Chemical and Pharmaceutical Bulletin
Online ISSN : 1347-5223
Print ISSN : 0009-2363
ISSN-L : 0009-2363
  • 71 巻 (2023) 10 号 p. 775-781
    Regiocontrol Using Fluoro Substituent on 3,6-Disubstituted Arynes もっと読む

    To enhance the structural diversity in aryne-based products, the aryne precursors bearing various functional groups have been continuously developed. However, the use of unsymmetrically substituted arynes is frequency constrained by the low regioselectivity. Authors achieved the regiocontrol by introducing a fluoro-substituent in unsymmetrically 3,6-disubstituted arynes as a directing group. Particularly, the use of 3,6-disubstituted aryne having fluorine and bromine atoms led to the good degree of regiocontrol in several reactions. These results consist with aryne distortion models reported by Garg and Houk’s group.

  • 71 巻 (2023) 10 号 p. 792-797
    Lithium Binaphtholate-Catalyzed Asymmetric Michael Reaction of Acrylamides もっと読む

    A chiral lithium binaphtholate base catalyst effectively mediates the asymmetric Michael addition of ketones to less reactive acrylamides in a highly enantioselective manner. A small excess of lithium tert-butoxide relative to the binaphthol is used to facilitate the enolization of the ketone, thereby improving conversion of the asymmetric Michael reaction. Computational studies support that the 3- and 3'-phenyl groups of the binaphtholate catalyst control the orientation of the lithium enolate and the subsequent approach of acrylamide to achieve high enantioselectivity.

  • 71 巻 (2023) 9 号 p. 687-694
    Effects of Granulated Lactose Characteristics and Lubricant Blending Conditions on Tablet Physical Properties in Direct Powder Compression もっと読む

    This study evaluated the effects of different forms of granulated lactose (GL) on the physical properties of tablets and the effect of magnesium stearate on each type of GL. The different forms of GL such as agitated granulation (GL-AG), spray-dried granulation (GL-SD), and fluidized bed granulation (GL-FB) were added as excipients during direct powder compression. When tablets with the same blending conditions were compared, the tensile strength and disintegration time followed the order as GL-FB > GL-SD > GL-AG. The authors presented selection criteria for the suitability of different forms of GL during tableting by examining the relevance between the type of GL and properties of the tablets produced.

  • 71 巻 (2023) 9 号 p. 701-716
    Synthesis and Evaluation of Novel Triaryl Derivatives with Readthrough-Inducing Activity もっと読む

    Readthrough therapy, which restores the biosynthesis of full-length proteins by incorporating an amino acid at a premature termination codon and allowing translation to continue, has recently been actively investigated for its application to nonsense mutation-related diseases. In this article, triaryl derivatives were synthesized and evaluated for the development of novel readthrough agents to treat mucopolysaccharidosis type I, which is caused by nonsense mutations in the IDUA gene. KY-516, a representative compound, exhibited excellent readthrough-inducing activity in the luciferase assay and significantly increased enzyme activity in mutant IDUA transgenic cells.

  • 71 巻 (2023) 9 号 p. 717-723
    Synthesis of New 26,27-Difluoro- and 26,26,27,27-Tetrafluoro-25-hydroxyvitamin D3: Effects of Terminal Fluorine Atoms on Biological Activity and Half-life もっと読む

    In this Article, the authors investigated the effects of fluorine atoms introduced to the terminal positions of the side chain (26 and 27-positions) of 25-hydroxyvitamin D3 (25(OH)D3) on vitamin D receptor (VDR) binding affinity, osteocalcin promoter transactivation activity, and levels of resistance against CYP24A1-dependant metabolism. They revealed that these biological activities were enhanced in the order of 26,27-difluoro, 26,26,27,27-tetrafluoro, and 26,26,26,27,27,27-hexafluoro-25(OH)D3. Introduction of fluorines at these positions lead to improvements on functions as VDR-ligands and biological activity. With regard to the VDR binding affinity, the authors considered those potency improvements might be attributed to the increased acidity of the 25-OH group.

  • 71 巻 (2023) 9 号 p. 730-733
    Synthesis and in Vitro Cytotoxicity Evaluation of Jadomycins もっと読む

    The authors synthesized jadomycins and their structural analogues, evaluated their cytotoxic activity, and addressed structure-activity relationship study of jadomycins. They achieved the total synthesis of jadomycin T and jadomycin aglycons using L-threonine and 1-amino-2-propanol as nitrogen sources. When the cytotoxicity of jadomycins were evaluated in several tumor cells, the jadomycin aglycons tended to be more cytotoxic than the jadomycins. The authors also demonstrated the potential application of jadomycins as lead compounds for the treatment of brain tumors. This paper provides important insights into the total synthesis of other natural organic compounds, structure-activity relationship studies, and development of new therapeutic drugs.

  • 71 巻 (2023) 8 号 p. 624-632
    Development of Transition-Metal-Catalyzed Dearomatization Reactions もっと読む

    To develop dearomatization reactions based on a nucleophilic activation of phenols, naphthols, and indoles, ipso-Friedel–Crafts-type C-alkylation must be selectively promoted over competitive O- or N-alkylation reactions. Resolving this chemoselectivity issue is essential for developing this class dearomatization reaction. Author’s research group found that various dearomatization reactions could be developed using appropriately designed aromatic substrates with an electrophilic moiety for intramolecular reactions. This review describes dearomatization reactions using Pd catalysis, Au catalysis, and Ag catalysis, which provided access to a wide variety of dearomatized products from planar aromatic compounds in a highly chemoselective manner.

  • 71 巻 (2023) 8 号 p. 650-654
    Identification of Methylsulochrin as a Partial Agonist for Aryl Hydrocarbon Receptors and Its Antiviral and Anti-inflammatory Activities もっと読む

    Aryl hydrocarbon receptor (AhR) is known to be related to the metabolic pathway of xenobiotics but recent studies revealed that AhR is also associated with the life cycle of the virus and inflammatory reactions. In this article, the authors screened a natural product library and identified methylsulochrin as a partial agonist of AhR. Methylsulochrin exhibited antiviral activity against the hepatitis C virus and suppressed the production of an inflammatory cytokine, interleukin-6, in macrophages. These results suggested the possibility of methylsulochrin derivatives as anti-hepatitis C virus compounds with anti-inflammatory activity.

  • 71 巻 (2023) 7 号 p. 466-484
    Novel Strategies for Enantio- and Site-Selective Molecular Transformations もっと読む

    Two topics on novel synthetic strategy are shown. The first topic concerns enolate chemistry. The enolate structure has been long believed to be achiral because all four substituents are in the same enolate plane. From the viewpoint of dynamic chirality, however, the enolate can exist as an axially chiral form or a planar chiral form in a limited time scale. The author demonstrated that these chiral enolates can be employed as reliable intermediates for asymmetric synthesis. The second topic concerns catalyst function. 4-pyrrolidinopyridine (PPY) had been known to be the most active catalyst for acylation. Based on the PPY skeleton, strategies for enantio- and site-selective catalysis were proposed. The latter opened up a new way to total syntheses of natural glycosides in extremely short overall steps.

  • 71 巻 (2023) 7 号 p. 485
    Foreword もっと読む

    This “Current Topics” contains one review and four regular articles describing the latest research on natural product chemistry that have been contributed by young researchers. These contents include computer science technology in natural products research, isolation of biological constituents from medicinal plants, evaluation of the biological activity of natural products, and synthesis of biological constituents from medicinal plants. These findings could be useful for the development of effective medicines from natural medicinal resources.

  • 71 巻 (2023) 7 号 p. 576-583
    Continuous Monitoring of the Hydration Behavior of Hydrophilic Matrix Tablets Using Time-Domain NMR もっと読む

    The hydration behavior of hydrophilic matrix tablets is a crucial process for the in vitro release of highly water-soluble drugs. This article presented a novel method for continuous monitoring of the hydration behavior by using time-domain nuclear magnetic resonance (TD-NMR). TD-NMR has an ability to identify the NMR signals corresponding to the nongelated core remaining in the sample from the measured T2 relaxation curves. The authors succeeded in characterizing fully the hydration behaviors of the model matrix tablets. The TD-NMR method is powerful to evaluate the hydration properties of hydrophilic matrix tablets.

  • 71 巻 (2023) 7 号 p. 584-615
    Isosteric Replacement of Ester Linkage of Lysophospholipids with Heteroaromatic Rings Retains Potency and Subtype Selectivity もっと読む

    The authors have reported various derivatives of lysophosphatidylserine (LysoPS) as potent and selective agonists for each LysoPS receptor subtype. In order to further develop these LysoPS analogs to drug candidates, appropriate pharmacokinetic consideration is essential. They found that the ester bond of LysoPS is highly susceptible to metabolic degradation in mouse blood and examined isosteric replacement of the ester linkage with heteroaromatic rings. The resulting compounds showed excellent retention of potency and receptor subtype selectivity, as well as increased metabolic stability. This work provides a molecular basis for the design of phospholipid-based agonists with improved metabolic stability.

  • 71 巻 (2023) 6 号 p. 435-440
    Establishment of One-Pot Disulfide-Driven Cyclic Peptide Synthesis with a 3-Nitro-2-pyridinesulfenate もっと読む

    In peptide drug discovery, it is important to develop efficient synthetic methodologies to access cyclic disulfide peptides with the expression of functional activity and resistance to metabolic enzymes. In this study, the authors developed a one-pot disulfide-driven cyclic peptide synthesis. The entire process is carried out using solid phase peptide synthesis, thus eliminating complicated work up procedures to remove by-products and enabling production of high-purity cyclic peptides by simple cleavage of a peptidyl resin. Consequently, the one-pot synthesis of oxytocin as a model cyclic disulfide peptide was successfully accomplished using this method. Their study has contributed for the preparation of more complex and artificial disulfide peptides.

  • 71 巻 (2023) 6 号 p. 441-446
    Palatability of Aripiprazole Gummies Prepared from Commercially Available Products: Pharmaceutical Formulation for Improving Patient Adherence もっと読む

    Good adherence to medication is critical for successfully treating psychiatric disorders. The authors developed two types of aripiprazole gummies (ARP-Gs) with organoleptic masking, cocoa- and fruit-flavoured ARP-Gs using a commercially available ARP formulation. They evaluated the overall palatability and acceptability of the ARP-Gs by performing a gustatory sensation test in healthy volunteers. The both ARP-Gs exhibited superior palatability, and greatly exceeded the cut-off values of acceptability. The ARP-Gs could be alternative dosing forms in patients with schizophrenia, and pharmacists can prepare these formulations in pharmacies to enhance medication adherence and meet the specific needs of individual patients.

  • 71 巻 (2023) 6 号 p. 447-450
    Substituent Effects at the N-Nitrosoaminophenol Moiety of a Photoinduced-Electron-Transfer-Driven Nitric Oxide Releaser もっと読む

    The authors have developed a series of photoinduced-electron-transfer-driven (PeT-driven) nitric oxide (NO) releasers that efficiently release NO upon irradiation with visible light. In this study investigating the substituent effects at the 2-position of the nitrosoaminophenol moiety, it was found that a methyl group had no significant effect on NO-releasing ability, while a nitro or methoxy group reduced it. The nitro group may suppress electron transfer to the antenna moiety, while the methoxy group may accelerate electron transfer but suppress deprotonation of nitrosoaminophenol. Understanding these structure-activity relationships could aid in further functionalizing PeT-driven NO releasers.

  • 71 巻 (2023) 5 号 p. 354-359
    Mechanistic Insight into the TBHP-Mediated Decarboxylative Condensation of α-Ketoacids: Reaction Development and Application to Oligopeptide Synthesis もっと読む

    The development of peptide bond formation reaction enabling a convergent peptide fragment coupling is a major challenge of recent years for synthetic chemists due to the rapidly growing interest in the discovery of drugs base on the middle molecule peptides. The decarboxylative amidation recently reported by authors’ group is a potential solution to this problem. In this article, a mechanistic analysis and the further development of the t-butyl hydroperoxide (TBHP) mediated-decarboxylative amidation of α-ketoacids are described. A systematic examination and understanding of the reaction mechanism enabled a modified epimerization-free reaction whereby peptide fragment couplings using peptide α-ketoacids were successfully achieved.

  • 71 巻 (2023) 5 号 p. 368-373
    Comparison of Growth in Hydrangea macrophylla var. thunbergii Grown in Different Soil pH and Quantitative Analysis of Its Sweetness-Related Constituents もっと読む

    The processed leaves of Hydrangea macrophylla Seringe var. thunbergii Makino is listed as a Sweet Hydrangea Leaf (Hydrangeae Dulcis Folium) in the 18th edition of the Japanese Pharmacopoeia. The authors reported soils with pH ranging from 7.0 to 5.5 was not only suitable for this plant growth but also increased the content of phyllodulcin as sweetener in the leaves. In addition, a correlation between the sweetness of the crude drug and phyllodulcin was shown. These findings could be useful for the development of the crude drug with high-quality.

  • 71 巻 (2023) 4 号 p. 289-298
    Effects and Mode of Action of Oleic Acid and Tween 80 on Skin Permeation of Disulfiram もっと読む

    Oral disulfiram (DSF) has been used clinically for alcohol dependence and recently has been found to have antitumor activity. A transdermal delivery system would be useful for reducing the frequency of administration of DSF for cancer treatment. The authors found that the combination of oleic acid (OA) and Tween 80 further enhanced skin permeation of DSF compared with individual application. The peak of CH2 asymmetric stretching vibration was blue-shifted by the application of OA, and DSF solubility increased in response to Tween 80. Their study clarified the detailed mechanism of action of skin permeation and promoting effect of DSF through the combined use of OA and Tween 80.

  • 71 巻 (2023) 4 号 p. 299-306
    Fragment Molecular Orbital Based Affinity Prediction toward Pyruvate Dehydrogenase Kinases: Insights into the Charge Transfer in Hydrogen Bond Networks もっと読む

    This computational paper describes the importance of treating electronic effects among hydrogen bond networks. Fragment Molecular Orbital (FMO) method, which is a fast quantum-mechanics method, was applied to the affinity prediction at the hydrogen bond networks of PDHK4. Authors found that the FMO calculation with the solvation method of polarizable continuum model (PCM) was important to increase the prediction accuracy. A considerable amount of charge was transferred among the target site in the FMO/PCM calculation, which was not described in the traditional molecular-mechanics method. These results highlight the importance of electronic effects in the affinity prediction toward hydrogen bond networks.

  • 71 巻 (2023) 3 号 p. 213-219
    Bioequivalence Dissolution Test Criteria for Formulation Development of High Solubility-Low Permeability Drugs もっと読む

    The biowaiver scheme based on the biopharmaceutics classification system (BCS-BWS) is used not only as terms of regulatory submissions but also as an indicator for formulation development in drug discovery. The authors investigated the in vitro dissolution rates of formulations of a BCS class III drug and compared them with the criterion in the BCS-BWS. They also discussed the impact of dissolution rates on bioequivalence for BCS class III drugs by virtual simulation. These findings contribute to a better understanding of the biowaiver approach and would help researchers in the formulation development of BCS class III drugs.