivery efficiency was significantly enhanced when the peptides were preincubated with FITC-dextran, suggesting that peptide-cargo complex formation plays a critical role in the delivery process. In addition, K9L9 exhibited rapid cellular uptake at early time points, whereas the Aib-containing peptides showed a gradual increase in uptake over time, indicating distinct uptake kinetics. These results demonstrate that Aib-induced helix stabilization modulates the membrane interaction and cellular uptake behavior of amphipathic peptides.</p>","PeriodicalId":9773,"journal":{"name":"Chemical & pharmaceutical bulletin","volume":"74 6","pages":"486-492"},"PeriodicalIF":1.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148293488","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Nonclassical N-Methyl Amidation Using N,N-Disubstituted Aminophosphonium Salts.","authors":"Natsuru Hiraguri, Aki Kohyama, Yoshiharu Iwabuchi, Kiyosei Takasu","doi":"10.1248/cpb.c26-00215","DOIUrl":"https://doi.org/10.1248/cpb.c26-00215","url":null,"abstract":"<p><p>Nonclassical N-methyl amidation reactions represent a valuable alternative to conventional coupling methods and expand access to drug-like molecules. Herein, we report a direct N-methyl amidation using N,N-disubstituted aminophosphonium salts. Treatment of a bench-stable trimethylaminophosphonium salt with silver acetate or quaternary ammonium carboxylates efficiently affords tertiary N-methyl amides at ambient temperature without the use of external coupling reagents. The aminophosphonium salts act as bench-stable and readily accessible N-methylamine equivalents, enabling the simultaneous activation of carboxylic acids and delivery of N-methylamine without overalkylation. Notably, the reaction proceeds via a mechanistically distinct pathway that does not involve iminophosphorane intermediates. This method provides a practical and mild approach to the synthesis of tertiary N-methyl amides.</p>","PeriodicalId":9773,"journal":{"name":"Chemical & pharmaceutical bulletin","volume":"74 6","pages":"493-497"},"PeriodicalIF":1.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148315833","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis of Coumarin Derivatives and Evaluation of Their Antioxidant Activities against Multiple Free Radicals.","authors":"Aolin Zhang, Yulin Wei, Huiyan Wang, Yu Liu, Weiming Hu, Xiaoli Qiao","doi":"10.1248/cpb.c26-00164","DOIUrl":"10.1248/cpb.c26-00164","url":null,"abstract":"<p><p>Coumarin and its derivatives exhibit diverse biological activities and have extensive applications in biomedicine. A series of coumarin derivatives (1-15) were designed and synthesized, among which eight compounds had not been reported previously. In particular, single crystals of compounds 8 and 10 were obtained and characterized by X-ray diffraction, which provided a molecular basis for analyzing their antioxidant activity. The antioxidant properties were evaluated through ‧OH scavenging assays, cyclic voltammetry (CV) assays, redox potential measurements, oxygen radical absorbance capacity (ORAC) tests, and in vivo reactive oxygen species (ROS) scavenging experiments using Caenorhabditis elegans (C. elegans). At the same time, density functional theory (DFT) calculations were also conducted to assist in the study of the antioxidant mechanism. IC₅₀ values for ·OH scavenging were significantly lower than those of the positive control, vitamin C. Furthermore, ORAC assays showed moderate to excellent scavenging ability (with Trolox equivalents of 1.08 for compound 13). CV assays assessed the abilities to scavenge ‧O₂^-, with results consistent with ORAC experimental findings. In vivo antioxidant activities were further investigated using C. elegans. Finally, through multiple free-radical scavenging experiments and DFT calculations, the antioxidant mechanism of the compounds was elucidated. In conclusion, through structural modification and the comparison of activities, profound insights were obtained. This work thereby established both a theoretical framework and an experimental basis for the rational design of new antioxidants.</p>","PeriodicalId":9773,"journal":{"name":"Chemical & pharmaceutical bulletin","volume":"74 5","pages":"425-431"},"PeriodicalIF":1.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148041258","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rigid Benzene Ring Substitution of Capsaicin's Double Bond: Synthesis of TRPV1 Agonist with Anti-fatigue Efficacy.","authors":"Yi-Fan Wu, Xu-Fei Zeng, Zhi-Wei Shen, Han-Yin Feng, Tao Peng, Shu-Chen Liu, Jing Xu, Lin Wang, Shou-Guo Zhang","doi":"10.1248/cpb.c26-00013","DOIUrl":"10.1248/cpb.c26-00013","url":null,"abstract":"<p><p>To search for safe and efficient anti-fatigue active molecules, 16 capsaicin (CAP) derivatives were synthesized by replacing the unsaturated carbon-carbon double bond in capsaicin with a rigid benzene ring via condensation, chlorination, and amidation reactions using vanillylamine hydrochloride as the starting material, with yields ranging from 44.1 to 79.1%. Their structures were confirmed by ¹H-NMR, ¹³C-NMR, and MS (electrospray ionization [ESI]). In vitro assays demonstrated that N8 exerted superior transient receptor potential vanilloid 1 (TRPV1) agonistic activity compared to CAP at a concentration of 10 μM, upregulated peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) expression in a concentration-dependent manner (1.25-10 μM), and showed no significant toxicity to C2C12 myotube cells at 0.78-100 μM. In vivo evaluations in mice (15 mg/kg, 31-d gavage) demonstrated that N8 had no adverse effect on body weight but significantly prolonged rotarod duration (143.5%, p < 0.001) and forced swimming time (75.6%, p < 0.001), increased serum lactate dehydrogenase (LDH) levels (p < 0.01), decreased serum urea nitrogen (SUN) levels (p < 0.001) and lactic acid (LA) accumulation (p < 0.001), and elevated hepatic and muscle glycogen contents (p < 0.001) compared with the fatigue control group. Mechanistic studies via Western blot, mitochondrial fluorescence staining, cellular thermal shift assay, and molecular docking revealed that N8 had better binding stability to TRPV1 than CAP (relative binding rate at 65°C: 86.7 vs. 21.5%), activated the TRPV1 channel, synergistically upregulated the expression of cluster of differentiation 36 (CD36), carnitine palmitoyltransferase 1M (CPT1M), SURF1, and cytochrome c1 (CYC1), promoted mitochondrial biogenesis, and optimized muscle energy metabolism. These results indicate that N8 demonstrates superior anti-fatigue activity both in vitro and in vivo compared to CAP, making it a potential candidate for anti-fatigue drug development.</p>","PeriodicalId":9773,"journal":{"name":"Chemical & pharmaceutical bulletin","volume":"74 4","pages":"323-335"},"PeriodicalIF":1.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147763735","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural Characterization of New 8,17-Epoxybriarane Diterpenoids from the Octocoral Briareum stechei.","authors":"Yuan-Hao Liu, Chih-Kai Hsu, Liu-Guo Zheng, Su-Ying Chien, Yu-Jen Wu, Jih-Jung Chen, Mingzi M Zhang, Zhi-Hong Wen, Yuan-Bin Cheng, Lun Kelvin Tsou, Mei-Chin Lu, Jyh-Horng Sheu, Shih-Hsiung Lin, Ping-Jyun Sung","doi":"10.1248/cpb.c26-00274","DOIUrl":"https://doi.org/10.1248/cpb.c26-00274","url":null,"abstract":"<p><p>An encrusting, algae-associated octocoral, Briareum stechei, afforded three 8,17-epoxybriarane diterpenoids, including the known compound briaexcavatolide B (1) and two previously undescribed analogues, briastecholides Q (2) and R (3). The absolute configuration of 1 was established for the first time by single-crystal X-ray diffraction analysis. The planar structures and relative configurations of 2 and 3 were determined through extensive spectroscopic analyses. In bioactivity evaluation, compound 2 exhibited cytotoxic effects toward the human acute lymphoblastic leukemia cell lines Molt-4 and CCRF-CEM.</p>","PeriodicalId":9773,"journal":{"name":"Chemical & pharmaceutical bulletin","volume":"74 8","pages":"635-643"},"PeriodicalIF":1.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148677296","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanistic Elucidation of the Acidic Hydrolysis of Triazolobenzodiazepines: Integration of Kinetic, Thermodynamic, and Quantum Chemical Analyses.","authors":"Koichi Saito, Kentaro Tsutsumi, Misayo Iguchi, Rie Ito, Hiroshi Akiyama","doi":"10.1248/cpb.c26-00261","DOIUrl":"https://doi.org/10.1248/cpb.c26-00261","url":null,"abstract":"<p><p>In this study, the degradation behavior and reaction mechanisms of triazolobenzodiazepines (TBZDs)-alprazolam (ALZ), triazolam, and etizolam-in artificial gastric juice were investigated. Degradation kinetics were evaluated by monitoring time-dependent changes in TBZD standard solutions after the addition of artificial gastric juice at various temperatures using LC with photodiode array detection. Arrhenius analysis provided kinetic parameters for each compound. All TBZDs underwent rapid degradation under acidic conditions, and the reaction was reversible, yielding a single major product that was characterized as the final degradation product. Structural elucidation of the ALZ degradation product by spectroscopic and mass spectrometric analyses identified it as (2-[3-(aminomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]-5-chlorophenyl)(phenyl)methanone. To gain mechanistic insight, quantum chemical calculations were performed, including geometry optimization, electrostatic potential analysis, and frontier molecular orbital analysis. These analyses indicated that protonation enhances the electrophilicity of the azomethine carbon, facilitating nucleophilic attack by water. These findings demonstrate that electronic structure analysis based on quantum chemical calculations provides valuable mechanistic insight into the hydrolysis of TBZDs under acidic conditions and may contribute to the rational assessment of chemical stability in future drug development.</p>","PeriodicalId":9773,"journal":{"name":"Chemical & pharmaceutical bulletin","volume":"74 9","pages":"693-698"},"PeriodicalIF":1.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148963229","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Compensated Förster Resonance Energy Transfer-Based Platform for Quantitative Assessment of Liposome Integrity in Inhalation Drug Delivery.","authors":"Kohei Togami, Mio Yasuda, Hiroki Miyajima, Koshiro Kawamura, Yuki Nakamura, Kiyomi Ishizawa, Sumio Chono","doi":"10.1248/cpb.c25-00576","DOIUrl":"https://doi.org/10.1248/cpb.c25-00576","url":null,"abstract":"<p><p>The structural integrity of inhalable liposomal carriers is a key determinant of drug release behavior, pulmonary residence time, and therapeutic efficacy. This study aimed to establish a compensated Förster resonance energy transfer (FRET)-based platform for the quantitative assessment of liposome integrity throughout the inhalation delivery process. By compensation for donor fluorescence bleed-through and direct acceptor excitation, the method enables accurate quantification of FRET signals from liposomes co-loaded with 1,1'-dioctadecyl-3,3,3',3'-tetramethylindodicarbocyanine, 4-chlorobenzenesulfonate (DiD, donor)/1,1'-dioctadecyl-3,3,3',3'-tetramethylindotricarbocyanine iodide (DiR, acceptor), using both spectrofluorometry and macroscopic imaging. Upon treatment with Triton X-100, decreases in the compensated FRET/donor ratio were detected at lower concentrations than those required to induce measurable changes in membrane anisotropy and within the same concentration range as the onset of encapsulated 6-carboxyfluorescein release. Using this platform, in vitro aerosol characterization with an Andersen cascade impactor enabled simultaneous analysis of aerodynamic particle size distribution and stage-specific liposome integrity. In vivo experiments in mice-including ex vivo lung imaging and bronchoalveolar lavage fluid analysis-revealed a time-dependent decline in liposome integrity during pulmonary residence. This ability to monitor carrier structural stability from initial deposition through residence-an aspect not readily achieved with conventional single-fluorophore labeling-offers significant advantages for formulation development, stabilization strategies, and dosing regimen optimization. The FRET-based platform could, in principle, be adapted for use with other standardized cascade impactors such as the Next Generation Impactor and is expected to be applicable to a wide range of lipid-based or polymeric nanocarriers, including inhalable vaccines and nucleic acid therapeutics.</p>","PeriodicalId":9773,"journal":{"name":"Chemical & pharmaceutical bulletin","volume":"74 1","pages":"43-54"},"PeriodicalIF":1.3,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145899219","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparative Study of Aβ Aggregation Inhibitors of Yamamomiji (Acer amoenum var. matsumurae) Red and Green Leaf Extracts with Isolation of Active Compound.","authors":"Anusha Venkatachalapathy, Koji Uwai","doi":"10.1248/cpb.c25-00721","DOIUrl":"https://doi.org/10.1248/cpb.c25-00721","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a brain disorder associated with amyloid beta (Aβ) aggregation, leading to neuronal damage and faster disease progression. The aggregation-inhibiting compounds are necessary to prevent and treat AD. Acer species are rich in phenolic compounds and possess diverse biological activities. In this study, we investigated the Aβ₄₂ aggregation inhibitory activity of the understudied species, Acer amoenum var. matsumurae red and green leaf extracts, using thioflavin T and also monitored 24-h Aβ₄₂ aggregation kinetics. The red leaf extract showed the strongest inhibition (half-maximal effective concentration [EC₅₀] = 1.28 mg/mL), and the green leaf extract showed moderate inhibition (EC₅₀ = 8.61 mg/mL). In addition, the time-course profile of Aβ₄₂ aggregation at a concentration of 75 µg/mL was performed. The red leaf extract indicated strong inhibition in the Aβ₄₂ fibril formation when compared to the green leaf extract and was analyzed by fitting the experimental data to an empirical sigmoidal function (logistic function). The red leaf exhibited significantly stronger 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity (IC₅₀ = 2.81 µg/mL) compared to the green leaf (IC₅₀ = 6.27 µg/mL). The red leaf extract exhibited greater monomeric anthocyanin content than the green leaf extract, as determined by the pH-differential method. The active compound was isolated and identified by using chromatographic and spectroscopic techniques. These results suggest that A. amoenum var. matsumurae red leaf extract and the active compound epicatechin may prove to be Aβ aggregation inhibitors to prevent or delay AD progression.</p>","PeriodicalId":9773,"journal":{"name":"Chemical & pharmaceutical bulletin","volume":"74 2","pages":"187-195"},"PeriodicalIF":1.3,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147302931","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}