Chemical and Pharmaceutical Bulletin
Online ISSN : 1347-5223
Print ISSN : 0009-2363
ISSN-L : 0009-2363
Featured articles
Displaying 41-40 of 255 articles
  • Volume 69 (2021) Issue 10 Pages 1005-1009
    Nitroxyl Radical/Copper-Catalyzed Electrooxidation of Alcohols and Amines at Low Potentials Read more
    Editor's pick

    Accurate quantitative and qualitative analysis of biological and clinical samples is important, and rapid and simple analytical methods are demanded. The authors investigate an electrochemical detection of alcohols and amines by cyclic voltammetry at low potential using nortropine N-oxyl (NNO) and a copper salt as catalysts. As a result, although the concentration that could be quantified with good accuracy was limited in both the detection of alcohols and the detection of amines, a correlation was observed between the current and the concentration.

  • Volume 69 (2021) Issue 10 Pages 1010-1016
    Electrophilic Epoxidation of α,β-Unsaturated Oximes with Dioxiranes and Ring Opening of the Epoxides Read more
    Editor's pick

    α,β-Unsaturated carbonyl compounds undergo nucleophilic reaction at electron-deficient carbon-carbon double bonds, as well as cycloaddition with dienes or 1,3-dipoles having a high HOMO energy levels. This character of the enones and enals can be transformed from electron-deficient to electron-rich by conversion to the corresponding oximes because of the electron-donating ability of an electron pair (umpolung). This paper describes that α,β-unsaturated oximes underwent electrophilic epoxidation with in-situ-generated dimethyldioxirane to give the corresponding epoxides in good yields. Nucleophilic ring-opening reactions of the epoxides afforded α-substituted products. Shi asymmetric epoxidation of the oximes proceeded with moderate asymmetric selectivity.

  • Volume 69 (2021) Issue 10 Pages 1034-1038
    Theoretical Study on the Mechanism of Spirocyclization in Spiroviolene Biosynthesis Read more
    Editor's pick

    Authors uses computational chemistry to scrutinize the biosynthetic mechanism of a diterpenoid, spiroviolene, which features a 5/5/5/5 tetracyclic system with a spirocyclic skeleton. Terpenes/terpenoids are biosynthesized via multiple stable carbocation intermediates, such as tertiary, allyl, and cyclopropylcarbinyl cations. However, formation of secondary carbocations have been proposed in the spiroviolene biosynthesis in earlier reports. On the basis of DFT calculations, authors propose a new 16-step carbocation cascade leading to the spiroviolene skeleton. This cascade bypasses the formation of unstable secondary carbocations by breaking the adjacent C–C bond to form a more stable tertiary carbocation and by Wagner-Meerwein 1,2-methyl rearrangement. 

  • Volume 69 (2021) Issue 9 Pages 819-831
    Molecular Transformation Based on an Innovative Catalytic System Read more
    Editor's pick

    Three hybrid catalysts have been designed based on the reaction mechanism of enzymes. These catalysts using non-covalent intermolecular interactions exhibit remarkable catalytic performance for the activation of α,β-unsaturated amides and carboxylic acids as well as the dynamic kinetic resolution of a racemic electrophile in an SN2-type reaction. These innovative catalytic systems allow the asymmetric synthesis of biologically important molecules such as atorvastatin, beraprost, sitagliptin, and avenaol.

  • Volume 69 (2021) Issue 9 Pages 840-853
    Environmental Risk Assessment of Active Human Pharmaceutical Ingredients in Urban Rivers in Japan Read more
    Editor's pick

    In Japan, environmental risk assessments (ERA) for human pharmaceuticals in aquatic environments have barely begun. This paper reports the first study assessing the validity of ERA guidance issued by the Ministry of Health, Labour, and Welfare in 2016 for new medicinal products in the environment, using selected pharmaceuticals already on the market. The accuracy of predicted environmental concentrations was evaluated by measuring environmental concentrations in urban rivers. The results will be useful information applicable to ERA for new medicinal products, and development of future ERA standards in Japan.

  • Volume 69 (2021) Issue 9 Pages 854-861
    2-Thioxothiazolidin-4-one Analogs as Pan-PIM Kinase Inhibitors Read more
    Editor's pick

    PIM kinases are attractive therapeutic targets for the treatment of multiple hematological malignancies. In search for novel PIM kinase inhibitors, the authors designed and synthesized a series of 5-benzylidene-2-thioxothiazolidin-4-one derivatives with various substitutions at the pyrazine rings. Several compounds exhibited subnanomolar to single-digit nanomolar potencies against all three PIM isoforms and showed anti-proliferative activities against human leukemic EOL-1 and MOLM-16 cell lines. The mechanism of action study of compound 17 clearly revealed that a pan-PIM inhibitor reduced phosphorylation of downstream substrates of PIM kinase such as BAD and 4EBP1 in a dose-dependent manner.

  • Volume 69 (2021) Issue 9 Pages 877-885
    Monitoring of Cocrystal Dissociation during the Wet Granulation Process in the Presence of Disintegrants by Using Low-Frequency Raman Spectroscopy Read more
    Editor's pick

    Understanding the dissociation behavior of cocrystals is an essential task in particular during manufacturing process of the solid dosage forms containing cocrystals as active pharmaceutical ingredients (APIs). The authors have established the promising technique with low-frequency Raman spectroscopy as a monitoring tool for molecular state of APIs during wet granulation, which can detect the dissociation of cocrystals successively and the rate calculated from the spectra enabled to evaluate the stable cocrystal and the formulation with various disintegrants. These findings would help researchers to consider developable pharmaceuticals containing cocrystals.

  • Volume 69 (2021) Issue 9 Pages 926-930
    Construction of Acyclic All-Carbon Quaternary Stereocenter Based on Asymmetric Michael Addition of Chiral Amine Read more
    Editor's pick

    An all-carbon quaternary stereocenter is found in many biologically and pharmaceutically active compounds, in spite of being one of the most difficult structures to construct in the field of synthetic organic chemistry. In the present study, we were able to construct all-carbon quaternary stereocenters in an acyclic system by utilizing a face-selective alkylation of enolate intermediates derived from an asymmetric Michael addition reaction of a chiral lithium amide with trisubstituted α,β-unsaturated esters. Moreover, the obtained Michael adduct was able to be converted to the β-amino ester having the all-carbon quaternary stereocenter by an oxidative deprotection.

  • Volume 69 (2021) Issue 8 Pages 707-716
    Construction of N-Heterocycles Fused with a Highly Substituted Benzene Ring by a Benzyne-Mediated Cyclization/Functionalization Cascade Reaction and Its Application to the Total Synthesis of Marine Natural Products Read more
    Editor's pick

    The cover figure schematically illustrates the divergent synthesis of various nitrogen-containing heteroaromatic marine natural products by benzyne-mediated cyclization / functionalization cascade reactions. The figure in the center is a slot machine, which represents the flask used in the Cascade reaction, showing that several coins with the structure of nitrogen-containing heteroaromatic complex marine natural products are popping out when three numbers 7 hit at the same time.

  • Volume 69 (2021) Issue 8 Pages 721-726
    Application of Quantitative NMR Spectroscopy to the Quality Evaluation of Diclofenac Gargles as Hospital Preparations Read more
    Editor's pick

    Hospital preparations are frequently prepared in Japanese hospitals, but quality evaluation is not necessarily sufficient. In this article, quantitative 1H NMR spectroscopy (qNMR) was applied to the quality evaluation of diclofenac gargles as an example of a hospital preparation. Aliquots of the gargles were analyzed by qNMR using an internal standard method, where the medicinal ingredients in the preparations were accurately and precisely determined, with the water signal being effectively suppressed by water suppression enhanced through T1 effects (WET). The quality and stability of the gargles were elucidated based on the results. As such, qNMR with WET is potentially useful for the quality control of various aqueous preparations because of its simplicity and convenience.

  • Volume 69 (2021) Issue 8 Pages 747-759
    Preparation of Fine-Drugs Layered Spherical Particles with Good Micromeritic and Dissolution Properties through Ultra Cryo-Milling and Mechanical Powder Processing Read more
    Editor's pick

    The authors have developed the novel composite ordered-mixed (OM) particles containing fine drug-particles. The composite OM particles were found to be double-structured spherical particles consisting of finely-milled particles layered around the core particles. It was also found that they have excellent characteristics from both pharmaceutical and micromeritic perspectives and could overcome manufacturing problems of solid dosage forms. Such unique OM particles could be precisely designed by ultra cryo-milling in liquid nitrogen and subsequent mechanical powder processing which would be a potential platform approach to develop the oral dosages (tablet, capsule, granule) with improved dissolution property of poorly water-soluble drugs.

  • Volume 69 (2021) Issue 8 Pages 796-801
    Photoinduced Atom Transfer Radical Addition Reaction of Olefins with α-Bromo Carbonyls Read more
    Editor's pick

    The authors developed ATRA reactions of olefins with bromomalonate ester catalyzed by an in situ-formed halogen-bonding complex. The use of 4-phenylpyridine as the halogen-bonding acceptor, the desired reaction proceeded well under external irradiation of 380 nm LED light to furnish the corresponding ATRA reaction product. The substrate activation through the halogen bonding from the CT complex is a novel activation method that can be used for challenging synthetic routes since halogen bond acceptors such as pyridine are relatively inexpensive and readily available. This approach offers a new strategy for other classes of compounds for photocatalysis, including alkyl halides with amines or phosphine.

  • Volume 69 (2021) Issue 7 Pages 601-607
    Functional Peptides That Target Biomembranes: Design and Modes of Action Read more
    Editor's pick

    Biological membranes are an important target for molecular design. Properly designed membrane-interacting peptides can induce physicochemical and physiological responses in cell membrane and modulate cell structure and function.

  • Volume 69 (2021) Issue 7 Pages 608-611
    Construction of 7-Diethylaminocoumarins Promoted by an Electron-Withdrawing Group Read more
    Editor's pick

    Previously, the authors developed a cyclization reaction-based turn-on probe (TCC probe) for protein labeling. The TCC probe is characterized by its ability to construct coumarin structures easily by conjugate addition to the ynone moiety, but the reactivity of the probe becomes poor when attempting to improve the fluorescence properties. The authors improved the reactivity by increasing the electron-withdrawing property of the leaving ester group and succeeded in constructing the coumarin skeleton with good yields. These results suggest an easy method to introduce a coumarin skeleton with good fluorescence properties.

  • Volume 69 (2021) Issue 7 Pages 674-680
    Latent Structure Analysis of Wet-Granulation Tableting Process Based on Structural Equation Modeling Read more
    Editor's pick

    Quality by design (QbD) is an essential concept for modern manufacturing processes of pharmaceutical products. Understanding the science behind manufacturing processes is crucial; however, the complexity of the manufacturing processes makes implementing QbD challenging. In this study, structural equation modeling (SEM) was applied to understand the causal relationships between variables such as process parameters, material attributes, and quality attributes. Based on SEM analysis, a model composed of the above-mentioned variables and their latent factors without including observational data was identified. The results indicate that SEM analysis could be useful for implementing QbD for the manufacturing processes of pharmaceutical products.

  • Volume 69 (2021) Issue 7 Pages 681-692
    Elaboration of Non-naturally Occurring Helical Tripeptides as p53–MDM2/MDMX Interaction Inhibitors Read more
    Editor's pick

    Because of the wide range of protein-protein interaction surfaces, it is important to develop molecules that satisfy the intrinsic shape recognition of the partner protein. The authors have previously shown that a stable non-naturally occurring helix trimer of all trans-amide-bonded bicyclic β-amino acid inhibits the p53-MDM2/MDMX-helix-helix interaction that plays a role in regulating p53 function. The authors showed herein that modification of the C-terminal/N-terminal residues improved the inhibitory activity, and confirmed that these peptides are membrane-permeable p53-MDM2/MDMX interaction antagonists and can rescue p53 function in cells.

  • Volume 69 (2021) Issue 6 Pages 503-515
    Target Protein-Oriented Isolations for Bioactive Natural Products Read more
    Editor's pick

    Structure and bioactivities of natural products are often beyond human knowledge and imagination. In this article, the author developed original screening methods based on protein binding activity. Protein beads method and protein plate method were described. Protein beads method led to the discovery of neural stem cell differentiation activators which inhibited Hes1 dimer formation as a new mechanism. The author also developed protein plate method for protein-protein interaction inhibitors to find new cancer drug candidates. Because protein binding ability is tightly related to bioactivity, protein-based natural products isolation is a powerful means to find new candidate medicines.

  • Volume 69 (2021) Issue 6 Pages 516-525
    Development of Catalytic Reactions for Precise Control of Chemoselectivity Read more
    Editor's pick

    A cooperative catalyst comprising a soft Lewis acid/hard Brønsted base enabled chemoselective activation of a hydroxyl group over an amino group. The present chemoselective catalysis could be applicable for a variety of amino alcohols, including pharmaceuticals, without requiring a tedious protection-deprotection process. Chemoselective enolization and subsequent α-functionalization of carboxylic acid derivatives were also achieved by a redox active catalyst through the radical process, providing unnatural α-amino/hydroxy acid derivatives bearing a complex carbon framework and a diverse set of functionalities. The present chemoselective catalysis described herein offers new opportunities to expand the chemical space for innovative drug discovery research.

  • Volume 69 (2021) Issue 6 Pages 526-528
    Fluorescent-Oxaboroles: Synthesis and Optical Property by Sugar Recognition Read more
    Editor's pick

    The optical property of fluorescent unit-conjugated aliphatic oxaboroles has been investigated in this featured article. The authors described the synthesis of fluorescent-oxaboroles by originally developed methods and the optical behavior of the boroles with various sugars. The oxaboroles provide good fluorescence quantum yields and selective recognition toward D-ribose and D-ribose-containing molecules. The molecular recognition induced significant fluorescence quenching. The authors also revealed the positive correlation between the LUMO energy of the oxaborole and the relative fluorescence intensity. The property of the boroles showed the possibility of the boron-based NAD sensor probe.

  • Volume 69 (2021) Issue 6 Pages 537-547
    A New Bitterness Evaluation Index Obtained Using the Taste Sensor for 48 Active Pharmaceutical Ingredients of Pediatric Medicines Read more
    Editor's pick

    Quantitative evaluation for bitterness of pediatric medicine is essential for adherence.  The authors proposed criteria, change in concentration-dependent potential (CCDP), dose-response slope of the sensor outputs of active pharmaceutical ingredients measured by an artificial taste sensor, which is new and useful bitterness evaluation index for 48 pediatric medicines from the recent edition of the WHO model list of essential medicines for children (7th ed., 2019). CCDP by individual basic bitterness sensor well correlated to various physicochemical factors related hydrophilicity and hydrophobicity. Therefore, CCDP proved to be useful as a bitterness evaluation index of APIs in pediatric medicines.