Chemical & pharmaceutical bulletin最新文献

{"title":"Genetic Code Expansion-Driven in Situ Click Labeling Enables Rapid Imaging-Based Selection of Functional Nanobody-Dye Conjugates.","authors":"Naoki Seike, Ryosuke Kojima, Ryo Tachibana, Kyohhei Fujita, Tatsuo Yanagisawa, Shigeyuki Yokoyama, Yasuteru Urano","doi":"10.1248/cpb.c25-00376","DOIUrl":"https://doi.org/10.1248/cpb.c25-00376","url":null,"abstract":"<p><p>Antigen-binding proteins, such as nanobodies, modified with functional small molecules hold great potential for applications including imaging probes, drug conjugates, and localized catalysts. However, traditional chemical labeling methods that randomly target lysine or cysteine residues often produce heterogeneous conjugates with limited reproducibility. Conventional site-specific conjugation approaches, which typically modify only the N- or C-terminus, may also be insufficient to achieve the desired functionalities. Genetic code expansion offers a powerful alternative by enabling the site-specific incorporation of noncanonical amino acids bearing reactive handles-such as trans-cyclooctene (TCO)-thereby allowing precise bioorthogonal conjugation via click chemistry. Nevertheless, identifying suitable incorporation sites that tolerate such modifications without disrupting antigen binding remains a time- and cost-intensive process, as this process typically requires labor-intensive screening involving the expression and purification of each candidate variant. Here, using HER2 and an anti-HER2 nanobody as a model antigen-binder pair, we present a convenient mammalian cell-based screening platform for rapid, purification-free evaluation of site-specifically labeled nanobodies. The nanobody is fused to blue fluorescent protein (BFP), secreted by HEK293T cells, and labeled in situ with a tetrazine-fluorescein probe. The resulting supernatant is then applied directly to HEK293T cells stably expressing HER2-mCherry. Labeling efficiency and retention of antigen-binding activity are simultaneously assessed by fluorescence imaging in the BFP, fluorescein, and mCherry channels. This approach enables efficient identification of labeling sites that support productive click conjugation while preserving binding function. It should be broadly applicable to other antigens and binders, streamlining early-stage screening of engineered antigen-binder conjugates for diverse applications.</p>","PeriodicalId":9773,"journal":{"name":"Chemical & pharmaceutical bulletin","volume":"73 9","pages":"793-801"},"PeriodicalIF":1.3,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145014037","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":"Side-Chain Fluorine Engineering of Vitamin D₃ Derivatives for VDR-Silent SREBP Inhibitors.","authors":"Fumihiro Kawagoe, Sayuri Mototani, Tomofumi Yatsu, Yasushi Takemoto, Yusuke Akagi, Toshie Fujishima, Yoshiki Miyata, Motonari Uesugi, Atsushi Kittaka","doi":"10.1248/cpb.c25-00363","DOIUrl":"https://doi.org/10.1248/cpb.c25-00363","url":null,"abstract":"<p><p>The present study reports on the structure-activity relationships of side-chain shortened and fluorinated vitamin D₃ analogs (5-13), with the goal of developing vitamin D analogs that are silent toward the vitamin D receptor (VDR) while retaining inhibitory activity against sterol regulatory element-binding protein (SREBP). The biological activities of the synthesized fluorinated vitamin D₃ analogs were assessed through their effects on the VDR ligand-binding domain (VDR_LBD), full-length VDR transcriptional activity, and SREBP transcriptional activity. Among the synthesized analogs, 8, 11, and 13 exhibited notable SREBP inhibitory activity, although their potency was lower than that of the natural vitamin D₃ metabolite, 25(OH)D₃ (1). Compound 11 emerged as the most effective analog, displaying selective SREBP inhibition with minimal VDR activation.</p>","PeriodicalId":9773,"journal":{"name":"Chemical & pharmaceutical bulletin","volume":"73 9","pages":"868-883"},"PeriodicalIF":1.3,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145111650","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":"Remote Diazenylation of Fluorinated Alkyl Iodides via 1,5-HAT.","authors":"Masahiro Abe, Akiho Mizukami, Aoi Hirata, Nagisa Yano, Airu Kataoka, Kiyofumi Inamoto","doi":"10.1248/cpb.c25-00506","DOIUrl":"https://doi.org/10.1248/cpb.c25-00506","url":null,"abstract":"<p><p>Herein, we demonstrated a site-selective diazenylation of fluorinated alkyl iodides via 1,5-hydrogen atom transfer using diazonium salts, in combination with iron metal and ferrocene as an inexpensive catalytic system. The reactions proceeded under mild conditions with high regioselectivity, thereby enabling the efficient synthesis of a diverse range of azo compounds that have been difficult to access by traditional synthetic methods.</p>","PeriodicalId":9773,"journal":{"name":"Chemical & pharmaceutical bulletin","volume":"73 10","pages":"933-937"},"PeriodicalIF":1.3,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145205780","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":"Elucidating Molecular State of Loxoprofen in Acrylic Adhesive Patches Which Could Relate Transdermal Drug Permeability.","authors":"Nanami Haraguchi, Yutaro Watanabe, Manabu Shimazaki, Mika Yoshimura Fujii, Vasanthi Palanisamy, Toshiro Fukami","doi":"10.1248/cpb.c23-00853","DOIUrl":"10.1248/cpb.c23-00853","url":null,"abstract":"<p><p>The purpose of this study was to investigate the effect of the interaction between hydrophilic drugs and acrylic polymers in the adhesive layer of matrix-type patches on skin permeability. Loxoprofen is a nonsteroidal anti-inflammatory drug which has poor permeability. To improve that, patches were prepared using loxoprofen sodium hydrate (LP-Na) as the active pharmaceutical ingredient and acrylic polymers with four different functional groups with different molecular weights. In addition, to enhance the permeability of the patches, we add the lactic acid (LA) as an additive. The crystalline state of the patches was examined by polarizing microscopy and powder X-ray diffraction. The interaction between LP-Na and acrylic polymers was also evaluated using ¹H-NMR. The drug release rate and in vitro skin permeation from the patches were evaluated by dissolution apparatus (paddle method) and Franz diffusion cell, respectively. In patches using acrylic polymers with carboxy groups (AO), the skin permeation test suggested that the LP-Na_AO patch system showed 2.5 times better permeability compared with other patches. Interestingly, addition of LA (LP-Na_AO + LA) also improved 1.5 times more diffusion rate than LP-Na_AO patch and other systems. The interaction of LP-Na with acrylic polymers and LA as pH modifier would enhance the permeability of LP from matrix-type adhesive patches.</p>","PeriodicalId":9773,"journal":{"name":"Chemical & pharmaceutical bulletin","volume":"73 4","pages":"298-306"},"PeriodicalIF":1.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143771444","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":"2-Azanorbornane-Based Amino Amide Organocatalysts for Asymmetric Michael Addition of β-Keto Esters with Nitroolefins.","authors":"Huang Yueming, Rei Togashi, Zubeda Begum, Chigusa Seki, Yuko Okuyama, Eunsang Kwon, Koji Uwai, Michio Tokiwa, Suguru Tokiwa, Mitsuhiro Takeshita, Hiroto Nakano","doi":"10.1248/cpb.c25-00296","DOIUrl":"https://doi.org/10.1248/cpb.c25-00296","url":null,"abstract":"<p><p>Newly designed optically active cage type 2-azanorbornane-based amino amide organocatalysts were developed and employed in the asymmetric Michael addition of β-keto esters with nitroolefins to afford the chiral Michael adducts with good chemical yields (up to 99%) and stereoselectivities (up to diastereomeric ratio (dr) = 97 : 3, up to 96% enantiomeric excess (ee)).</p>","PeriodicalId":9773,"journal":{"name":"Chemical & pharmaceutical bulletin","volume":"73 7","pages":"616-620"},"PeriodicalIF":1.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144599510","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":"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 Film-Forming Ability for Heparinoid Cream Formulations.","authors":"Niina Shikamura, Toshiro Fukami, Tatsuo Koide, Yoshihisa Yamamoto","doi":"10.1248/cpb.c25-00382","DOIUrl":"10.1248/cpb.c25-00382","url":null,"abstract":"<p><p>We compared the film-forming ability of a heparinoid cream (HP-C) formulation, an oil-in-water-type emulsion used as a moisturizer, and found that the original HP-C (HP-C_O) formulation formed a thick and robust film that floated easily on an acrylic plate. It is suggested that the thickness and robustness of HP-C_O contributed to the retention of its high keratin water content, while its floatability helped prevent adhesion to clothing after application. Among the generic HP-C formulations tested, only one (HP-C_G1) formed a film with properties similar to those of HP-C_O. When the HP-C formulations were mixed with white petrolatum, the floatability of the resulting film was eliminated, and the film easily disintegrated upon physical stimulation with a spatula. These results suggest that mixing the HP-C formulations with other ointment bases, such as white petrolatum, is not appropriate from the standpoint of film formation. Because peaks corresponding to glycerin (GL) were clearly observed in the near-IR spectra of both HP-C_O and HP-C_G1 after 24 h at room temperature, we explored the addition of water-soluble polyhydric alcohols, such as GL and propylene glycol (PG), to generic HP-C formulations that did not initially demonstrate good film-forming properties. The state of the film and its floatability tended to improve when these generic HP-C formulations were mixed with GL or PG. Thus, these results indicate that the film-forming ability differed depending on the HP-C formulation. Furthermore, the results suggest that GL played a key role in the successful film formation observed in both HP-C_O and HP-C_G1.</p>","PeriodicalId":9773,"journal":{"name":"Chemical & pharmaceutical bulletin","volume":"73 9","pages":"852-856"},"PeriodicalIF":1.3,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145085120","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":"Development of a Novel TLC Identification Test for \"Rosemary Oil\" and \"Rosemary Water\" Listed in the Japanese Standards of Quasi-Drug Ingredients.","authors":"Taichi Yoshitomi, Takaaki Ando, Yuu Uchida, Takahiro Iwahashi, Chikako Hada, Nahoko Uchiyama","doi":"10.1248/cpb.c25-00277","DOIUrl":"10.1248/cpb.c25-00277","url":null,"abstract":"<p><p>Rosemary oil (RO) and rosemary water (RW) are widely used ingredients in cosmetics. According to the Japanese Standards of Quasi-Drug Ingredients (JSQDI), RO is defined as an essential oil obtained by the steam distillation of fresh rosemary (Rosmarinus officinalis L.) leaves, branches, and flowers, whereas RW is the water layer obtained from the steam distillation of the leaves. Although the JSQDI outlines a specific TLC identification test for RW, this test is time-consuming (15-cm development distance) and requires the use of hazardous reagents (toluene). Additionally, no identification tests are available for RO. This study therefore aimed to establish a new TLC-based identification test for RO in JSQDI, while also improving the RW identification test. Using cyclohexane/methyl tert-butyl ether/acetonitrile (20 : 10 : 1) as the developing solvent and 4-methoxybenzaldehyde sulfuric acid as the visualization reagent, 1,8-cineole and borneol were universally detected in 19 RO market products. Thus, 1,8-cineole was selected as the primary marker compound and borneol as the secondary marker compound. Additionally, the extraction process was optimized by applying these TLC conditions to RW, significantly simplifying the process. TLC analysis of the RW market products confirmed the presence of 1,8-cineole in all samples. Thus, in addition to representing a novel method for the identification of RO, these results indicate the suitability of the new extraction conditions for use as an alternative method to identify RW.</p>","PeriodicalId":9773,"journal":{"name":"Chemical & pharmaceutical bulletin","volume":"73 9","pages":"843-851"},"PeriodicalIF":1.3,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145085154","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}