Chemical & pharmaceutical bulletin最新文献

{"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}

{"title":"Stereoselective Synthesis of Aromatic Polyketide Prealnumycin.","authors":"Kei Kitamura, Taiki Yamasaki, Hiroto Kaku","doi":"10.1248/cpb.c24-00781","DOIUrl":"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":"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}

{"title":"Ion-Pair Extraction with Tetracyanocyclopentadienides: A Method for Estimating Extraction Efficiency.","authors":"Takeo Sakai, Masanari Ota, Miho Ito, Riho Miura, Yuto Fumimoto, Yuji Mori","doi":"10.1248/cpb.c24-00630","DOIUrl":"10.1248/cpb.c24-00630","url":null,"abstract":"<p><p>Ion-pair extraction with tetracyanocyclopentadienides (TCCPs) is an effective method for isolating ammonium cations; however, predicting the extractability of ammonium-TCCP ion pairs is challenging. Herein, the measured extraction coefficients (LogK_ex) of ammonium-TCCP ion pairs allowed the values of A (an index for anion extractability) for the TCCP anions to be determined (-3.1 to -1.4); these values were higher than and similar to those of perchlorate and picrate anions, respectively. The correlation between LogK_ex and the sum of the values of A and the calculated Log P of ammonium cations revealed that LogK_ex can be estimated by the equation LogK_ex = A + CLOGP_NR4 + 1.6, where CLOGP_NR4 is the CLOGP value obtained using the \"no-plus\" ammonium structure. The LogK_ex value can be used to predict the extractability of quaternary ammonium ions.</p>","PeriodicalId":9773,"journal":{"name":"Chemical & pharmaceutical bulletin","volume":"73 2","pages":"121-135"},"PeriodicalIF":1.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536687","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":"Guided Isolation of Isopentenyl Flavonoids from Daphne giraldii Based on the Combination of GNPS and SMART.","authors":"Bo-Yuan Zhao, Ben-Song Xin, Shuang Qiu, Guo-Dong Yao, Xiao-Xiao Huang, Shao-Jiang Song","doi":"10.1248/cpb.c24-00462","DOIUrl":"https://doi.org/10.1248/cpb.c24-00462","url":null,"abstract":"<p><p>Six flavonoids (1-6), including 3 previously undescribed compounds (1-3), were isolated from the dried roots and stem skins of Daphne giraldii Nitsche. The strategy of LC-tandem mass spectrometry-based Global Natural Products Social Molecular Networking (GNPS) molecular network technology and NMR-based Small Molecule Accurate Recognition Technology (SMART) technology facilitated the precise separation of isopentenyl flavonoids in D. giraldii. The structures were determined through comprehensive spectroscopic analysis. Furthermore, all compounds were evaluated for their cytotoxic activity against Hep3B cells. Specifically, compounds 1 and 3 exhibited significant cytotoxicity with IC₅₀ values of 5.52 ± 0.57 and 2.53 ± 0.49 μM, respectively, compared to the positive control sorafenib (IC₅₀ = 7.08 ± 0.23 μM).</p>","PeriodicalId":9773,"journal":{"name":"Chemical & pharmaceutical bulletin","volume":"73 3","pages":"189-194"},"PeriodicalIF":1.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584868","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":"Spiromeroterpenoids from the Higher Plants.","authors":"Yohei Saito, Tomoya Nishida, Kyoko Nakagawa-Goto","doi":"10.1248/cpb.c24-00733","DOIUrl":"https://doi.org/10.1248/cpb.c24-00733","url":null,"abstract":"<p><p>Meroterpenoids are a distinctive class of natural products found in various organisms, including animals, plants, bacteria, algae, and particularly fungi. Among them, spiromeroterpenoids, which have a spiro-ring connecting a terpenoid and a non-terpenoid moiety, are markedly unique. Currently, only a limited number of plants from the families Myrtaceae, Hypericaceae, Annonaceae, Asteraceae, and Lauraceae are known to biosynthesize spiromeroterpenoids. The non-terpene moiety of plant-derived spiromeroterpenoids is generally a polyketide, mainly a functionalized phloroglucinol derivative such as syncarpic acid and tasmanone. However, a flavanone, as found in the syzygioblanes isolated from Syzygium oblanceolatum (Myrtaceae), is another rare non-terpene component. The terpene moieties are restricted to monoterpenes or sesquiterpenes. The spiro-ring is generally formed by [m + n] cyclization or, in some cases, by radical or ionic cyclization.</p>","PeriodicalId":9773,"journal":{"name":"Chemical & pharmaceutical bulletin","volume":"73 3","pages":"138-155"},"PeriodicalIF":1.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584878","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":"Theoretical Framework for Novel Catalytic Biomolecules Composed of Multiple Peptides","authors":"Akihiro Ambo, Shiho Ohno, Yoshiki Yamaguchi, Masayuki Seki","doi":"10.1248/cpb.c24-00155","DOIUrl":"https://doi.org/10.1248/cpb.c24-00155","url":null,"abstract":"</p><p>Protein-based enzymes are among the most efficient catalysts on our planet. A common feature of protein enzymes is that all catalytic amino acids occupy a limited, narrow space and face each other. In this study, we created a theoretical novel biomimetic molecule containing different multiple catalytic peptides. Although single peptides are far less catalytically efficient than protein enzymes, Octopus-arms-mimicking biomolecules containing eight different peptides (Octopuzymes) can efficiently catalyze organic reactions. Since structural information for extant protein enzymes, predicted enzymes based on genome data, and artificially designed enzymes is available for designing Octopuzymes, they could in theory mimic all protein enzyme reactions on our planet. Moreover, besides L-amino acids, peptides can contain D-amino acids, non-natural amino acids, chemically modified amino acids, nucleotides, vitamins, and manmade catalysts, leading to a huge expansion of catalytic space compared with extant protein enzymes. Once a reaction catalyzed by an Octopuzyme is defined, it could be rapidly evolvable <i>via</i> multiple amino acid substitutions on the eight peptides of Octopuzymes.</p>\u0000<p></p>\u0000<img alt=\"\" src=\"https://www.jstage.jst.go.jp/pub/cpb/72/9/72_c24-00155/figure/72_c24-00155.png\"/>\u0000<span style=\"padding-left:5px;\">Fullsize Image</span>","PeriodicalId":9773,"journal":{"name":"Chemical & pharmaceutical bulletin","volume":"8 1","pages":""},"PeriodicalIF":1.7,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142211630","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":"Two Preparation Methods for Peptide Thioester Containing Tyr(SO3H) Residue(s) without the Use of Protecting Group for Sulfate Moiety","authors":"Yumi Sekigawa, Shinichi Asada, Yurie Ichikawa, Kazuaki Tsubokawa, Shoh Watanabe, Shinobu Honzawa, Kouki Kitagawa","doi":"10.1248/cpb.c24-00212","DOIUrl":"https://doi.org/10.1248/cpb.c24-00212","url":null,"abstract":"</p><p>We report two methods for the preparation of peptide thioesters containing Tyr(SO₃H) residue(s), <i>without use of a protecting group for the sulfate moiety</i>. The first was based on direct thioesterification using carbodiimide on a fully protected peptide acid, prepared on a 2-chlorotrityl (Clt) resin with fluoren-9-ylmethoxycarbonyl (Fmoc)-based solid-phase peptide synthesis (Fmoc-SPPS). Subsequent deprotection of the protecting groups with trifluoroacetic acid (TFA) (0 °C, 4 h) yielded peptide thioesters containing Tyr(SO₃H) residue(s). Peptide thioesters containing one to three Tyr(SO₃H) residue(s), prepared by this method, were used as building blocks for the synthesis of the <i>N</i>^α-Fmoc-protected N-terminal part of P-selectin glycoprotein ligand 1 (PSGL-1) (Fmoc-PSGL-1(43–74)) <i>via</i> silver-ion mediated thioester segment condensation. The other method was based on the thioesterification of peptide azide, derived from a peptide hydrazide prepared on a NH₂NH-Clt-resin with Fmoc-SPPS. Peptide thioester containing two Tyr(SO₃H) residues, prepared <i>via</i> this alternative method, was used as a building block for the one-pot synthesis of the N-terminal extracellular portion of CC-chemokine receptor 5 (CCR5(9–26)) by native chemical ligation (NCL). The two methods for the preparation of peptide thioesters containing Tyr(SO₃H) residue(s) described herein are applicable to the synthesis of various types of sulfopeptides.</p>\u0000<p></p>\u0000<img alt=\"\" src=\"https://www.jstage.jst.go.jp/pub/cpb/72/7/72_c24-00212/figure/72_c24-00212.png\"/>\u0000<span style=\"padding-left:5px;\">Fullsize Image</span>","PeriodicalId":9773,"journal":{"name":"Chemical & pharmaceutical bulletin","volume":"55 1","pages":""},"PeriodicalIF":1.7,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141772423","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 STAT3 Inhibition by Cancer Chemopreventive Trichothecenes Derived from Metabolites of Trichothecium roseum","authors":"Mitsuaki Yamashita, Akari Nakanishi, Chiehming Chang, Kosei Tsurushima, Kiyoshige Nakamoto, Akira Iida","doi":"10.1248/cpb.c24-00300","DOIUrl":"https://doi.org/10.1248/cpb.c24-00300","url":null,"abstract":"</p><p>This study evaluated the ability of isolated or semisynthesized trichothecene sesquiterpenes to prevent cancer emergence and proliferation and inhibit signal transducer and activator of transcription-3 (STAT3) phosphorylation through <i>in vitro</i> assays. Trichothecinol A (TTC-A), which bears a hydroxy group at C3, exhibited greater cancer prevention, antiproliferation, and STAT3 phosphorylation inhibition effects than trichothecin (TTC), which lacks a hydroxy group at C3. Furthermore, trichothecinol B (TTC-B), which is a reduced derivative of TTC and has similar cytotoxic effect, showed substantially weaker chemoprotection and STAT3 phosphorylation inhibition effects than TTC. These results clearly indicate that the hydroxy group at C3 and carbonyl group at C8 are crucial for inducing both potent chemoprevention and STAT3 phosphorylation inhibition.</p>\u0000<p></p>\u0000<img alt=\"\" src=\"https://www.jstage.jst.go.jp/pub/cpb/72/7/72_c24-00300/figure/72_c24-00300.png\"/>\u0000<span style=\"padding-left:5px;\">Fullsize Image</span>","PeriodicalId":9773,"journal":{"name":"Chemical & pharmaceutical bulletin","volume":"204 1","pages":""},"PeriodicalIF":1.7,"publicationDate":"2024-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141753930","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}