Chemical and Pharmaceutical Bulletin
Online ISSN : 1347-5223
Print ISSN : 0009-2363
ISSN-L : 0009-2363
  • 70 巻 (2022) 8 号 p. 506
    Foreword もっと読む

    Biomembranes constitute the boundary between the living organism and the external environment, and their function is essential for maintaining biological activities. Quantitative understanding and precise control of the transport and conversion of various substances across biomembranes are important issues in biophysics and cell biology, but dealing with biomembranes, which are multi-component, heterogeneous, and complex systems, is not an easy task. In the Current Topics, investigators who are boldly tackling this area of research introduce recent advances in biophysical and molecular biological aspects and technology.

  • 70 巻 (2022) 8 号 p. 540-543
    Site-Selective α-Alkylation of 1,3-Butanediol Using a Thiophosphoric Acid Hydrogen Atom Transfer Catalyst もっと読む

    The linear 1,3-diol structure is a common motif in biologically active molecules. C-H functionalization at an α-position of alcohols leads to efficient synthesis of sugars and polyols. However, regioselective conversions at the alcohol α-position of linear 1,3-diols have been limited. Nakao et al. developed secondary-alcohol-selective C-H alkylation of 1,3-butane diol by combining an acridinium photoredox catalyst and a thiophosphoric acid hydrogen atom transfer (HAT) catalyst. The use of DCM as a solvent with a relatively small dipole moment improved secondary α-alkoxy C-H selectivity by making the C-H abstraction process the rate-limiting step.

  • 70 巻 (2022) 8 号 p. 558-565
    Determination of Hardness of a Pharmaceutical Oral Jelly by Using T2 Relaxation Behavior Measured by Time-Domain NMR もっと読む

    Hardness is a critical quality characteristic of pharmaceutical oral jelly. The purpose of this study is to determine the hardness using time-domain NMR (TD-NMR). After measurement of the T2 relaxation curves of the test jellies by TD-NMR, the acquired data were analyzed by partial least squares (PLS) regression analysis. Eventually, an accurate and reliable PLS model was created that enabled accurate assessment of the hardness of the test jellies. TD-NMR enables the measurement of samples nondestructively and rapidly with low cost, and so could be a promising method for evaluation of the hardness of pharmaceutical oral jellies.

  • 70 巻 (2022) 8 号 p. 566-572
    Aryne Generation from o-Triazenylarylboronic Acids Induced by Brønsted Acid もっと読む

    This paper describes acid-mediated aryne generation from o-triazenylarylboronic acids. The authors previously reported these practical aryne precursors generate arynes by the treatment with silica gel. In this paper, they reported acids including Brønsted acids, Lewis acids, and solid acids are also effective for aryne generation from the precursors. In particular, the use of camphorsulfonic acid provided high yields in reactions with a range of arynophiles, and enabled chemoselective reaction with a furan in the presence of an amine. Hammett plot analyses revealed that an aryne generation mechanism induced by the acid is distinct from the mechanism induced by silica gel.

  • 70 巻 (2022) 7 号 p. 458-468
    Progress in Chiral Stationary Phases Based on Proteins and Glycoproteins もっと読む

    The ligand-binding sites of F1*S and A variants of human α-acid glycoprotein (hAGP), and chicken AGP were completely different. The former sites were located in lobs I-III including W122, while the later ones were located near W26. Both (R)- and (S)-benzoin were docked onto a cavity of the generated model structure of cAGP. In addition to hydrophobic interactions, some of hydrogen bonding interactions worked for chiral recognition of (R)- and (S)-benzoin. (R)-Benzoin bound to cAGP more tightly than (S)-benzoin. The elution order of benzoin enantiomers on chiral stationary phases based on cAGP in LC were consistent with the docking results.

  • 70 巻 (2022) 7 号 p. 498-504
    Application of the Functionality Transfer Oligodeoxynucleotide for the Site-Selective Modification of RNA with a Divers Molecule もっと読む

    Due to the importance of chemical modification of RNA, methods for chemical modification at a predetermined site in an internal position of RNA have attracted much attention. The authors have developed an original method for the base- and sequence-specific modification by transferring the functional group of the oligonucleotides to RNA through the formation of hybrid complexes. To achieve further modification by copper-catalyzed alkyne-azide cycloadditions, the authors investigated transfer groups with the tri-, tetra- and pentaethylene glycol-linked alkynes. As a result, the transfer groups with tetra- and pentaethylene linkers were determined to be promising compounds to internally modify long RNA.

  • 70 巻 (2022) 6 号 p. 420-426
    Enhancing Anticancer Potency of a 13-Substituted Berberine Derivative with Cationic Liposomes もっと読む

    This paper reports the successful use of a cationic liposomal-encapsulated novel 13-substituted berberine derivative for the targeted cell uptake and delivery to the cancer cell nucleus. Additionally the liposome also assists with stabilization of the selectively toxic anticancer berberine derivative with respect to oxidative cleavage in solution.  Liposomes derived from a cholesterol-based lipid with a polar side chain which would become cationic after amine protonation, were of particular interest. Enhanced cancer cell toxicity was seen in vitro with the cationic liposomal formulation of the berberine derivative possibly via inhibitory interactions with the cell’s telomere/telomerase system.

  • 70 巻 (2022) 6 号 p. 435-442
    Model Synthetic Study of Tutin, a Picrotoxane-Type Sesquiterpene: Stereoselective Construction of a cis-Fused 5,6-Ring Skeleton もっと読む

    This paper describes a stereoselective synthesis of a cis-fused 5,6-ring skeleton in picrotoxane-type sesquiterpenes. This bicyclic skeleton is a synthetic challenging structure because of the presence of multiple consecutive stereocenters including two tetrasubstituted carbons at the angular positions. The authors developed a synthetic method of the core structure via DL-proline-mediated intramolecular aldol reaction accompanied with the desymmetrization of the 2-methyl-1,3-cyclopentanedione moiety and the construction of four contiguous stereocenters. This reaction can be also applied to the kinetic resolution using L-proline, implying that the established method would be useful for the synthesis of natural products classified as picrotoxane-type sesquiterpenes.

  • 70 巻 (2022) 6 号 p. 448-453
    Design, Synthesis and Cytotoxicity Evalufation of Substituted Benzimidazole Conjugated 1,3,4-Oxadiazoles もっと読む

    Many drugs being used in chemotherapy of cancer has nitrogen-containing heterocyclic moieties as their basic structure, and the authors extensively focused on the 1,3,4-oxadiazole and benzimidazole scaffolds. In this article, two series of novel hybrids combining the 1,2-disubstituted benzimidazole and 1,3,4-oxadiazole or thioether linked 1,3,4-oxadiazole were designed and successfully synthesized. The in vitro cytotoxicity bioassays came up with the discovery of three lead compounds which displayed 4.5-13 fold increase in activity compared to 5-FU against the three human cancer cell lines (HeLa, MCF-7, A549), meriting further characterization and serving as promising scaffolds in the discovery of new potent anticancer agents.

  • 70 巻 (2022) 5 号 p. 309
    Foreword もっと読む

    The authors had held a symposium, “New modalities and strategies in drug delivery and discovery”, in the 36th Annual Meeting of the Academy of Pharmaceutical Science and Technology, Japan (APSTJ) in Tokushima (online), Japan, 2021. In the symposium, the active young researchers from the Graduate School of Biomedical Sciences of Tokushima University presented various topics on their own researches. This Current Topics accumulated the review articles from the invited speakers of the symposium. These reviews will provide a wide range of intimate information regarding new modalities and strategies in drug delivery and discovery.

  • 70 巻 (2022) 5 号 p. 362-368
    Monitoring and Predicting the Size of Fine Particles Prepared in a Fluidized-Bed Granulator Using a Handheld-Type Raman Spectrometer もっと読む

    Particle size-monitoring method using a handheld-type Raman spectrometer is proposed in this study. Two types of fine particles with the same formulation under different operating conditions were prepared for calibration purposes. There was a relationship between particle size and Raman intensity during processing and calibration curves could be obtained in both operating conditions. Two other types of fine particles with the same formulation, but on different scales or using different processing mechanisms were also prepared for verification purposes. The particle size could be successfully predicted using the calibration curve obtained taking powder porosity into consideration.

  • 70 巻 (2022) 5 号 p. 383-390
    Mechanism of Solubility Enhancement of Poorly Water-Soluble Drugs Triggered by Zeolitic Imidazolate Frameworks もっと読む

    The authors elucidated the mechanism of solubilization of poorly water-soluble drugs using zeolitic imidazolate frameworks (ZIFs), a member of metal-organic frameworks. The solubility of ZIF-trapped drugs was enhanced compared to the raw drugs. The authors focused on 2-methylimidazole (2-MIM), used as an organic ligand in ZIFs. Drugs were easily dissolved by the addition of 2-MIM, suggesting that the presence of 2-MIM enhanced the drug solubility. The findings of this study demonstrated the solubilization mechanism of poorly water-soluble drugs using ZIFs. ZIFs are expected to be used as drug carriers to maximize the bioavailability of poorly water-soluble drugs.

  • 70 巻 (2022) 5 号 p. 391-399
    Lipase-Catalyzed Kinetic Resolution of C1-Symmetric Heterocyclic Biaryls もっと読む

    The highly enantioselective lipase-catalyzed kinetic resolution (KR) of racemic C1-symmetric biaryl compounds including heterocyclic moieties, such as carbazole and dibenzofuran, has been achieved for the first time. This enzymatic esterification was accelerated by the addition of disodium carbonate while maintaining its high enantioselectivities (up to 99% ee), and was particularly effective for biaryls having N-substituted carbazole moieties. Furthermore, mesoporous silica-supported oxovanadium-catalyzed cross-dehydrogenative coupling of 3-hydroxycarbazole and 2-naphthol was followed by the lipase-catalyzed KR in one-pot to synthesize the optically active heterocyclic biaryl compounds with high optical purity.

  • 70 巻 (2022) 4 号 p. 245-253
    Formulation of Biopharmaceutical Dry Powder Inhaler Using the Void Forming Index (VFI) to Detect and Avoid Powder Caking in Dry Powder Inhaler Formulations もっと読む

    Biopharmaceutical dry powder inhaler (Bio-DPI) is an attractive formulation for non-invasive administration method for biopharmaceutical compounds. In Bio-DPI to ensure spray stability, it is important to control the powder caking risk of the formulation. To detect powder caking risk, Void Forming Index (VFI) is a useful method for DPI formulation study. The authors conducted formulation screening using VFI, to develop a high-dose Bio-DPI formulation containing 50 mg of lysozyme per capsule. As a result, VFI clarified the powder caking risk of each formulations and contributed to selection of high spray stability formulation.

  • 70 巻 (2022) 4 号 p. 261-268
    Synthesis and Evaluation of Habiterpenol Analogs もっと読む

    This paper describes the synthesis of new derivatives of habiterpenol and their structure-activity relationships. Habiterpenol is a G2 checkpoint inhibitor that has recently attracted attention as a new vital molecular-targeting therapeutic agent. Combination therapy using low-doses of anticancer agents and G2 checkpoint inhibitors has great potential as an effective treatment for cancer because it minimizes the dosage of the DNA-damaging anticancer agents and results in fewer side effects. The authors have independently developed a total synthesis to obtain new habiterpenol derivatives that cannot be derived from natural products, and have further studied their structure-activity relationships.

  • 70 巻 (2022) 4 号 p. 283-285
    Caulophyine A, a Rare Azapyrene Alkaloid from the Roots of Caulophyllum robustum もっと読む

    This paper reports one rare azapyrene alkaloid named caulophyine A along with six known compounds identified from the roots of Caulophyllum robustum Maxim., which was collected on Taibai mountain, the highest peak of the Qinling mountains, Shaanxi province, China. Caulophyine A is a nitrogen containing polycyclic aromatic hydrocarbon, possess a naphtho[2,1,8-def]isoquinoline fragment. This is the first report of the nitrogen containing azapyrene alkaloid identified from plant. The in vitro bioassays revealed that caulophyine A displayed weak acetylcholinesterase (AChE) inhibitory activity.

  • 70 巻 (2022) 4 号 p. 304-308
    Isolation of Natural Prodrug-Like Metabolite by Simulating Human Prodrug Activation in Filamentous Fungus もっと読む

    The authors successfully demonstrated that expression of a hCYP gene in a filamentous fungus led to the identification of a bioactive natural product from a strain previously not reported to produce the compound, and a prodrug-like secondary metabolite that can be activated by an hCYP. Our approach can be further developed by employing other types of CYPs and prodrug-activating enzymes in combination with microbes, with differing secondary metabolite biosynthetic potentials, to explore a wider biosynthetic space for identification of interesting prodrug-type natural products.

  • 70 巻 (2022) 3 号 p. 199-201
    Application of Acoustic Ejection MS System to High-Throughput Screening for SARS-CoV-2 3CL Protease Inhibitors もっと読む

    The application of mass spectrometry has been reevaluated in the field of pharmaceutical research. The recent launch of the EchoMS system, which combines an MS/MS system with an acoustic nano-liter dispensing system, has enabled label-free high-throughput screening (HTS) assays for disease-related enzyme reactions without time-consuming chromatographic separation. As the search for therapeutic agents for COVID-19 is currently underway, the authors conducted an HTS campaign for SARS-CoV-2 3CL protease using this system. A library of 32,033 compounds was assayed in 12 hours, and several inhibitors with antiviral activity were found in further cell-based assay.

  • 70 巻 (2022) 3 号 p. 211-219
    Synthesis and Characterization of Hydroxyethylamino- and Pyridyl-Substituted 2-Vinyl Chromone Derivatives for Detection of Cerebral Abnormal Prion Protein Deposits もっと読む

    Pathogenic scrapie PrP (PrPSc) accumulates in the brain resulting in the prion disease progression. SPECT imaging of PrPSc could non-invasively diagnose prion disease. The authors developed novel radioiodinated styryl chromone (SC) and vinyl pyridyl chromone (VPC) derivatives for PrPSc imaging. They found that the SC derivatives possess affinity for PrPSc, while the conversion to the VPC derivatives abolishes the affinity. These results indicate that a single aromatic ring in the imaging agents can make a significant difference in the recognition of PrPSc. [125I]SC-NHEtOH was shown to be a potential scaffold for the further development of prion imaging agents.

  • 70 巻 (2022) 3 号 p. 220-225
    Synthesis and Anti-dengue Virus Activity of 5-Ethynylimidazole-4-carboxamide (EICA) Nucleotide Prodrugs もっと読む

    Because 40% of the world’s population is faced with the risk of Dengue virus (DENV) infection and no drug has yet been approved, development of an anti-DENV agent is a key priority for human health. In this article, the authors revealed that a combination of 4’-thio-modification and introduction of monophosphate prodrug skeleton to nucleoside analog, for example 5-ethynyl-(1-b-D-ribofuranosyl)imidazole-4-carboxamide (EICAR), is valuable tactic to develop an effective anti-DENV agent.