Chemical & pharmaceutical bulletin最新文献

{"title":"Efficient Drug Release from Liposomes Introduced Tetrazine Derivatives with Pyrimidine Rings Using Click Chemistry.","authors":"Mizuho Yamasaki, Masayuki Munekane, Kento Kannaka, Kohei Sano, Toshihide Yamasaki, Takahiro Mukai","doi":"10.1248/cpb.c24-00591","DOIUrl":"10.1248/cpb.c24-00591","url":null,"abstract":"<p><p>We developed a novel drug release method using a bioorthogonal inverse electron demand Diels-Alder reaction on liposomal membranes. Based on reports that replacing pyridine with pyrimidine in tetrazine derivatives improves the reaction rate with strained dienophiles, we investigated if liposomes with tetrazine derivatives containing pyrimidine rings efficiently release drugs via click chemistry. We synthesized and evaluated a tetrazine compound (Tz2) bearing a pyrimidine ring. The reaction rate constant of Tz2 with a norbornene (NB) derivative, 5-norbornenecarboxylic acid (NBCOOH), was higher than that of Tz1 with a pyridine ring. Liposomes containing the synthesized Tz2 (Tz2-liposomes) were prepared, and the reaction between Tz2 and NBCOOH on the liposomal membranes was confirmed using high-resolution mass spectrometry. We encapsulated indium-111-labeled diethylenetriaminepentaacetic acid ([¹¹¹In]In-DTPA) in liposomes as a model drug. The release of [¹¹¹In]In-DTPA from Tz2-liposomes was observed after the addition of NBCOOH, with release dependent on NBCOOH concentration. Moreover, release from Tz2-liposomes was significantly higher than that from Tz1-liposomes. These results suggested that tetrazine derivatives with pyrimidine rings efficiently released drugs, likely due to enhanced reaction rates. These findings would advance the development of controlled drug release methods using click chemistry.</p>","PeriodicalId":9773,"journal":{"name":"Chemical & pharmaceutical bulletin","volume":"73 2","pages":"108-111"},"PeriodicalIF":1.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143490975","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":"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":"Design, Synthesis, and Antitumor Activity of Novel Eupatilin Derivatives Based on the Mannich Reaction.","authors":"Yaqi Meng, Yuqing Wang, Shujiao Li, Zhiyan Cai, Guo Zhuang, Yanli Yang","doi":"10.1248/cpb.c24-00599","DOIUrl":"10.1248/cpb.c24-00599","url":null,"abstract":"<p><p>Eupatilin, a natural bioactive flavone, is the active ingredient in traditional Chinese medicine Artemisia argyi Levl. et Vant. To enhance the antitumor effect of eupatilin, we designed a series of novel eupatilin-Mannich derivatives and investigated antitumor activity against several human cancer cell lines, including gastric cancer cells (AGS), esophageal cancer cells (Eca-109), and breast cancer cells (MDA-MB-231). Among all derivatives, the majority demonstrated superior antitumor activity compared to eupatilin, with compound 3d exhibiting the most effective antitumor activity against AGS cells. Furthermore, compound 3d effectively inhibited colony formation and migration of AGS cells. Network pharmacology combined with molecular docking studies indicated that compound 3d exerts antitumor activity by targeting the Hsp90AA1 and multiple signaling pathways. In addition, the Western blot experiment results showed that compound 3d reduced the expression of Hsp90AA1 in AGS cells, indicating that Hsp90AA1 may be the potential target of compound 3d. In summary, several novel eupatilin derivatives were prepared via the Mannich reaction, representing the first structure modification study of eupatilin. The mechanism of action of compound 3d was estimated through cell experiments, network pharmacology, molecular docking, and Western blot experiments, to provide lead compounds for the discovery of natural product-based antitumor candidates.</p>","PeriodicalId":9773,"journal":{"name":"Chemical & pharmaceutical bulletin","volume":"73 2","pages":"112-120"},"PeriodicalIF":1.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143514806","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":"¹H-NMR-Based Biochemometric Strategy to Identify Transient Receptor Potential Vanilloid 1-Stimulating Compounds from Alpinia officinarum Rhizome.","authors":"Tomohisa Kanai, Tatsuya Shirahata, Shunsuke Nakamori, Rin Sato, Akito Hayashi, Yota Koizumi, Kenichiro Nagai, Susumu Ohkawara, Takayuki Hoshino, Toshiko Tanaka-Kagawa, Hideto Jinno, Yoshinori Kobayashi","doi":"10.1248/cpb.c24-00707","DOIUrl":"https://doi.org/10.1248/cpb.c24-00707","url":null,"abstract":"<p><p>This study established a ¹H-NMR-based biochemometric approach for the isolation of biologically active compounds from complex extracts. In both pharmacognosy and natural product chemistry, reliably isolating bioactive compounds typically necessitates repeating time-consuming and laborious isolation and purification steps, presenting a bottleneck in many studies. We applied biochemometric methods to accurately estimate active compounds, thus minimizing the number of assays and isolation steps. The rhizomes of Alpinia officinarum Hance (Zingiberaceae) have been continuously prescribed in traditional Japanese medicine as stomachics and analgesics, despite a limited understanding of the mechanisms underlying these effects. Additionally, transient receptor potential vanilloid subtype 1 (TRPV1) plays a role in modulating nociception, respiratory defense responses, and gastrointestinal protection. Accordingly, ¹H-NMR-based biochemometry was employed to search for TRPV1-active components in A. officinarum rhizome extracts by combining TRPV1 activity intensity with ¹H-NMR data. However, initially, the active component could not be identified because the principal component analysis loading plot primarily displayed only buckets of primary metabolites. Consequently, we applied orthogonal partial least squares to the ¹H-NMR spectra, which allowed us to identify specific spectral bins at 1.66 ppm (aliphatic) and 7.02, 6.98, 6.82, and 6.74-6.58 ppm (aromatic), correlating with TRPV1-stimulating activity. Based on this prediction, diarylheptanoids were swiftly identified, and their potential to activate TRPV1 was confirmed by administering the identified compounds to TRPV1-expressing cells. These findings highlight the potential of chemometric analysis using ¹H-NMR spectroscopy for identifying the chemical classes responsible for the bioactive properties of complex crude drug extracts.</p>","PeriodicalId":9773,"journal":{"name":"Chemical & pharmaceutical bulletin","volume":"73 3","pages":"195-204"},"PeriodicalIF":1.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584865","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":"Identification of a Novel Retinoid X Receptor Agonist from Boenninghausenia albiflora var. japonica.","authors":"Ryura Tateiwa, Yudai Nakama, Ayaka Murase, Tomoki Mizoguchi, Makoto Inoue, Ken-Ichi Nakashima","doi":"10.1248/cpb.c24-00728","DOIUrl":"https://doi.org/10.1248/cpb.c24-00728","url":null,"abstract":"<p><p>Retinoid X receptors (RXRs) are nuclear receptors involved in various crucial biological processes, such as gene regulation, metabolism, and cell differentiation. They predominantly function as heterodimers with other nuclear receptors and modulate gene expression in response to ligand binding. Additionally, they act as therapeutic targets for different conditions, such as cancer and metabolic disorders. Although synthetic RXR agonists, such as bexarotene, are used in clinical settings, they exert adverse side effects. In this study, to explore insights into potential natural RXR agonists as alternatives to existing drugs, we isolated 14 coumarins, including 1 new compound from Boenninghausenia albiflora var. japonica (Rutaceae). Among them, daphnoretin methyl ether (14), a known biscoumarin, was found to exhibit subtype-nonspecific RXR agonist activity.</p>","PeriodicalId":9773,"journal":{"name":"Chemical & pharmaceutical bulletin","volume":"73 3","pages":"173-178"},"PeriodicalIF":1.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584870","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":"Identification of Acidic Triterpenoid Saponins from Silene vulgaris Using a Methylation-Based Isolation and LC-MS Analysis Strategy.","authors":"Takashi Kikuchi, Danyang Liu, Kouharu Otsuki, Kazuo Koike, Wei Li","doi":"10.1248/cpb.c24-00809","DOIUrl":"https://doi.org/10.1248/cpb.c24-00809","url":null,"abstract":"<p><p>The Silene genus plants in the Caryophyllaceae family are a large genus with over 850 species. It has been known that Silene genus plants contain triterpenoid saponins. These saponins have glucuronic acid in the sugar chain and are difficult to separate in chromatography. In this study, a strategy was developed to clarify the distribution of triterpenoid saponins in whole plants of Silene vulgaris by isolation of neutralized saponins using methylation reactions, which were used as standard substances for LC-MS analysis, and elucidating their characteristic MS and MS/MS fragment patterns. The n-butanol fraction of the methanol extract from the whole plant of S. vulgaris was separated to obtain fractions including saponins by octadecyl silica column chromatography. Then, each fraction was treated with trimethylsilyl diazomethane for methylation of the carboxyl groups of glucuronic acid in the molecules, and five triterpenoid methylated saponins (7a, 13a, 14a, 16a, and 17a) were isolated using HPLC. The chemical structures of the isolated compounds were determined by spectroscopic analyses including NMR and MS, and their characteristic fragmentations were also clarified in LC-MS and MS/MS. It was performed on the n-butanol fraction from the whole plant of S. vulgaris, and the chemical structures of 22 triterpenoid saponins were estimated based on the MS and MS/MS fragmentation patterns of the isolated triterpenoid saponins.</p>","PeriodicalId":9773,"journal":{"name":"Chemical & pharmaceutical bulletin","volume":"73 3","pages":"179-188"},"PeriodicalIF":1.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584872","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":"Isoflavone Constituents of the Underground Parts of Iris florentina and Their Inhibitory Activity on the Formation of Advanced Glycation End Products.","authors":"Yuka Yoshizawa, Nana Fujita, Akihito Yokosuka, Yoshihiro Mimaki","doi":"10.1248/cpb.c24-00776","DOIUrl":"https://doi.org/10.1248/cpb.c24-00776","url":null,"abstract":"<p><p>Two new isoflavone glucosides, irisolone 4'-O-[O-β-d-glucopyranosyl-(1→6)-O-β-d-glucopyranosyl-(1→6)-β-d-glucopyranoside] (1) and iriskashmirianin 4'-O-[O-β-d-glucopyranosyl-(1→6)-O-β-d-glucopyranosyl-(1→6)-β-d-glucopyranoside] (2) were isolated from the underground parts of Iris florentina (Iridaceae). The structures of 1 and 2 were determined based on extensive spectroscopic data analyses and hydrolytic cleavage results. The isoflavone derivatives previously isolated from this plant were evaluated for their ability to inhibit the formation of advanced glycation end products.</p>","PeriodicalId":9773,"journal":{"name":"Chemical & pharmaceutical bulletin","volume":"73 3","pages":"168-172"},"PeriodicalIF":1.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584874","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":"Isolation and Identification of Three New Iridoid Glucosides from the Aerial Parts of Paederia scandens.","authors":"Masashi Fukaya, Kaori Ryu, Tetsuro Ito","doi":"10.1248/cpb.c24-00777","DOIUrl":"https://doi.org/10.1248/cpb.c24-00777","url":null,"abstract":"<p><p>Sulfur-containing compounds are found in various medicinal products, where they play crucial roles in biological activities such as antimicrobial, anticancer, and other therapeutic effects. These compounds are commonly found in species of Allium, especially onions and garlic; however, there is little evidence of their presence in other plants. In particular, sulfur-containing iridoid glycosides with anticancer properties, which are very promising compounds as pharmaceutical seeds, have been isolated from Paederia scandens (Rubiaceae), also known as the skunk vine because of its strong smell caused by methyl mercaptan. Herein, we describe the isolation and structural elucidation of 3 new iridoid glycosides from the aerial parts of P. scandens. Their biosynthetic pathways are also discussed.</p>","PeriodicalId":9773,"journal":{"name":"Chemical & pharmaceutical bulletin","volume":"73 3","pages":"156-161"},"PeriodicalIF":1.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584876","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":"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}