Chemical and Pharmaceutical Bulletin
Online ISSN : 1347-5223
Print ISSN : 0009-2363
ISSN-L : 0009-2363
Featured articles
Showing 1-20 articles out of 138 articles
  • Volume 68 (2020) Issue 5 Pages 405-420
    Development of Copper-Catalyzed Chemoselective Reactions Read more
    Editor’s picks

    “Soft” nature of copper catalysis enabled two types of chemoselective reactions. First, C-C bond forming reactions at an anomeric carbon of unprotected aldoses were developed by taking advantage of orthogonal reactivity between “soft” organocopper species and “hard” polar functional groups, free hydroxy groups. Second, preferential reaction between “soft” copper species and “soft” C-C multiple bonds enabled difunctionalization of the multiple bonds by controlling the reaction order of three reactive species. Well-controlled stereo- and/or regioselectivity of the reactions is another important feature of the copper catalysts.

  • Volume 68 (2020) Issue 5 Pages 436-442
    Constituents of the Fruiting Body of Poisonous Mushroom Omphalotus japonicus Read more
    Editor’s picks

    Omphalotus japonicus (Tsukiyotake in japanese) is well-known as a poisonous mushroom in Japan. In this study, the authors isolated six new sesquiterpenes, four known sesquiterpenes and two known steroids from the fruiting body of O. japonicus with column chromatography, solid-phase extraction (SPE), and HPLC. The chemical structures were determined with NMR, MS and IR spectra. Relative configuration was determined with NOE correlations and absolute configuration was determined with ECD calculation. Three new compounds showed growth-restoring activity against mutant yeast via calcium-signal transduction.

  • Volume 68 (2020) Issue 5 Pages 452-465
    Novel Indirect AMP-Activated Protein Kinase Activators: Identification of a Second-Generation Clinical Candidate with Improved Physicochemical Properties and Reduced hERG Inhibitory Activity Read more
    Editor’s picks

    This paper describes that the synthesis and evaluation of novel indirect adenosine monophosphate-activated protein kinase (AMPK) activators. The series of compounds selectively inhibited cell growth in several human breast cancer cell lines by activating AMPK. The back-up medicinal chemistry synthetic research on ASP4132, a previously reported clinical compound that acts as an indirect AMPK activator, led to the successful identification of 27b as a second-generation clinical candidate with promising profiles such as high aqueous solubility and less human Ether-a-go-go Related Gene (hERG) channel inhibitory activity.

  • Volume 68 (2020) Issue 5 Pages 466-472
    Discovery of 1,3-Disubstituted 2,5-Diketopiperazine Derivatives as Potent Class I HDACs Inhibitors Read more
    Editor’s picks

    The 2, 5-diketopiperazine (DKP) scaffold exists in many natural product families, ranging from fungi and bacteria to the plant kingdom and mammals. Because of the privileged structure and the ability to bind vast receptors, it has become extremely attractive synthetic target for the assembly of natural product-like libraries for drug discovery. In this article, a series of novel derivatives containing DKP skeleton were developed as targeted inhibitors. Several compounds exhibited distinct HDAC1 inhibitory activities and showed antiproliferative activities against K562 and HL-60 tumor cell line.

  • Volume 68 (2020) Issue 5 Pages 473-478
    Instrument-Dependent Factors Affecting the Precision in the Atomic Force Microscopy Stiffness Measurement of Nanoscale Liposomes Read more
    Editor’s picks

    Instrument-dependent factors affecting the precision in the atomic force microscopy stiffness measurement of nanoscale liposomes was examined. The tip shape evaluation method previously developed can be widely used via IC-mode force curve measurements as well as via QI mode. It was also revealed that spatial drift of the cantilever position was instrument-dependent factors which could affect the precision of liposome stiffness measurements in the case of IC-mode force curve measurement. These findings will promote the usage of the AFM stiffness measurement method for the characterization of lipid nanoparticle-based drug delivery systems.

  • Volume 68 (2020) Issue 4 Pages 316-325
    Smart Strategies for Therapeutic Agent Delivery into Brain across the Blood–Brain Barrier Using Receptor-Mediated Transcytosis Read more
    Editor’s picks

    In drug development, drug delivery into brain across the blood-brain barrier (BBB) is a serious problem. Particularly, the BBB is impermeable to large and medium-sized molecules. Accordingly, drugs for diseases of the central nervous system (CNS) are unable to elicit their activity in brain. However, receptor-mediated transcytosis can solve such impermeability. Actually, using receptors such as transferrin receptor (TfR), low-density lipoprotein receptor (LDLR), and insulin receptor (InsR), that express on the surface of brain capillary endothelial cells, delivered well-designed drugs into brain through endocytosis and exocytosis. This methodology will be a promising approach to cure patients suffering from CNS diseases.

  • Volume 68 (2020) Issue 4 Pages 332-335
    Cobalt-Catalyzed Hydroamination of Alkenes with 5-Substituted Tetrazoles: Facile Access to 2,5-Disubstituted Tetrazoles and Asymmetric Intermolecular Hydroaminations Read more
    Editor’s picks

    An efficient synthetic method for 2,5-disubstituted tetrazoles from 5-substituted tetrazoles is developed. In this paper, the authors established a cobalt-catalyzed site-selective alkylation of tetrazoles via atom-economic hydroamination reaction between tetrazoles and non-activated olefins. The authors also applied the developed reaction to an asymmetric intermolecular hydroamination of non-activated olefins, which is one of the longstanding problems in synthetic organic chemistry.

  • Volume 68 (2020) Issue 4 Pages 345-362
    Design and Synthesis of 2-(1-Alkylaminoalkyl)pyrazolo[1,5-a]pyrimidines as New Respiratory Syncytial Virus Fusion Protein Inhibitors Read more
    Editor’s picks

    This report describes the design, synthesis, and evaluation of a new series of pyrazolo[1,5-a]pyrimidine derivatives for treatment against respiratory syncytial virus (RSV). The pyrazolo[1,5-a]pyrimidine series of compounds containing a piperidine ring at the 2-position of the pyrazolo[1,5-a]pyrimidine scaffold are known as candidate RSV fusion (F) protein inhibitor drugs. The piperidine ring has been revealed to facilitate the formation of an appropriate dihedral angle between the pyrazolo[1,5-a]pyrimidine scaffold and the plane of the amide bond for exertion of anti-RSV activity. A molecular-dynamic study on pyrazolo[1,5-a]pyrimidine derivatives focusing on the dihedral angles proposed and demonstrated potent anti-RSV inhibitors with an acyclic chain instead of a piperidine ring. A subsequent optimization study on pyrazolo[1,5-a]pyrimidine derivatives containing 1-methylaminopropyl group led to a highly potent anti-RSV agent with an EC50 value of less than 1 nM.

  • Volume 68 (2020) Issue 4 Pages 380-383
    Total Syntheses and Cytotoxic Evaluations of Cryptolactones A1, A2, B1, B2, and Their Derivatives Read more
    Editor’s picks

    Aphids have unique polyketide pigments, which possess interesting biological activities such as cytotoxicity. In this article, the authors have focused on cryptolactone A1, A2, B1, and B2, colorless polyketide lactones, isolated from a colorless aphid, Cryptomyzus sp., and accomplished the asymmetric total syntheses of these compounds, their analogs bearing shorter carbon chains, and their antipodes. The investigation of structure-activity relationships among these compounds was carried out and revealed that both enantiomers exhibited similar cytotoxic properties towards HL-60 cell lines. However, compounds with shorter carbon chains were less cytotoxic than the others.

  • Volume 68 (2020) Issue 4 Pages 384-391
    Nucleophilic Addition Reaction with Dearomatization of Naphthalene Ring Read more
    Editor’s picks

    Organic reactions using dearomatization have attracted much attention as a new approach to constructing complicated cyclic molecules. This paper describes the regioselectivity of nucleophilic addition of organolithium species (in particular, n-BuLi and sec-BuLi) to various aromatic lactones. The results of many experiments indicated that the regioselectivity varied greatly depending on various factors, such as the bulkiness of both substrates and organolithium species, and types of solvent and cosolvent. It is particularly interesting that the reactions mechanism of the addition of organolithium species differed between n-BuLi (via ionic process) and sec-BuLi (via one electron transfer process).

  • Volume 68 (2020) Issue 3 Pages 181
    Foreword Read more
    Editor’s picks

    Cutting-edge contributions from invited poster presentations providing significant research works in the fifth International Symposium for Medicinal Sciences (ISMS) in the 139th Chiba annual meeting in 2019 are assembled for the Current Topics section in this issue of the Chemical and Pharmaceutical Bulletin.

  • Volume 68 (2020) Issue 3 Pages 258-264
    Catalytic Production of Oxo-fatty Acids by Lipoxygenases Is Mediated by the Radical–Radical Dismutation between Fatty Acid Alkoxyl Radicals and Fatty Acid Peroxyl Radicals in Fatty Acid Assembly Read more
    Editor’s picks

    The principal catalytic reaction of ferric lipoxygenases is dioxygenation of polyunsaturated fatty acids under normoxia. On the contrary, at a lower oxygen content, lipoxygenases concomitantly convert polyunsaturated fatty acids and their hydroperoxides into fatty acid allyl-radicals and fatty acid alkoxyl radicals, respectively, through one-electron redox reaction. The former radicals simultaneously react with oxygen molecule, producing fatty acid peroxyl radicals. In general, free radicals tend to abstract one electron from molecules. However, fatty acid alkoxyl radicals donate one electron to the aggressive free radicals including fatty acid peroxyl radicals, resulting in the oxo-fatty acids generation, which act as PPAR agonists.

  • Volume 68 (2020) Issue 3 Pages 265-272
    Synthesis of One Double Bond-Inserted Retinal Analogs and Their Binding Experiments with Opsins: Preparation of Novel Red-Shifted Channelrhodopsin Variants Read more
    Editor’s picks

    Optogenetics is a new technology to control neural activity by light using ChRs. ChRs now used in optpgenitics are mostly sensitive to blue-green light (430-550 nm), and have several limitations. To overcome these problem, the development of red-shifted ChRs are eagerly required. In this paper, six kinds of new chromophores with one double bond inserted into the polyene side chain of retinal (A1) or 3,4-didehydroretinal (A2) were prepared. Among them, A2-10ex (an extra double bond was inserted at C10-C11 position of A2) bound with ChrimsonR to afford new ChR with the greatest red-shifted absorption peak at 654 nm.

  • Volume 68 (2020) Issue 3 Pages 273-287
    Novel Steroidal Glycosides from the Whole Plants of Helleborus foetidus Read more
    Editor’s picks

    Phytochemical analysis of the whole Helleborus foetidus plants identified 28 steroidal glycosides, including 20 novel spirostanol glycosides and a novel furostanol glycoside. The structures of the newly identified compounds were elucidated by two-dimensional NMR spectroscopy and hydrolytic cleavage. Three isolated compounds were determined to be spirostanol trisdesmosides, which are unique in structure bearing sugar moieties at the C-1, -21, and -24 hydroxy groups of the aglycone unit. The isolated compounds were evaluated for cytotoxic activity against HL-60 human promyelocytic leukemia cells and A549 human lung carcinoma cells, and several compounds exhibited moderate cytotoxic activity.

  • Volume 68 (2020) Issue 2 Pages 103-116
    Total Syntheses of Lycopodium and Monoterpenoid Indole Alkaloids Based on Biosynthesis-Inspired Strategies Read more
    Editor’s picks

    The lessons from nature on biosynthesis of natural products might be beneficial for synthetic organic chemists to design unique synthetic approaches as well as to facilitate development of new synthetic methodologies. This review emphasized the merits of biosynthetic consideration in the chemical synthesis of complex natural products by describing the total syntheses of Lycopodium alkaloids and monoterpenoid indole alkaloids conducted in author’s laboratory.

  • Volume 68 (2020) Issue 2 Pages 117-128
    Synthetic Studies toward Dimeric Indole Alkaloids Based on Convergent Synthetic Strategy Read more
    Editor’s picks

    Various dimeric compounds comprising two structurally different indole units are ubiquitous in nature. These compounds are a pharmaceutically important class of natural products because several compounds in this class exhibit display greater potency and unique biological activities compared with the corresponding monomeric compounds. In particular, these dimeric compounds, which possess molecular weights that deviate from Lipinski’s rule, are anticipated to be useful as new drug candidates in the middle molecule drug discovery. This review presents an overview of efficient convergent syntheses of dimeric indole alkaloids, haplophytine, and T988s with the development of synthetic methodologies for linking the two indole units.

  • Volume 68 (2020) Issue 2 Pages 129-132
    Intracellular Delivery of Antisense DNA and siRNA with Amino Groups Masked with Disulfide Units Read more
    Editor’s picks

    A new efficient delivery method of oligonucleotide (ON) therapeutics is developed. Here, antisense ON and small interfering RNA (siRNA) with disulfide-masked amino units were designed and synthesized for efficient intracellular delivery. The developed method actually enabled direct delivery of these ON into the cytosol, where these ON showed the targeted silencing effects, with minimal cytotoxicity. The molecular design and evaluation reported in this article would be very informative for further developing efficient cytosol-delivery methods of therapeutic ONs for medicinal application.

  • Volume 68 (2020) Issue 2 Pages 140-149
    Quality Evaluation and Characterization of Fractions with Biological Activity from Ephedra Herb Extract and Ephedrine Alkaloids-Free Ephedra Herb Extract Read more
    Editor’s picks

    The structural characteristics of the fractions from Ephedra Herb extract (EHE) having c-Met kinase inhibitory effects and the fractions from ephedrine alkaloids-free Ephedra Herb extract (EFE) having analgesic and anti-influenza activities were characterized. The fractions comprised high-molecular-mass condensed tannins, which were mainly of the procyanidin B and partly procyanidin A types, including pyrogallol- and catechol-type flavan 3-ols as the extension and terminal units. HPLC and gel permeation chromatography (GPC) analyses estimated that the ratio of pyrogallol- and catechol-type was approximately 9:2 and the weight-average molecular weight based on polystyrene standard was >45,000. The authors propose GPC-based analysis as the quality method for evaluating of high-molecular-mass condensed tannin in EHE and EFE.

  • Volume 68 (2020) Issue 1 Pages 1-33
    Development of New Synthetic Reactions Using Hetero-Heavy Atoms and Their Application to Synthesis of Biofunctional Molecules Read more
    Editor’s picks

    Novel reactions using hetero-heavy atoms (P, S, Si, Se, and Sn) were developed and applied to the synthesis of biofunctional molecules and some medicine-candidates. 1) Development of introduction of C1-unit using cyanophosphates (CPs). 2) Carbene-generation from CPs and its application to organic synthesis. 3) [3,3]Sigmatropic rearrangement-ring expansion reactions of medium-sized cyclic thionocarbonates containing a sulfur atom and their application to natural product synthesis. 4) Stereoselective synthesis of novel b-imidazole C-nucleosides via diazafulvene intermediates and their application to investigating ribozyme reaction mechanism. 5) Developments of novel histamine H3- and H4-receptor ligands using new synthetic methods involving Se or Sn atoms.

  • Volume 68 (2020) Issue 1 Pages 34-45
    Drug Discovery Researches on Modulators of Lysine-Modifying Enzymes Based on Strategic Chemistry Approaches Read more
    Editor’s picks

    Because lysine modifications on proteins control various cellular processes and aberrations of the modifications are associated with various diseases, chemical modulation of lysine-modifying enzymes is interesting as a method to regulate the cellular functions or as a therapeutic strategy. Therefore, the author has identified some modulators of lysine-modifying enzymes. To find the modulators, the author has combined conventional drug design with “strategic chemistry approaches,” such as drug design based on enzyme catalytic mechanism. In this review, the author’s drug discovery studies are presented.

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