Chemical and Pharmaceutical Bulletin
Online ISSN : 1347-5223
Print ISSN : 0009-2363
Volume 66 , Issue 1
Showing 1-16 articles out of 16 articles from the selected issue
Review
  • Hideyuki Konishi
    2018 Volume 66 Issue 1 Pages 1-19
    Published: January 01, 2018
    Released: January 01, 2018
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    The use of toxic gas surrogates in organic reactions instead of the gas itself contributes to enhancing the safety, practicality, and efficiency of the reactions involved. Our efforts toward the creation of toxic gas surrogates and the development of a series of catalytic reactions using these surrogates are described. Improvements in substrate scope during the hydroesterification of alkenes using formates facilitated by the Ru–imidazole catalyst system provided the opportunity to discover that phenyl formate is a useful carbon monoxide (CO) surrogate for the generation of CO and phenol under weakly basic conditions. This discovery triggered the development of highly reactive but stable CO surrogates and a variety of Pd-catalyzed carbonylative transformations. N-Formylsaccharin facilitated the use of additional nucleophiles in carbonylation reactions that provided access to a variety of carbonyl compounds. Detailed experimental and theoretical mechanistic studies into the generation of CO from phenyl formate suggest that CO generation proceeds via a concerted E2 α-elimination. Furthermore, a known surrogate of sulfur dioxide was applied for the first time to the selective syntheses of cyclic sulfonamides and sulfinamides, confirming that the surrogate operates as an “S=O” source. Notably, the reactions described herein are scalable and can be performed without the use of external toxic gases and specialized reaction vessels; they are easy and simple to perform and demonstrate enormous potential for industrial application.

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    Editor’s picks

    Utilization of toxic gas surrogates can contribute to improving the safety and practicality for implementation of synthetic organic reactions. This review describes the author’s discovery, development, and applications of toxic gas surrogates. Various carbonyl compounds were obtained by Pd-catalyzed carbonylative transformations under mild conditions using novel carbon monoxide (CO) surrogates. Mechanistic studies of the CO generation and gram-scale syntheses using CO surrogates were successfully performed. Furthermore, the use of an inexpensive sulfur dioxide surrogate led to the development of unprecedented selective syntheses of sulfonamides and sulfinamides.



Current Topics - Recent Progress in Medicinal Chemistry
  • Takaaki Sumiyoshi
    2018 Volume 66 Issue 1 Pages 20
    Published: January 01, 2018
    Released: January 01, 2018
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    Editor’s picks

    Technological progress in medicinal chemistry has contributed to develop a variety of drug candidates in pharmaceuticals. Focusing on the significant progress in the fields shown in the cover, the present current topics include three reviews, “New Gateways to Platinum Group Metal-Catalyzed Direct Deuterium-Labeling Method Utilizing Hydrogen as a Catalyst Activator,” “7-Azaindole: A Versatile Scaffold for Developing Kinase Inhibitors” and “Discovery and Development of Muscarinic Acetylcholine M4 Activators as Promising Therapeutic Agents for CNS Diseases” and one communication, “A Peptide–Glycolipid Interaction Probed by Retroinverso Peptide Analogues.”



Current Topics : Reviews
  • Yoshinari Sawama, Kwihwan Park, Tsuyoshi Yamada, Hironao Sajiki
    2018 Volume 66 Issue 1 Pages 21-28
    Published: January 01, 2018
    Released: January 01, 2018
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    Deuterium-labeled compounds are widely utilized in various scientific fields. We summarize the recent advances in the direct deuteration of sugar, saturated fatty acid, and arene derivatives using heterogeneous platinum group metal on carbon catalysts by our research group. Hydrogen gas is a key catalyst-activator to facilitate the present H–D exchange reactions. In this review, the direct activation method of catalysts using in situ-generated hydrogen based on the dehydrogenation of alcohols is introduced. The obtained multiple deuterium-labeled products, including bioactive compounds, are expected to contribute to the development of many scientific investigations.

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  • Takayuki Irie, Masaaki Sawa
    2018 Volume 66 Issue 1 Pages 29-36
    Published: January 01, 2018
    Released: January 01, 2018
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    The majority of kinase inhibitors have been developed as ATP competitors to interact with a hinge region in ATP binding sites of kinases. 7-Azaindole has been found as an excellent hinge binding motif by making two hydrogen bonds with the kinase hinge region. Vemurafenib, a B-RAF kinase (serine–threonine kinase [STK]) inhibitor approved by the U.S. Food and Drug Administration (FDA) for the treatment of melanoma, was created from this simple 7-azaindole fragment by successful use of structure-based drug design techniques. The huge potential of 7-azaindole as a hinge-binding motif has encouraged many researchers to employ it as a kinase privileged fragment. This paper will review recent examples of 7-azaindole-based kinase inhibitors, and discusses their binding interactions with the kinase hinge regions.

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  • Kentaro Takai, Takeshi Enomoto
    2018 Volume 66 Issue 1 Pages 37-44
    Published: January 01, 2018
    Released: January 01, 2018
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    Among the muscarinic acetylcholine receptor (mAChR) subtypes, the M4 receptor has been investigated as a promising drug target for the treatment of schizophrenia. These investigations have been based on findings from M4-deficient mice studies as well as on the results of a clinical trial that used xanomeline, an M1/M4 mAChRs-preferring agonist. Both orthosteric agonists and positive allosteric modulators of M4 mAChR have been reported as promising ligands that not only have antipsychotic effects, but can also improve cognitive impairment and motor dysfunction. However, challenges remain due to the high homology of the orthosteric binding site among all muscarinic receptors. In this review, we summarize our approach to the identification of M4 mAChR activators, orthosteric agonists, and positive allosteric modulators based on M4 mAChR structural information and structure–activity relationship studies. These findings indicate that selective M4 mAChR activators are promising potential therapeutic agents for several central nervous system conditions.

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Current Topics : Communication to the Editor
  • Kaori Sakurai
    2018 Volume 66 Issue 1 Pages 45-50
    Published: January 01, 2018
    Released: January 01, 2018
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    Cell surface glycolipids are implicated in the formation of lipid rafts and membrane microdomains, where they interact with protein receptors to mediate a variety of cellular processes such as cell–cell recognition, cell adhesion, and membrane signaling. Studies of glycolipid function at the local membrane structures have not been straightforward to date, because the locally clustered structures are labile and their protein binding affinities tend to be weak. While specific glycolipid-binding proteins have been employed as molecular probes for detecting lipid rafts, small peptides may be more suitable for probing glycolipids at the cell surface due to their small size as well as their ease of synthetic preparation and functionalization. Here we report an application of the retroinverso approach as a rapid method to obtain novel glycolipid-binding D-peptide sequences. We have prepared analogues of two known GM1-binding peptides by replacing L-amino acids with D-amino acids, followed by inverting the sequences and characterized their conformational propensity and glycolipid binding properties. Circular dichroism (CD) spectroscopic analysis indicated that all the peptide sequences interacted with GM1 under a micellar condition. We found, by a microplate-based competitive glycolipid binding assay, that one of the retroinverso D-peptide analogues, peptide 3, also binds GM1 as the parent L-peptide 1. These results suggested that in this glycolipid–peptide interaction, the positioning of the side chain functionalities of the peptide is important, while the peptide backbone polarity is not. Glycolipid binding retroinverso D-peptides should be useful for the design of new peptide-based probes for investigating the biological role of cell surface glycolipids.

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Communication to the Editor
Regular Articles
  • Jie Li, Tu-cai Zheng, Yi Jin, Jian-guo Xu, Jian-gang Yu, Yan-wen Lv
    2018 Volume 66 Issue 1 Pages 55-60
    Published: January 01, 2018
    Released: January 01, 2018
    [Advance publication] Released: November 09, 2017
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    A series of novel quinolone derivatives (8aj) were synthesized, and their anticancer activities were tested in human cancer cell lines, human lung carcinoma cell (A549), human promyelocytic leukemia cell (HL-60), and human cervical cancer cell (Hela). Compound 8i was found to be 5-times more potent in cell-killing activity for cell lines A549, HL-60, and Hela than the positive control irinotecan or cisplatin, with IC50 of 0.009, 0.008 and 0.010 µM, respectively. The docking study revealed that compound 8i might have strong interactions with the active site of DNA-topoisomerase I.

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  • Thiago Inácio Barros Lopes, Roberta Gomes Coelho, Neli Kika Honda
    2018 Volume 66 Issue 1 Pages 61-64
    Published: January 01, 2018
    Released: January 01, 2018
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    Several applications have been proposed for tyrosinase inhibitors in the pharmaceutical, food bioprocessing, and environmental industries. However, only a few compounds are known to serve as effective tyrosinase inhibitors. This study evaluated the tyrosinase-related activity of resorcinol (1), orcinol (2) lecanoric acid (3), and derivatives of this acid (415). Subjected to alcoholysis, lecanoric acid (3), a depside isolated from the lichen Parmotrema tinctorum, produces orsellinic acid (2,4-dihydroxy-6-methylbenzoic acid) (4) and orsellinates (2,4-dihydroxy-6-methyl benzoates) (515). At 0.50 mM, methyl (5), ethyl (6), n-propyl (7), tert-butyl (11), and n-cetyl orsellinates (15) acted as tyrosinase activators, whereas n-butyl (8), iso-propyl (9), sec-butyl (10), n-pentyl (12), n-hexyl (13), and n-octyl orsellinates (14) behaved as inhibitors. Tyrosinase inhibition rose with chain elongation-n-butyl (8)<n-pentyl (12)<n-hexyl (13)<n-octyl orsellinates (14)-suggesting that the enzyme site can accept an eight-carbon alkyl chain. A kinetic study of n-octyl orsellinate (14) revealed uncompetitive inhibition of tyrosinase, with an inhibition constant of 0.99 mM.

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  • Bancha Yingngam, Adelheid Brantner, Damrongsak Jinarat, Rawiwun Kaewam ...
    2018 Volume 66 Issue 1 Pages 65-70
    Published: January 01, 2018
    Released: January 01, 2018
    [Advance publication] Released: October 26, 2017
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    A method for quantification of diarylheptanoids in Curcuma comosa rhizomes and selected pharmaceutical preparations was established by using HPLC-diode array detector (DAD). The chromatographic separation of three diarylheptanoids [(3S)-1-(3,4-dihydroxy-phenyl)-7-phenyl-(6E)-6-hepten-3-ol (1), (3R)-1,7-diphenyl-(4E,6E)-4,6-heptadien-3-ol (2), and (3S)-1,7-diphenyl-(6E)-6-hepten-3-ol (3)] was performed on a Luna C18 analytical column using gradient elution with 0.5% acetic acid in water and acetonitrile with a flow rate of 1 mL/min and a column temperature of 35°C. The calibration curves for the analytes showed good linearity (R2>0.999), high precision (relative standard deviation (RSD) <2%) and acceptable recovery (98.35–103.90%, RSD <2%). The limit of detection (LOD) and limit of quantification (LOQ) were 0.06–0.22 and 0.18–0.69 µg/mL, respectively. The results of all validated parameters were within the limits according to the International Conference on Harmonization (ICH) Guidelines. The established method was successfully applied for qualitative and quantitative determination of the three constituents in different samples of C. comosa and some commercial products in capsules. The simplicity, rapidity, and reliability of the method could be useful for the fingerprint analysis and standardization of diarylheptanoids, which are responsible for the estrogenic activity in raw materials and herbal medicinal products of C. comosa.

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  • Tamami Haraguchi, Takahiro Uchida, Miyako Yoshida, Honami Kojima, Masa ...
    2018 Volume 66 Issue 1 Pages 71-77
    Published: January 01, 2018
    Released: January 01, 2018
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    The purpose of this study was to examine the ability of the artificial taste sensor to evaluate the bitterness of drugs by comparing the responses of the taste sensor with documented responses of human TASTE2 receptors (hTAS2Rs). For this purpose 22 bitter compounds, used as ingredients of pharmaceutical medicines in Japan and known ligands of hTAS2Rs, were selected for testing. Their solutions (0.01, 0.03, 0.1 mM) were evaluated by five different taste sensors (AC0, AN0, BT0, C00, AE1). Correlations between physicochemical parameters of the compounds and the responses of the taste sensors and hTAS2Rs were evaluated. From taste sensor measurements, diphenidol, haloperidol, diphenhydramine, dextromethorphan and papaverine, all ligands of hTAS2R 10 and/or hTAS2R14, were predicted to express strong bitterness, surpassing that of quinine. Responses of taste sensors BT0 were found to be significantly correlated with responses of hTAS2R14. High log P values (≧2.73) and responses of hTAS2R14 were also significantly correlated (** p<0.01, chi-square test). In conclusion, taste sensor BT0 is highly sensitive to bitterness and correlates significantly with hTAS2R14, making it useful for evaluating the bitterness of hydrophobic compounds which respond to hTAS2R14 and their inhibitors.

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  • Won Se Suh, Oh Kil Kwon, Tae Hyun Lee, Lalita Subedi, Sun Yeou Kim, Ka ...
    2018 Volume 66 Issue 1 Pages 78-83
    Published: January 01, 2018
    Released: January 01, 2018
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    Two new secoiridoid glycosides, obtusifolisides A and B (1, 2), together with 7 known secoiridoid glycosides (39) were isolated from the twigs of Ligustrum obtusifolium. The chemical structures of new compounds were determined by a spectroscopic data analysis, including one and two dimensional (1D-, 2D)-NMR, High resolution-MS, and experiments involving chemical reactions. The isolated secoiridoid glycosides were evaluated for their anti-inflammatory effects in lipopolysaccharide (LPS)-stimulated BV-2 murine microglia cells. Compounds 2, 5, 6, 8, and 9 significantly reduced the production of nitric oxide (NO), with IC50 values of 5.45, 11.17, 14.62, 15.45, and 14.96 µM, respectively. None of the compounds were toxic to the cells. Additionally, we evaluated the neuroprotective effects of compounds 19 on nerve growth factor (NGF) induction in a C6 rat glioma cell line. Compounds 2 and 6 upregulated NGF secretion to 155.56±7.16%, and 139.35±11.65%, respectively, without significant cell toxicity.

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    Editor’s picks

    This study showed that secoiridoid glycosides are the main constituents of the twigs of L. obtusifolium, and two new secoiridoid derivatives, obtusifoliside A and B (1, 2), were isolated from this plant. Moreover, anti-inflammatory, and neuroprotective activities of the isolated compounds were investigated. Among the isolates, the new compound 2 showed remarkably better anti-inflammatory effects without cell toxicity. This study could be useful for the development of novel anti-inflammatory and neuroprotective agents.



  • Akira Katsuyama, Kousuke Sato, Fumika Yakushiji, Takanori Matsumaru, S ...
    2018 Volume 66 Issue 1 Pages 84-95
    Published: January 01, 2018
    Released: January 01, 2018
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    A solid-phase synthesis of Park nucleotide as well as lipids I and II analogues, which is applicable to the synthesis of a range of analogues, is described in this work. This technique allows highly functionalized macromolecules to be modularly labeled. Multiple steps are used in a short time (4 d) with a single purification step to synthesize the molecules by solid-phase synthesis.

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    Editor’s picks

    The paper describes solid-phase synthesis of peptidoglycan biosynthesis precursor and its analogues: Park nucleotide (1), neryl-lipid I (2) and neryl-lipid II (3). The higher acidity of activators accelerated the reaction rate of diphosphate formation, and solid-phase diphosphate formation was accomplished by using triazolium triflate (29) as an activator. The synthetic strategy enables to prepare 1-3 in a short time with a single purification. These analogues could be useful as chemical probes for discovering novel antibacterial agent and elucidating mechanistic studies.



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