Chemical and Pharmaceutical Bulletin
Online ISSN : 1347-5223
Print ISSN : 0009-2363
ISSN-L : 0009-2363
Featured articles
Displaying 1-20 of 284 articles
  • Volume 71 (2023) Issue 6 Pages 435-440
    Establishment of One-Pot Disulfide-Driven Cyclic Peptide Synthesis with a 3-Nitro-2-pyridinesulfenate Read more
    Editor's pick

    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.

  • Volume 71 (2023) Issue 6 Pages 441-446
    Palatability of Aripiprazole Gummies Prepared from Commercially Available Products: Pharmaceutical Formulation for Improving Patient Adherence Read more
    Editor's pick

    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.

  • Volume 71 (2023) Issue 6 Pages 447-450
    Substituent Effects at the N-Nitrosoaminophenol Moiety of a Photoinduced-Electron-Transfer-Driven Nitric Oxide Releaser Read more
    Editor's pick

    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.

  • Volume 71 (2023) Issue 5 Pages 354-359
    Mechanistic Insight into the TBHP-Mediated Decarboxylative Condensation of α-Ketoacids: Reaction Development and Application to Oligopeptide Synthesis Read more
    Editor's pick

    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.

  • Volume 71 (2023) Issue 5 Pages 368-373
    Comparison of Growth in Hydrangea macrophylla var. thunbergii Grown in Different Soil pH and Quantitative Analysis of Its Sweetness-Related Constituents Read more
    Editor's pick

    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.

  • Volume 71 (2023) Issue 4 Pages 289-298
    Effects and Mode of Action of Oleic Acid and Tween 80 on Skin Permeation of Disulfiram Read more
    Editor's pick

    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.

  • Volume 71 (2023) Issue 4 Pages 299-306
    Fragment Molecular Orbital Based Affinity Prediction toward Pyruvate Dehydrogenase Kinases: Insights into the Charge Transfer in Hydrogen Bond Networks Read more
    Editor's pick

    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.

  • Volume 71 (2023) Issue 3 Pages 213-219
    Bioequivalence Dissolution Test Criteria for Formulation Development of High Solubility-Low Permeability Drugs Read more
    Editor's pick

    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.

  • Volume 71 (2023) Issue 3 Pages 234-239
    Synthesis and Characterization of Novel Radioiodinated Triazole-Pyrolidine Derivative to Detect Orexin 2 Receptor in the Brain Read more
    Editor's pick

    The orexin 2 receptor plays a critical role in the arousal-promoting function. In vivo imaging of orexin 2 receptor is expected to contribute to elucidation of orexin systems and the development of drugs to treat sleep disorder. The authors newly developed a radioiodinated triazole-pyrolidine derivative to detect orexin 2 receptor in the brain. The authors described that an additional structure-activity relationship study based on the triazole-pyrolidine scaffold to improve brain pharmacokinetics may lead to the development of useful orexin 2 receptor imaging probes.

  • Volume 71 (2023) Issue 3 Pages 250-256
    An Amphipathic Structure of a Dipropylglycine-Containing Helical Peptide with Sufficient Length Enables Safe and Effective Intracellular siRNA Delivery Read more
    Editor's pick

    Cell-penetrating peptides (CPPs) are promising intracellular delivery tools for membrane-impermeable compounds such as small interfering RNAs (siRNAs). In this study, the authors designed amphipathic CPPs containing unnatural amino acids dipropylglycine (Dpg) and explored the cellular uptake and cytotoxicity of peptide/siRNA complexes. The results suggested that the amphipathic structure of peptides played a key role in complexation with siRNAs and intracellular siRNA delivery. A Dpg-containing peptide formed an amphipathic a-helical structure and achieved effective intracellular delivery using small amounts of peptides with negligible cytotoxicity. These findings could be valuable for the design of novel CPPs for siRNA delivery.

  • Volume 71 (2023) Issue 2 Pages 120-128
    Design, Synthesis, and Biological Evaluation of mTOR-Targeting PROTACs Based on MLN0128 and Pomalidomide Read more
    Editor's pick

    In this study, several novel PROTACs for the degradation of mTOR were designed based on MLN0128 (mTOR-binding ligand) and pomalidomide (E3 ligase CRBN ligand). PROTAC compounds exhibited mTOR inhibitory activity and suppressed MCF-7 cell proliferation. The representative compound P1 could degrade mTOR and reduce the expression of the mTOR downstream protein p-S6 (Ser240/244) and p-AKT (Ser473). Further studies showed that this compound could inhibit cancer cell growth by inducing autophagy, but it did not affect the cell cycle and apoptosis. This is the first mTOR PROTAC reported and these findings provide new insights in the study of mTOR inhibitors.

  • Volume 71 (2023) Issue 2 Pages 140-147
    Synthesis and Evaluation of 2-Amine-4-oxyphosaniline Pyrimidine Derivatives as EGFR L858R/T790M/C797S Mutant Inhibitors Read more
    Editor's pick

    Non-small cell lung cancer (NSCLC) is the most common type of lung cancers. However, drug resistance via an acquired triple EGFR mutation were inevitably observed after treatment with current inhibitors. So far, there are no effective therapeutic strategies to overcome the L858R/T790M/C797S triple mutation. In this paper, a class of 2-amine-4-oxyphosaniline pyrimidine derivatives were developed to overcome L858R/T790M/C797S (CTL) triple mutant drug resistance, and a candidate compound was discovered and showed good activity against L858R/T790M/C797S triple mutant in vitro.

  • Volume 71 (2023) Issue 2 Pages 165-174
    Quality Evaluation of Humidified Magnesium Oxide Tablet Formulations with Respect to Disintegration Time Prolongation Read more
    Editor's pick

    Authors conducted a detailed evaluation of the effects of humidification on the quality of five types of commercial magnesium oxide (MgO) tablet formulations by near-infrared spectroscopy, microscopic infrared spectroscopy and thermogravimetry. From these analysis results, it is qualitatively confirmed that the MgO was changed to magnesium hydroxide by humidification. In addition, most tablet formulations tended to prolong disintegration time due to humidification. Thus, in most commercial MgO tablet formulations, it is suggested magnesium hydroxide significantly contributes to prolongation of disintegration time by humidification. The results obtained in this study will provide useful information regarding the handling of MgO tablets in medical sites.

  • Volume 71 (2023) Issue 2 Pages 175-182
    Palladium-Catalyzed C–H Arylation of [1,1′-Biphenyl]-2-ols with Chloroarenes Read more
    Editor's pick

    Hydroxy-directed, Pd-catalyzed C‒H arylation of [1,1'-biphenyl]-2-ol with haloarenes, developed by Miura et al., is a useful method to synthesize ortho-teraryls. However, only bromo- and iodoarenes were used as arylating agents. In this paper, the authors report that chloroarenes including chloro-containing pharmaceuticals were successfully used as haloarenes for the reactions under optimized reaction conditions. In addition, it was revealed that substituted [1,1'-biphenyl]-2-ols and 2-heteroarylphenols instead of [1,1'-biphenyl]-2-ol were also usable for the reactions. Transformation of the ortho-teraryl product into a triphenylene derivative is also presented.

  • Volume 71 (2023) Issue 1 Pages 31-40
    Distribution of Domains Formed by Lateral Packing of Intercellular Lipid in the Stratum Corneum Read more
    Editor's pick

    The packing structure of intercellular lipids in the stratum corneum plays a pivotal role in the skin’s barrier function. The distribution of the packing structure domain is not well understood. The authors collected human stratum corneum cell samples by grid stripping and performed focal plane array-based Fourier transform infrared imaging analysis. The result suggested the distribution of packing structure domain was not uniform, and that the proportion of orthorhombic packing domain was lower in barrier-deficient skin with high transdermal water loss. Authors discussed the relationship between the distribution of packing structure domain and ceramide composition and its chain length.

  • Volume 71 (2023) Issue 1 Pages 41-51
    Comparative Study of General Notices in Pharmacopoeias in Japan, the United States, and Europe Read more
    Editor's pick

    With the globalization of pharmaceutical supply chains, manufacturers are required to manufacture products in compliance with the pharmacopoeial standards used in all exporting countries/regions to ensure product quality. However, since pharmacopoeias have been developed individually under the regulatory framework of each country/region, the structures and contents are unique. When using pharmacopoeias, an understanding of General Notices is essential because they list general rules applied to the entire pharmacopoeia. The authors compared the existence of items and the contents in the General Notices of the pharmacopoeias in Japan, the United States, and Europe comprehensively and revealed their similarities and differences.

  • Volume 71 (2023) Issue 1 Pages 58-63
    Advanced Solid-State NMR Analysis of Two Crystal Forms of Ranitidine Hydrochloride: Detection of 1H–14N Intra-/Intermolecular Correlations Read more
    Editor's pick

    It is important to develop new analytical methods for crystal polymorphs as one of the characterizations of active pharmaceutical ingredients. In this study, advanced solid-state NMR (SSNMR) methods were developed to investigate crystal polymorphs of the model drug ranitidine hydrochloride, which is known to exist in two forms, Form 1 and Form 2. 1H-14N dipolar-based heteronuclear multiple quantum coherence analysis revealed an intermolecular correlation of ranitidine hydrochloride Form 1. In addition, the multiple SSNMR experiments resulted in the reassignment of the 13C SSNMR signals for each form of ranitidine hydrochloride.

  • Volume 71 (2023) Issue 1 Pages 64-69
    Site-Specific Tritium Labeling at the Predefined Internal Position of the Chemically-Modified RNA Read more
    Editor's pick

    In nucleic acid drug discovery, it is extremely important to develop a technology to understand the distribution in target organs and to trace the degradation process in the body. In this study, the authors have demonstrated a new and efficient method for site-specific tritium labeling of the cytosine base at a predefined internal position in nucleic acid drugs. This method was developed by the chemical modification of the cytosine 4-amino group, followed by reduction with sodium tetratritioboranuide. Tritium-labeled nucleic acid drug candidates may be used for the preclinical ADME studies.

  • Volume 70 (2022) Issue 12 Pages 885-891
    Natural Compounds with BMI1 Promoter Inhibitory Activity from Mammea siamensis and Andrographis paniculata Read more
    Editor's pick

    B cell-specific Moloney murine leukemia virus insertion region 1 (BMI1) is known to be highly expressed in cancer stem cells that contribute to cancer recurrence and metastasis. The authors isolated a new coumarin derivative (1) and 30 known compounds from two plants (Mammea siamensis and Andrographis paniculata), guided by BMI1 promoter inhibitory activity. Among the isolated compounds, 15 compounds showed BMI1 promoter inhibitory activity, and five compounds were found to be cytotoxic against cancer cells. 14-Deoxy-11,12-dehydroandrographolide (18) was highly cytotoxic to DU145 cells. Western blotting analysis of compound 18 in DU145 cells suggested that compound 18 suppresses BMI1 expression.

  • Volume 70 (2022) Issue 12 Pages 892-900
    Quantitative 31P-NMR for Purity Determination of Sofosbuvir and Method Validation Read more
    Editor's pick

    31P-qNMR in organic solvents was performed by using an organophosphorus compound, sofosbuvir (SOF) with phosphonoacetic acid (PAA) as the qNMR reference standard. In a protic solvent, methanol-d4, the purity of SOF determined by 31P-qNMR was 1.6% higher than that by 1H-qNMR. This difference most likely arose from the instability in the chemical shift due to the deuterium exchange of the acidic protons of PAA. In an aprotic solvent, DMSO-d6, the purity determined by 31P-qNMR agreed with the 1H-qNMR one, suggesting that an aprotic solvent is preferable for 31P-qNMR because it is unnecessary to consider the effect of deuterium exchange.