Chemical & pharmaceutical bulletin最新文献

{"title":"Experimental and DFT Studies of Intermolecular Interaction-Assisted Oxindole Cyclization Reaction of Di-t-butyl 2-Aminophenyl-2-methyl Malonate.","authors":"Ryo Kakehi, Yu-Suke Yamai, Akio Tanaka, Kyoji Ishida, Shinichi Uesato, Yasuo Nagaoka, Takaaki Sumiyoshi","doi":"10.1248/cpb.c24-00663","DOIUrl":"https://doi.org/10.1248/cpb.c24-00663","url":null,"abstract":"<p><p>Density functional theory calculations on the cyclization of di-t-butyl 2-(2-aminophenyl)-2-methyl malonate (1) to t-butyl 3-methyloxindole-3-carboxylate (2) reveal that acetic acid-assisted protonation of the carbonyl oxygen atom reduces the activation Gibbs free energy significantly lower than methanol-assisted pathways. Experimental data confirm that reaction concentration plays a pivotal role in oxindole formation. Experimental results also indicate distinct reaction mechanisms at low and high concentrations. Achieving high enantioselectivity for chiral compound 2 in high-concentration reactions requires discovering a novel chiral acid.</p>","PeriodicalId":9773,"journal":{"name":"Chemical & pharmaceutical bulletin","volume":"73 1","pages":"63-66"},"PeriodicalIF":1.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143064074","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 Analysis of Needleless and Needle-Based Electrospinning Methods for Polyamide 6: A Technical Note.","authors":"Arash Yavari, Takaaki Ito, Kouji Hara, Kohei Tahara","doi":"10.1248/cpb.c24-00611","DOIUrl":"https://doi.org/10.1248/cpb.c24-00611","url":null,"abstract":"<p><p>This study investigates the influence of needleless versus needle-based electrospinning methods on the fiber diameter of polyamide 6 (PA6) nanofibers under comparable conditions, with an emphasis on potential pharmaceutical applications. Additionally, it examines how varying solvent systems impact fiber diameter specifically in needleless electrospinning. In this study, it was found that fibers produced by the needleless method were thicker compared to those produced by the needle-based method, a trend attributable to the specific solution characteristics and parameter settings unique to this study. Notably, a 2 : 1 acetic acid : formic acid solvent mixture yielded the largest fiber diameters among the solvent systems assessed for needleless electrospinning. These results underscore the potential of PA6 nanofibers in pharmaceutical applications, suggesting that further optimization of electrospinning conditions could enhance their suitability. The study also discusses the implications of scale-up production using needleless technology, highlighting its viability for industrial applications over single-needle electrospinning.</p>","PeriodicalId":9773,"journal":{"name":"Chemical & pharmaceutical bulletin","volume":"73 1","pages":"18-24"},"PeriodicalIF":1.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142977785","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":"Preparation of a Stable Indomethacin Supersaturated Solution Using Hydrophobically Modified Hydroxypropylmethylcellulose and α-Cyclodextrin.","authors":"Hiroki Akahoshi, Fumitoshi Hirayama, Kenjirou Higashi, Daisuke Iohara","doi":"10.1248/cpb.c24-00748","DOIUrl":"https://doi.org/10.1248/cpb.c24-00748","url":null,"abstract":"<p><p>In the present study, the stability of a supersaturated solution of indomethacin (IM) was evaluated in hydrophobically modified hydroxypropylmethylcellulose (HM-HPMC) solutions, with and without parent cyclodextrins (CDs). A highly supersaturated state of IM was maintained in the HM-HPMC solution and was further stabilized by the addition of α-CD and β-CD. Notably, the highest level of supersaturation was achieved in HM-HPMC/α-CD solution, which maintained a high concentration of IM for up to 120 h. IM concentrations in these solutions exceeded the amorphous solubility, indicating that phase separation had occurred. To explore this phase separation, Nile Red, a fluorescent probe sensitive to hydrophobic environments, was added to the supersaturated solutions. A higher fluorescence intensity was observed in the HM-HPMC/α-CD solution compared with the HM-HPMC solution, indicating a significant formation of colloidal amorphous aggregates in the supersaturated solution. Cryogenic transmission electron microscopy (Cryo TEM) analysis confirmed the presence of these aggregates, which appeared irregularly shaped. These findings suggest that the combination of HM-HPMC and α-CD effectively stabilized the colloidal amorphous aggregates in the IM supersaturated solution. The addition of α-CD facilitated the dissociation of HM-HPMC into smaller particles, increasing the number of hydrophobic stearyl moieties available for interactions with amorphous IM aggregates, thereby enhancing the stability of the supersaturated state. The combination of HM-HPMC and α-CD offers a promising approach to improving the oral bioavailability of drugs with poor water solubility.</p>","PeriodicalId":9773,"journal":{"name":"Chemical & pharmaceutical bulletin","volume":"73 1","pages":"39-45"},"PeriodicalIF":1.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143022318","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":"Toward the Synthesis of Strychnos Alkaloids: Effective Construction of Fused Cyclohexane and Pyrrolidine Portion of the Strychnos Skeleton via Domino Intermolecular and Intramolecular S_N2 Cyclization.","authors":"Tadahiro Hosoda, Tomohiro Tsutsumi, Ichiro Hayakawa","doi":"10.1248/cpb.c24-00783","DOIUrl":"https://doi.org/10.1248/cpb.c24-00783","url":null,"abstract":"<p><p>A method for preparing the fused cyclohexane and pyrrolidine portion of the strychnos skeleton has been developed using domino intermolecular and intramolecular S_N2 cyclization. Using this method, the formation of pyrrolidine proceeded smoothly with good yield without the E2 elimination product. This reaction condition is effective for synthesizing the fused cyclohexane and pyrrolidine portion of the strychnos skeleton.</p>","PeriodicalId":9773,"journal":{"name":"Chemical & pharmaceutical bulletin","volume":"73 1","pages":"46-57"},"PeriodicalIF":1.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143045616","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":"Bioinspired Total Synthesis of Polycyclic Natural Products.","authors":"Hayato Ishikawa","doi":"10.1248/cpb.c24-00843","DOIUrl":"https://doi.org/10.1248/cpb.c24-00843","url":null,"abstract":"<p><p>Despite the great strides in biopharmaceuticals and monoclonal antibodies today, natural products remain highly attractive as drug candidates. Therefore, building a library of natural products through total synthesis is critically important for drug discovery. This perspective article details the collective total synthesis of polycyclic natural products using \"bioinspired reactions\" that mimic natural product biosynthesis. It discusses the total syntheses of 20 natural products, including dimeric diketopiperazine alkaloids, monoterpenoid indole alkaloids, and iridoid glycosides, each achieved in fewer than 14 steps starting from commercially available materials.</p>","PeriodicalId":9773,"journal":{"name":"Chemical & pharmaceutical bulletin","volume":"73 2","pages":"67-77"},"PeriodicalIF":1.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143078591","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":"In-Situ Monitoring of Dissolution and Crystallization Processes of Carbamazepine Using Low-Frequency Raman Spectroscopy and Multivariate Analysis.","authors":"Takayuki Kudo, Haruka Uchida, Mana Yamato, Ryo Ohashi, Vasanthi Palanisamy, Toshiro Fukami","doi":"10.1248/cpb.c24-00745","DOIUrl":"https://doi.org/10.1248/cpb.c24-00745","url":null,"abstract":"<p><p>Optimization of the manufacturing process based on scientific evidence is essential for quality control of active pharmaceutical ingredients. Real-time monitoring can ensure the production of stable quality crystals in the crystallization process. Raman spectroscopy is an attractive tool for pharmaceutical quality evaluation and process analytical technology because of its ability to analyze samples non-destructively and rapidly. In this study, we attempted to monitor the crystal polymorphs of carbamazepine (CBZ I and CBZ III) during the dissolution and crystallization processes using low-frequency Raman spectroscopy, which can reflect differences in lattice vibrations originating from polymorphs in the scattering peaks. Furthermore, using multivariate analysis of the obtained spectra, we attempted to develop a model that enables the quantification of each polymorph. A partial least squares was performed to build the prediction model. The prediction model was built using a set of 33 calibration samples, and an external set of 12 validation samples was used to evaluate the model. The model presents a good prediction capacity. The quantitative results for the solid amount of carbamazepine in suspension calculated using the model during the dissolution and crystallization process showed results that correlated very well with the particle view results. It is suggested that low-frequency Raman spectroscopy can be used as a useful process analytical technology tool.</p>","PeriodicalId":9773,"journal":{"name":"Chemical & pharmaceutical bulletin","volume":"73 1","pages":"58-62"},"PeriodicalIF":1.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143064081","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":"Synthetic Studies on Vitamin D Derivatives with Diverse but Selective Biological Activities.","authors":"Atsushi Kittaka","doi":"10.1248/cpb.c24-00598","DOIUrl":"https://doi.org/10.1248/cpb.c24-00598","url":null,"abstract":"<p><p>2α-Functionalization of 1α,25-dihydroxyvitamin D₃ (active vitamin D₃) A-ring enhances binding affinity for the vitamin D receptor (VDR) and prolongs the half-life in target cells due to gaining resistance to CYP24A1-dependant metabolism. The wide variety of modified A-ring precursor enynes for Trost coupling with CD-ring bromoolefin were synthesized from d-glucose. The A-ring modification provided potent, selective biological activities without calcemic side-effects in vivo; for example, 2α-(3-hydroxypropyl)-19-nor-1α,25-dihydroxyvitamin D₃ (MART-10) exhibits potent antitumor activity (0.3µg/kg/d, twice/week for 3 weeks) in nude mice inoculated with BxpC-3 cancer cells, 2α-[2-(tetrazol-2-yl)ethyl]-1α,25-dihydroxyvitamin D₃ (AH-1) shows better bone-forming effects (0.02µg/kg/d, 5d/week for 4 weeks) in ovariectomized (OVX) rats as an osteoporosis model than natural active vitamin D₃, and NS-74c exhibits potent VDR-antagonistic activity (IC₅₀ 7.4pM) in HL-60 culture cells. The A-ring modification was also applicable to the synthesis of stable 14-epi-19-nortachysterols, and their novel VDR binding mode was confirmed by X-ray co-crystallographic analysis. 25-Hydroxyvitamin D₃ has two independent target molecules: VDR and a sterol regulatory element-binding protein (SREBP)/SREBP cleavage-activating protein (SCAP) complex, and 25-hydroxyvitamin D₃ shows SREBP/SCAP inhibitory activity. The VDR-silent vitamin D analog KK-052 with selective SREBP/SCAP inhibitory activity in vivo was developed. A chemical library of side-chain fluorinated vitamin D analogs is currently under construction, and some analogs have shown potent anti-inflammatory activity and therapeutic effects on psoriasis model mice.</p>","PeriodicalId":9773,"journal":{"name":"Chemical & pharmaceutical bulletin","volume":"73 1","pages":"1-17"},"PeriodicalIF":1.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142930797","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 Mixing Characteristics of Magnesium Stearate Using Triboelectric Properties.","authors":"Kenta Fujinuma, Masataka Ito, Etsuo Yonemochi, Katsuhide Terada, Hironori Suzuki, Shuji Noguchi","doi":"10.1248/cpb.c24-00694","DOIUrl":"https://doi.org/10.1248/cpb.c24-00694","url":null,"abstract":"<p><p>Magnesium stearate (MgSt), which is often used as a lubricant in the production of solid formulations, has different stearic acid and palmitic acid contents depending on the lot and manufacturer, resulting in differences in mixability and lubricating effect. However, there are few reports on the effect of the different physical properties of MgSt samples on mixing and tablet formation. Additionally, it is known that the triboelectric properties of components affect the mixability. Overmixing of formulations can decrease tablet hardness. In this study, the triboelectric properties and mixability of MgSt samples with different lots and manufacturers were evaluated. Tablet hardness was used as an index of the mixability of the MgSt samples with various excipients. The triboelectric properties of the MgSt samples depended on the production lot. Mixability was higher when the triboelectric properties of the excipient and MgSt were different. By evaluating the charge properties of MgSt, it should be possible to select the optimum lot and manufacturer of MgSt for specific formulations.</p>","PeriodicalId":9773,"journal":{"name":"Chemical & pharmaceutical bulletin","volume":"73 2","pages":"78-85"},"PeriodicalIF":1.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143254710","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":"Stereoselective Synthesis of Aromatic Polyketide Prealnumycin.","authors":"Kei Kitamura, Taiki Yamasaki, Hiroto Kaku","doi":"10.1248/cpb.c24-00781","DOIUrl":"https://doi.org/10.1248/cpb.c24-00781","url":null,"abstract":"<p><p>Prealnumycin (1), a benzoisochromanequinone compound, produces biologically active exfoliamycin or alnumycin through hybridization with D-ribose or oxidation. We report herein a concise and stereoselective synthesis of 1. The anionic annulation of phthalide 5 with enone 6, prepared via a transition metal-catalyzed enantioselective route, afforded tricyclic lactone 4. This intermediate then underwent a highly diastereoselective introduction of an n-propyl group through nucleophilic addition followed by silane reduction. Subsequent regioselective arene oxidation of 18 using cerium(IV) ammonium nitrate (CAN) afforded naphthoquinone 2. Further manipulations, including acidic deprotection and elimination, yielded prealnumycin in 8 steps.</p>","PeriodicalId":9773,"journal":{"name":"Chemical & pharmaceutical bulletin","volume":"73 2","pages":"86-93"},"PeriodicalIF":1.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143254712","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 and Structure-Activity Relationships of Novel Benzofuran Derivatives with Osteoblast Differentiation-Promoting Activity.","authors":"Masafumi Ando, Shota Kawai, Ko Morishita, Shunsuke Takashima, Kazuya Otake, Megumi Yamamoto, Yoshimichi Shoji, Eiichi Hinoi, Tatsuya Kitao, Hiroaki Shirahase","doi":"10.1248/cpb.c24-00664","DOIUrl":"https://doi.org/10.1248/cpb.c24-00664","url":null,"abstract":"<p><p>Osteoporosis is caused by an imbalance between bone resorption and formation, which decreases bone mass and strength and increases the risk of fracture. Therefore, osteoporosis is treated with oral resorption inhibitors, such as bisphosphonates, and parenteral osteogenic drugs, including parathyroid hormone and antisclerostin antibodies. However, orally active osteogenic drugs have not yet been developed. In the present study, to find novel candidates for oral osteogenic drugs, various benzofuran derivatives were synthesized and their effects on osteoblast differentiation were examined in mouse mesenchymal stem cells (ST2 cells). Among the compounds tested, 3-{4-[2-(2-isopropoxyethoxy)ethoxy]phenyl}benzofuran-5-carboxamide (23d) exhibited potent osteoblast differentiation-promoting activity, estimated as EC₂₀₀ for increasing alkaline phosphatase activity, and good oral absorption in female rats, resulting in high C_max/EC₂₀₀. Dual-energy X-ray absorptiometry scanning revealed that 23d at 10 mg/kg/d for 8 weeks increased femoral bone mineral density in ovariectomized rats with an elevation in plasma bone-type alkaline phosphatase activity, and micro-computed tomography showed that it increased bone volume, mineral contents, and strength in femoral diaphysis cortical, but not trabecular bone during the experiment period. 23d potently inhibited cyclin-dependent kinase 8 (CDK8) activity, suggesting that its osteoblastogenic activity is mediated by the suppression of CDK8, as previously reported for diphenylether derivatives. In conclusion, the structure-activity relationships of novel benzofuran derivatives were clarified and 3,5-disubstituted benzofuran was identified as a useful scaffold for orally active osteogenic compounds. Compound 23d exhibited potent osteoblastogenic activity through CDK8 inhibition and osteogenic effects in ovariectomized rats, indicating its potential as an orally active anti-osteoporotic drug.</p>","PeriodicalId":9773,"journal":{"name":"Chemical & pharmaceutical bulletin","volume":"73 1","pages":"25-38"},"PeriodicalIF":1.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142977865","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}