Chemical and Pharmaceutical Bulletin
Online ISSN : 1347-5223
Print ISSN : 0009-2363
ISSN-L : 0009-2363
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Volume 64, Issue 7
Displaying 1-50 of 63 articles from this issue
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Special Collection of Papers
Special Collection of Papers: Reviews
  • π-Delocalized Lipophilic Cations as New Candidates for Antimalarial, Antitrypanosomal and Antileishmanial Agents: Synthesis, Evaluation of Antiprotozoal Potency, and Insight into Their Action Mechanisms
    Kiyosei Takasu
    2016 Volume 64 Issue 7 Pages 656-667
    Published: July 01, 2016
    Released on J-STAGE: July 01, 2016
    DOIhttps://doi.org/10.1248/cpb.c16-00234
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    The search for new drugs that could treat tropical protozoan diseases, such as malaria or neglected tropical diseases (NTDs), motivates many medicinal chemists. New classes of antiprotozoal drugs that act through a novel mechanism of action must be developed. This review presents our efforts toward finding new candidate treatments for malaria, American trypanosomiasis, human African trypanosomiasis and leishmaniasis based on π-delocalized lipophilic cations (DLCs). DLCs, such as rhodacyanines, azarhodacyanines, β-carbolinium salts, and phenoxazinium salts, displayed strong antiprotozoal activities with highly selective indices. Several DLCs displayed moderate to excellent in vivo efficacies against Plasmodium berghei when administered intraperitoneally or orally. This review also discusses chemical biology approaches to understanding the mechanism of action underlying the antimalarial rhodacyanines.
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  • Bioactive Secondary Metabolites with Unique Aromatic and Heterocyclic Structures Obtained from Terrestrial Actinomycetes Species
    Mohamed S. Abdelfattah, Midori A. Arai, Masami Ishibashi
    2016 Volume 64 Issue 7 Pages 668-675
    Published: July 01, 2016
    Released on J-STAGE: July 01, 2016
    Advance online publication: March 02, 2016
    DOIhttps://doi.org/10.1248/cpb.c16-00038
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    Natural products from actinomycetes are important and valuable sources for drug discovery and the development of biological tools. The present review describes our recent study on the isolation of new natural products mainly possessing heterocyclic and aromatic ring structures with biological effects on cancer-related cellular pathways such as tumor necrosis factor-α-related apoptosis-inducing ligand (TRAIL) and Wnt signaling.
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  • Mechanism of Creaming Down Based on Chemical Characterization of a Complex of Caffeine and Tea Catechins
    Takashi Ishizu, Hiroyuki Tsutsumi, Takashi Sato
    2016 Volume 64 Issue 7 Pages 676-686
    Published: July 01, 2016
    Released on J-STAGE: July 01, 2016
    DOIhttps://doi.org/10.1248/cpb.c16-00131
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    The component of a precipitate resulting from creaming down, which was made from caffeine and a catechin mixture, was determined by an integrated value of H2 proton signals of tea catechins in the quantitative 1H-NMR spectrum. The results showed that gallate-type catechins formed a precipitate by creaming down more predominantly than non-gallate-type catechins. X-ray crystallographic analysis showed that the gallate-type catechin (−)-epigallocatechin-3-O-gallate (EGCg), (−)-epicatechin-3-O-gallate (ECg) formed 2 : 2 and 2 : 4 complexes with caffeine, respectively, and the non-gallate-type catechin (−)-epicatechin (EC) and caffeine formed a 1 : 1 complex. The 2 : 2, 2 : 4 complexes of caffeine and EGCg, ECg formed a hydrophobic space with three aromatic A, B, and B′ rings of two EGCg, ECg molecules, and one caffeine molecule was captured in this hydrophobic space. However, no such hydrophobic space in the 1 : 1 complex of caffeine and EC formed. It was thought that the hydrophobicity of the 2 : 2, 2 : 4 complexes of caffeine and EGCg, ECg was stronger than that of the 1 : 1 complex of caffeine and EC, with the result that the 2 : 2, 2 : 4 complexes of caffeine and EGCg, ECg precipitated by creaming down more predominantly than the 1 : 1 complex of caffeine and EC in an aqueous solution. Furthermore, the molecular capture of various heterocyclic compounds by formation of the 2 : 2 complex of EGCg from the aqueous solution was investigated using the quantitative 1H-NMR spectrum.
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  • Chemical Approaches to Elucidate Enzymatic Profiles of UDP-Glucose: Glycoprotein Glucosyltransferase
    Masakazu Hachisu, Yukishige Ito
    2016 Volume 64 Issue 7 Pages 687-690
    Published: July 01, 2016
    Released on J-STAGE: July 01, 2016
    DOIhttps://doi.org/10.1248/cpb.c16-00209
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    In the endoplasmic reticulum (ER), uridine 5′-diphosphate-glucose: glycoprotein glucosyltransferase 1 (UGGT1) recognizes misfolded glycoproteins and transfers a glucose residue to the specific non-reducing end of high-mannose-type glycans. However, precise molecular mechanism by which UGGT1 senses the folding has not been understood clearly. To address this issue, various model substrates for UGGT1 have been prepared using biological approaches. Recently, we introduced chemical approaches using synthetic glycan probes that were designed for studying N-glycan processing in the ER and Golgi apparatus. Our approach can outfit the homogeneous and functionalized glycan probes. In this review, recent results on functional analysis of UGGT1 are summarized.
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  • Bromopyrrole Alkaloids from Okinawan Marine Sponges Agelas spp.
    Naonobu Tanaka, Taishi Kusama, Yoshiki Kashiwada, Jun’ichi Kobayashi
    2016 Volume 64 Issue 7 Pages 691-694
    Published: July 01, 2016
    Released on J-STAGE: July 01, 2016
    DOIhttps://doi.org/10.1248/cpb.c16-00245
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    In our continuing study for structurally and biogenetically interesting natural products from marine organisms, Okinawan marine sponges Agelas spp. were investigated, resulting in the isolation of 18 unique alkaloids including five dimeric bromopyrrole alkaloids (1–5), ten monomeric bromopyrrole alkaloids (6–15), and three conjugates of monomeric bromopyrrole alkaloid and hydroxykynurenine (16–18). In this mini-review, the isolation, structure elucidation, and antimicrobial activities of these alkaloids are summarized.
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Special Collection of Papers: Regular Articles
  • In Situ Click Chemistry for the Identification of a Potent D-Amino Acid Oxidase Inhibitor
    Shohei Toguchi, Tomoyasu Hirose, Kazuko Yorita, Kiyoshi Fukui, K. Barr ...
    2016 Volume 64 Issue 7 Pages 695-703
    Published: July 01, 2016
    Released on J-STAGE: July 01, 2016
    Advance online publication: December 18, 2015
    DOIhttps://doi.org/10.1248/cpb.c15-00867
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    In situ click chemistry is a target-guided synthesis approach for discovering novel lead compounds by assembling organic azides and alkynes into triazoles inside the affinity site of target biogenic molecules such as proteins. We report in situ click chemistry screening with human D-amino acid oxidase (hDAO), which led to the identification of a more potent hDAO inhibitor. The hDAO inhibitors have chemotherapeutic potential as antipsychotic agents. The new inhibitor displayed competitive inhibition of hDAO and showed significantly increased inhibitory activity against hDAO compared with that of an anchor molecule of in situ click chemistry.
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  • Chiral Integrated Catalysts Composed of Bifunctional Thiourea and Arylboronic Acid: Asymmetric Aza-Michael Addition of α,β-Unsaturated Carboxylic Acids
    Noboru Hayama, Takumi Azuma, Yusuke Kobayashi, Yoshiji Takemoto
    2016 Volume 64 Issue 7 Pages 704-717
    Published: July 01, 2016
    Released on J-STAGE: July 01, 2016
    DOIhttps://doi.org/10.1248/cpb.c15-00983
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    The first intermolecular asymmetric Michael addition of nitrogen-nucleophiles to α,β-unsaturated carboxylic acids was achieved through a new type of arylboronic acid equipped with chiral aminothiourea. The use of BnONH2 as a nucleophile gives a range of enantioenriched β-(benzyloxy)amino acid derivatives in good yields and with high enantioselectivity (up to 90% yield, 97% enantiomeric excess (ee)). The obtained products are efficiently converted to optically active β-amino acid and 1,2-diamine derivatives.
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  • Beckmann Fragmentation and Successive Carbon–Carbon Bond Formation Using Grignard Reagents via Phosphonium Salt Intermediates
    Hiromichi Fujioka, Nao Matsumoto, Yuichi Kuboki, Hidenobu Mitsukane, R ...
    2016 Volume 64 Issue 7 Pages 718-722
    Published: July 01, 2016
    Released on J-STAGE: July 01, 2016
    DOIhttps://doi.org/10.1248/cpb.c16-00006
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    The intermediates formed during the Beckmann fragmentation of α-alkoxy and α-alkoxy-α-alkyl oxime acetates have been successfully trapped as phosphonium salts, which were subsequently reacted with a variety of Grignard reagents to give the corresponding substituted products in good yields. Notably, this reaction proceeded smoothly even from α-alkoxy-α-alkyl oxime acetates.
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  • Practical Total Syntheses of Acromelic Acids A and B
    Makoto Inai, Hitoshi Ouchi, Aya Asahina, Tomohiro Asakawa, Yoshitaka H ...
    2016 Volume 64 Issue 7 Pages 723-732
    Published: July 01, 2016
    Released on J-STAGE: July 01, 2016
    Advance online publication: February 24, 2016
    DOIhttps://doi.org/10.1248/cpb.c16-00009
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    Practical total syntheses of acromelic acids A (1) and B (2), which were scarce natural products isolated from toxic mushroom by Shirahama and Matsumoto, were accomplished in 13 (36% total yield) and 17 steps (6.9% total yield), respectively, from 2,6-dichloropyridine (8). Beginning with regioselective transformation of symmetric 8 by either ortho-lithiation or bromination, nitroalkenes 15 and 16 were provided. Stereoselective construction of the vicinal stereocenters at the C-3, 4 positions of 1 and 2 was performed by a Ni-catalyzed asymmetric conjugate addition of α-ketoesters to the nitroalkenes. Construction of the pyrrolidine ring was accomplished in a single operation via a sequence consisting of reduction of the nitro group, intramolecular condensation with the ketone, and reduction of the resulting ketimine.
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  • Isopetrosynol, a New Protein Tyrosine Phosphatase 1B Inhibitor, from the Marine Sponge Halichondria cf. panicea Collected at Iriomote Island
    Delfly Booby Abdjul, Hiroyuki Yamazaki, Ohgi Takahashi, Ryota Kirikosh ...
    2016 Volume 64 Issue 7 Pages 733-736
    Published: July 01, 2016
    Released on J-STAGE: July 01, 2016
    DOIhttps://doi.org/10.1248/cpb.c16-00061
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    A new polyacetylene compound, isopetrosynol (1), was isolated from the Okinawan marine sponge Halichondria cf. panicea together with petrosynol (2), adociacetylene D (3), (5R)-3,15,27-triacontatriene-1,29-diyn-5-ol (4), and petrosterol (5). The structure of 1 was assigned on the basis of spectroscopic data for 1 and 2. Compound 1 inhibited protein tyrosine phosphatase 1B (PTP1B) activity with an IC50 value of 8.2±0.3 µM, while compound 2, a diastereomer of 1, showed only 28.9±4.5% inhibition at 21.6 µM. The IC50 values of compounds 3 and 4 were 7.8±0.5 and 12.2±0.5 µM, respectively. Oleanolic acid, a positive control, inhibited PTP1B activity at 0.7±0.1 µM (IC50) in the same experiment. The inhibitory activity of 1 was stronger than that of its diastereomer (2). This is the first study to show the inhibitory effects of polyacetylene compounds on PTP1B.
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  • Enhanced Structural Variety of Nonplanar N-Oxyl Radical Catalysts and Their Application to the Aerobic Oxidation of Benzylic C–H Bonds
    Yoichi Kadoh, Kounosuke Oisaki, Motomu Kanai
    2016 Volume 64 Issue 7 Pages 737-753
    Published: July 01, 2016
    Released on J-STAGE: July 01, 2016
    DOIhttps://doi.org/10.1248/cpb.c16-00083
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    The design and synthesis of structurally variable, nonplanar N-oxyl radical catalysts and their application to the aerobic oxidation, etherification, and acetoamidation of benzylic C–H bonds are described. The catalytic oxidation of C–H bonds represents a powerful tool to synthesize oxygenated functional molecules from simple hydrocarbons in a straightforward way. Electron-deficient N-oxyl radical catalysts, such as phthalimidoyl N-oxyl (PINO) radical, generated from N-hydroxyphthalimide (1), have attracted much attention because of their applications in the oxidation of C–H bonds with high bond dissociation energy (BDE). However, a few sites in 1 are available for structural modifications and improvements of the catalytic performance. By replacing one carbonyl group in 1 with a trifluoromethyl (CF3)-substituted sp3-carbon, we generated an additional tunable site and a nonplanar backbone, while retaining the desirable electron-withdrawing properties and increasing the lipophilicity with respect to 1. We synthesized a variety of N-hydroxy precatalysts containing such a CF3 moiety, and investigated their utility in the aerobic oxidation of benzylic C–H bonds. Precatalysts with electron-withdrawing substituents, such as trifluoroethoxy and the acetophenone moieties, afforded higher yields than a corresponding methoxy-substituted analogue. The introduction of substituents at the aromatic ring was also effective, as evident from the performance of 7-CF3 and 4,5,6,7-tetrafluoro precatalysts. Especially the combination of trifluoroethoxy- and 4,5,6,7-tetrafluoro substitution afforded a superior performance. These catalyst systems exhibited high functional group tolerance during the aerobic oxidation of C–H bonds, and benzylic etherification and Ritter-type reactions could be carried out at room temperature when a selected precatalyst and N-bromosuccinimide (NBS) were used.
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  • Design, Synthesis, and Biological Evaluation of Beauveriolide Analogues Bearing Photoreactive Amino Acids
    Yuichi Masuda, Kazumasa Aoyama, Masahito Yoshida, Keisuke Kobayashi, T ...
    2016 Volume 64 Issue 7 Pages 754-765
    Published: July 01, 2016
    Released on J-STAGE: July 01, 2016
    Advance online publication: March 26, 2016
    DOIhttps://doi.org/10.1248/cpb.c16-00095
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    Beauveriolides I and III, which are naturally occurring cyclodepsipeptides, have been reported to bind to sterol O-acyltransferase (SOAT), inhibiting its ability to synthesize cholesteryl esters. To facilitate an analysis of the binding site(s) of these compounds, we designed beauveriolide analogues 1a–d wherein the Leu or D-allo-Ile residue was replaced by photoreactive amino acids possessing methyldiazirine or trifluoromethyldiazirine in the side chains. The methyldiazirine moiety was installed by reaction of methyl ketones with liquid ammonia to provide imine intermediates, followed by treatment with hydroxylamine-O-sulfonic acid to provide the diaziridines. Subsequent oxidation gave methyldiazirines. In contrast, trifluoromethyldiazirine derivatives were prepared from trifluoromethyl ketones via the oxime intermediates, which were transformed into diaziridines. Subsequent oxidation afforded trifluoromethyldiazirines. The synthesized photoreactive amino acids 3a–d were coupled with 3-hydroxy-4-methyloctanoic acid 4 and dipeptide 5, followed by macrolactamization to provide beauveriolide analogues 1a–d. The SOAT inhibitory activities of 1a–d were found to be as potent as those of beauveriolides I and III. Moreover, 1a–d inhibited SOAT1 selectively rather than SOAT2, which was also consistent with the behavior of beauveriolides I and III.
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  • N-Methylniphatyne A, a New 3-Alkylpyridine Alkaloid as an Inhibitor of the Cancer Cells Adapted to Nutrient Starvation, from an Indonesian Marine Sponge of Xestospongia sp.
    Masayoshi Arai, Kentaro Kamiya, Dayoung Shin, Hirokazu Matsumoto, Tomo ...
    2016 Volume 64 Issue 7 Pages 766-771
    Published: July 01, 2016
    Released on J-STAGE: July 01, 2016
    DOIhttps://doi.org/10.1248/cpb.c16-00118
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    In the course of searching for selective growth inhibitors of the cancer cells adapted to nutrient starvation, a new 3-alkylpyridine alkaloid named N-methylniphatyne A (1) was isolated from an Indonesian marine sponge of Xestospongia sp. The chemical structure of 1 was determined on the basis of the spectroscopic analysis and comparison with the synthesized 1 and its analogues. Compound 1 showed the cytotoxic activity against PANC-1 cells under the condition of glucose starvation with IC50 value of 16 µM, whereas no growth-inhibition was observed up to 100 µM under the general culture conditions.
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  • Enantioselective Total Synthesis of the Proposed Structure of Furan-Containing Polyketide
    Hideki Abe, Satoko Itaya, Kei Sasaki, Toyoharu Kobayashi, Hisanaka Ito
    2016 Volume 64 Issue 7 Pages 772-777
    Published: July 01, 2016
    Released on J-STAGE: July 01, 2016
    DOIhttps://doi.org/10.1248/cpb.c16-00147
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    Enantioselective total synthesis of the proposed structure of furan-containing polyketide was accomplished. The key features include a chemo- and enantioselective epoxidation of 1,4-cyclohexadiene by Shi asymmetric epoxidation, a regioselective epoxide ring opening, chemo- and diastereoselective dihydroxylation of the conjugated dienone derivative, and vinylation of the lactone accompanied by formation of the furan ring.
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  • Additional Nucleophile-Free FeCl3-Catalyzed Green Deprotection of 2,4-Dimethoxyphenylmethyl-Protected Alcohols and Carboxylic Acids
    Yoshinari Sawama, Masahiro Masuda, Akie Honda, Hiroki Yokoyama, Kwihwa ...
    2016 Volume 64 Issue 7 Pages 778-784
    Published: July 01, 2016
    Released on J-STAGE: July 01, 2016
    DOIhttps://doi.org/10.1248/cpb.c16-00161
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    The deprotection of the methoxyphenylmethyl (MPM) ether and ester derivatives can be generally achieved by the combinatorial use of a catalytic Lewis acid and stoichiometric nucleophile. The deprotections of 2,4-dimethoxyphenylmethyl (DMPM)-protected alcohols and carboxylic acids were found to be effectively catalyzed by iron(III) chloride without any additional nucleophile to form the deprotected mother alcohols and carboxylic acids in excellent yields. Since the present deprotection proceeds via the self-assembling mechanism of the 2,4-DMPM protective group itself to give the hardly-soluble resorcinarene derivative as a precipitate, the rigorous purification process by silica-gel column chromatography was unnecessary and the sufficiently-pure alcohols and carboxylic acids were easily obtained in satisfactory yields after simple filtration.
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  • Synthesis and GGCT Inhibitory Activity of N-Glutaryl-L-alanine Analogues
    Hiromi Ii, Tatsuhiro Yoshiki, Naoyuki Hoshiya, Jun’ichi Uenishi
    2016 Volume 64 Issue 7 Pages 785-792
    Published: July 01, 2016
    Released on J-STAGE: July 01, 2016
    DOIhttps://doi.org/10.1248/cpb.c16-00167
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    γ-Glutamylcyclotransferase (GGCT) is an important enzyme that cleaves γ-glutamyl-amino acid in the γ-glutamyl cycle to release 5-oxoproline and amino acid. Eighteen N-acyl-L-alanine analogues including eleven new compounds have been synthesized and examined for their inhibitory activity against recombinant human GGCT protein. Simple N-glutaryl-L-alanine was found to be the most potent inhibitor for GGCT. Other N-glutaryl-L-alanine analogues having methyl and dimethyl substituents at the 2-position were moderately effective, while N-(3R-aminoglutary)-L-alanine, the substrate having an (R)-amino group at the 3-position or N-(N-methyl-3-azaglutaryl)-L-alanine, the substrate having an N-methyl substituent on the 3-azaglutaryl carbon, in constract, exhibited excellent inhibition properties.
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  • New Lycopodine-Type Alkaloids from Lycopodium carinatum
    Noriyuki Kogure, Moe Maruyama, Sumphan Wongseripipatana, Mariko Kitaji ...
    2016 Volume 64 Issue 7 Pages 793-799
    Published: July 01, 2016
    Released on J-STAGE: July 01, 2016
    Advance online publication: March 25, 2016
    DOIhttps://doi.org/10.1248/cpb.c16-00171
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    The structures of new lycopodine-type alkaloids, lycopocarinamines A–F, which were isolated from Lycopodium carinatum, were elucidated by spectroscopic analysis and chemical conversions. The proposed structure of lycocarinatine A was revised.
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  • Conversion of Vindoline into 11-Mesyloxytabersonine
    Yuki Han-ya, Tomohiko Inui, Satoshi Yokoshima, Hidetoshi Tokuyama, Toh ...
    2016 Volume 64 Issue 7 Pages 800-804
    Published: July 01, 2016
    Released on J-STAGE: July 01, 2016
    DOIhttps://doi.org/10.1248/cpb.c16-00175
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    Conversion of readily available vindoline to 11-mesyloxytabersonine, a versatile synthetic intermediate for indole alkaloids, has been achieved by a 9-step sequence in 39% overall yield.
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  • Construction of Azabicyclo[6.4.0]dodecatrienes Based on Rhodium(I)-Catalyzed Intramolecular [6+2] Cycloaddition between Azetidine, Allene, and Alkynes
    Shigeo Yasuda, Haruna Yokosawa, Chisato Mukai
    2016 Volume 64 Issue 7 Pages 805-810
    Published: July 01, 2016
    Released on J-STAGE: July 01, 2016
    DOIhttps://doi.org/10.1248/cpb.c16-00178
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    Treatment of the allenylazetidine–alkynes with a catalytic amount of [RhCl(CO)dppp]2 (dppp: 1,3-bis(diphenylphosphino)propane) effected the intramolecular hetero-[6+2]-type ring-closing reaction via the C–C bond cleavage of the azetidine ring to produce azabicyclo[6.4.0]dodecatriene derivatives in good to excellent yields. The formation of the oxa analogue could also be achieved.
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  • Design, Synthesis and Biological Evaluation of a Structurally Simplified Syringolin A Analogues
    Takuya Chiba, Shun Kitahata, Akira Matsuda, Satoshi Ichikawa
    2016 Volume 64 Issue 7 Pages 811-816
    Published: July 01, 2016
    Released on J-STAGE: July 01, 2016
    DOIhttps://doi.org/10.1248/cpb.c16-00182
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    In this study, we designed and synthesized a structurally simplified syringolin A analogue 4, which could have a switched hydrogen bonding interaction with the β5 subunit of 20S proteasome. This analogue exhibits potent β5 proteasome inhibitory activity with an IC50 value of 107 nM. It also shows cytotoxicity against a range of human cancer cells at submicromolar level (109–254 nM). This analogue is expected to be a lead compound as a next generation proteasome inhibitor because of its simple structure.
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  • Peptide Nucleic Acid with a Lysine Side Chain at the β-Position: Synthesis and Application for DNA Cleavage
    Toru Sugiyama, Keiko Kuwata, Yasutada Imamura, Yosuke Demizu, Masaaki ...
    2016 Volume 64 Issue 7 Pages 817-823
    Published: July 01, 2016
    Released on J-STAGE: July 01, 2016
    DOIhttps://doi.org/10.1248/cpb.c16-00191
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    This paper reports the synthesis of new β-Lys peptide nucleic acid (PNA) monomers and their incorporation into a 10-residue PNA sequence. PNA containing β-Lys PNA units formed a stable hybrid duplex with DNA. However, incorporation of β-Lys PNA units caused destabilization of PNA–DNA duplexes to some extent. Electrostatic attractions between β-PNA and DNA could reduce this destabilization effect. Subsequently, bipyridine-conjugated β-Lys PNA was prepared and exhibited sequence selective cleavage of DNA. Based on the structures of the cleavage products and molecular modeling, we reasoned that bipyridine moiety locates within the minor groove of the PNA–DNA duplexes. The lysine side chain of β-PNA is a versatile handle for attaching various functional molecules.
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  • Convergent Synthesis of 2-Aryl-Substituted Quinolines by Gold-Catalyzed Cascade Reaction
    Hirofumi Ueda, Minami Yamaguchi, Hidetoshi Tokuyama
    2016 Volume 64 Issue 7 Pages 824-829
    Published: July 01, 2016
    Released on J-STAGE: July 01, 2016
    DOIhttps://doi.org/10.1248/cpb.c16-00193
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    Gold-catalyzed auto-tandem catalysis has been developed for synthesizing 2-aryl-substituted quinolines. The reaction of an aniline bearing an acetal moiety with an aryl alkyne proceeded via formal [4+2]-cycloaddition, which involved the addition of gold acetylide to an oxonium ion to give amino alkyne intermediate and sequential 6-endo-dig cyclization of amino alkyne intermediate by attacking of nitrogen to alkyne moiety activated by gold catalyst. The cationic gold catalyst promoted two different processes by enhancing the nucleophilicity and electrophilicity of alkyne. This convergent synthetic methodology enabled the synthesis of a variety of 2-aryl-substituted quinolines.
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  • Substituent Effect at the C4-Position of 1,3a,6a-Triazapentalene
    Atsushi Nakayama, Satoshi Nishio, Akira Otani, Akane Mera, Ayumi Osawa ...
    2016 Volume 64 Issue 7 Pages 830-837
    Published: July 01, 2016
    Released on J-STAGE: July 01, 2016
    DOIhttps://doi.org/10.1248/cpb.c16-00196
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    Various 2,4-disubstituted-1,3a,6a-triazapentalenes possessing methyl and phenyl groups at the C4-position were synthesized. Fluorescence observation of the synthetic 4-methyl- and 4-phenyl-1,3a,6a-triazapentalenes revealed that the introduction of a substituent at the C4-position allowed a long-wavelength shift of the fluorescence maximum. Furthermore, the phenyl group at the C4-position was found to induce a substantial increase in the extinction coefficient value.
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  • Glycosylation Reaction of Thioglycosides by Using Hypervalent Iodine(III) Reagent as an Excellent Promoter
    Tetsuya Kajimoto, Koji Morimoto, Ryosuke Ogawa, Toshifumi Dohi, Yasuyu ...
    2016 Volume 64 Issue 7 Pages 838-844
    Published: July 01, 2016
    Released on J-STAGE: July 01, 2016
    DOIhttps://doi.org/10.1248/cpb.c16-00203
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    Thioglycosides are available donors in glycosylation due to the stability of the anomeric C–S bond under general reaction conditions of protection and deprotection, and offer orthogonality in their activation. We report now that the hypervalent iodine effectively induced glycosylation reaction of thioglycosides with various alcohols. This method features a high efficiency, completion in a short time, and proceeding under very mild conditions.
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  • Gold-Catalyzed Cyclization of Alkyne Alcohols: Regioselective Construction of Functionalized 6,6- and 6,7-Bicyclic Ethers
    Mio Kubota, Tatsuo Saito, Kazunori Miyamoto, Keiichi Hirano, Chao Wang ...
    2016 Volume 64 Issue 7 Pages 845-855
    Published: July 01, 2016
    Released on J-STAGE: July 01, 2016
    DOIhttps://doi.org/10.1248/cpb.c16-00204
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    We describe an efficient regioselective formation of six-/seven-membered cyclic ethers based on gold-catalyzed intramolecular hydroalkoxylation. Sequential gold-catalyzed cyclization and palladium-catalyzed cross-coupling reactions afforded 6,6-bicyclic ethers, while reversing the reaction sequence (cross-coupling then cyclization) afforded 6,7-bicyclic ethers. This methodology should provide access to a range of functional polycyclic ethers.
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  • Organocatalytic Site-Selective Acylation of Avermectin B2a, a Unique Endectocidal Drug
    Takeshi Yamada, Koh Suzuki, Tomoyasu Hirose, Takumi Furuta, Yoshihiro ...
    2016 Volume 64 Issue 7 Pages 856-864
    Published: July 01, 2016
    Released on J-STAGE: July 01, 2016
    Advance online publication: April 12, 2016
    DOIhttps://doi.org/10.1248/cpb.c16-00205
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    The organocatalytic site-selective monoacylation of avermectin B2a, an insecticidal and anti-parasitic drug, was accomplished. Although an acetylation of avermectin B2a using a 4-dimethylaminopyridine (DMAP) as a catalyst gave poor site-selectivity, use of our organocatalyst increased site-selectivity of the acylation at the C-5-OH as well as the yield of monoacetate. This catalyst was also effective in other acylations. Interestingly, trihaloacetylation under same conditions gave poor site-selectivity. However, the use of an enantiomer of our organocatalyst provided the C-4″-O-trihaloacetyl avermectin B2a with excellent site-selectivity. These results indicate that the site-selective acylation of avermectin B2a can be controlled by the combination of a suitable organocatalyst and an acid anhydride.
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  • Synthesis and Antigenicity against Human Sera of a Biotin-Labeled Oligosaccharide Portion of a Glycosphingolipid from the Parasite Echinococcus multilocularis
    Noriyasu Hada, Ayaka Kitamura, Kimiaki Yamano, Frank Schweizer, Fumiyu ...
    2016 Volume 64 Issue 7 Pages 865-873
    Published: July 01, 2016
    Released on J-STAGE: July 01, 2016
    DOIhttps://doi.org/10.1248/cpb.c16-00211
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    Synthesis of a biotinylated analog of the carbohydrate portion of a glycosphingolipid from the parasite Echinococcus multilocularis has been achieved. We synthesized β-D-Galp-(1→6)-β-D-Galp-(1→6)-[α-L-Fucp-(1→3)]-β-D-Galp-(1→R: biotin probe) (1) and compared the antigenicity by an enzyme linked immunosorbent assay (ELISA) with biotinylated trisaccharide α-D-Galp-(1→4)-β-D-Galp-(1→3)-α-D-Galp-(1→R: biotin probe) (F), which has been shown to have significant antigenicity. Both of the oligosaccharides reacted with sera of alveolar echinococcosis (AE) patients, but showed different reactivity. Among the 60 sera of AE patients, more sera reacted with the linear sequence Galα1→4Galβ1→3GalNAcα1→R of oligosaccharide (F) than for branched compound 1. Some sera showed high specificity to one of the compound, indicating that the antibodies in the sera of AE patients differ in their specificity to recognize carbohydrate sequences of glycosphingolipids. Our results demonstrate that both of the biotinylated oligosaccharides 1 and F have good serodiagnostic potential and are complementary to detect infections caused by the parasite Echinococcus multilocularis.
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  • Chemical Conversion of Ryanodol to Ryanodine
    Kengo Masuda, Masanori Nagatomo, Masayuki Inoue
    2016 Volume 64 Issue 7 Pages 874-879
    Published: July 01, 2016
    Released on J-STAGE: July 01, 2016
    Advance online publication: March 23, 2016
    DOIhttps://doi.org/10.1248/cpb.c16-00214
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    Ryanodine (1) is a plant-derived natural product with powerful pharmacological and insecticidal action, and is a potent modulator of intracellular calcium release channels. Compound 1 possesses a 1H-pyrrole-2-carboxylate ester at the C3-position of heptahydroxylated terpenoid ryanodol (2). Whereas 2 was readily obtained from 1 by basic hydrolysis, 1 has never been synthesized from 2, due to the extreme difficulty in selectively introducing the bulky pyrrole moiety at the severely hindered C3-hydroxyl group of heptaol 2. Here we report chemical conversion of 2 to 1 for the first time. The derivatization was realized through the use of a new protective group strategy and the application of on-site construction of the pyrrole-2-carboxylate ester from the glycine ester and 1,3-bis(dimethylamino)allylium tetrafluoroborate.
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  • Aromatase Inhibitory Activity of Geranylated Coumarins, Mammeasins C and D, Isolated from the Flowers of Mammea siamensis
    Kiyofumi Ninomiya, Kanae Shibatani, Mayumi Sueyoshi, Saowanee Chaipech ...
    2016 Volume 64 Issue 7 Pages 880-885
    Published: July 01, 2016
    Released on J-STAGE: July 01, 2016
    DOIhttps://doi.org/10.1248/cpb.c16-00218
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    A methanol extract of the flowers of Mammea siamensis (Calophyllaceae) was found to inhibit enzymatic activity against aromatase (IC50=16.5 µg/mL). From the extract, two new geranylated coumarins, mammeasins C (1) and D (2), were isolated together with seven coumarins: 8-hydroxy-5-methyl-7-(3,7-dimethyl-octa-2,6-dienyl)-9-(2-methyl-1-oxobutyl)-4,5-dihydropyrano[4,3,2-de]chromen-2-one (9), 8-hydroxy-5-methyl-7-(3,7-dimethyl-octa-2,6-dienyl)-9-(3-methyl-1-oxobutyl)-4,5-dihydropyrano[4,3,2-de]chromen-2-one (10), mammeas A/AA (14), A/AB (15), A/AA cyclo D (18), E/BA (23), and E/BC cyclo D (25). The structures of 1 and 2 were elucidated on the basis of spectroscopic evidence. Among the isolates including 17 previously reported coumarins, 1 (IC50=2.7 µM), 2 (3.6 µM), and mammea B/AB cyclo D (21, 3.1 µM) showed relatively strong inhibitory activities comparable to the activity of the synthetic nonsteroidal aromatase inhibitor aminoglutethimide (2.0 µM).
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  • Structure–Activity Relationship Study of 3-Amino-2-indolyllactam Derivatives: Development of Inhibitors of Oxidative Stress-Induced Necrosis
    Kosuke Dodo, Kenji Hayamizu, Tadashi Shimizu, Mikiko Sodeoka
    2016 Volume 64 Issue 7 Pages 886-898
    Published: July 01, 2016
    Released on J-STAGE: July 01, 2016
    DOIhttps://doi.org/10.1248/cpb.c16-00259
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    Modification of our previously reported selective inhibitor of oxidative stress-induced necrosis, 2-(1H-indol-3-yl)-3-pentylamino-maleimide (IM-54) by regioselective reduction of the C-4 carbonyl group afforded a 3-amino-2-indolyllactam (IL-1) with more potent activity. To examine the structure–activity relationship of IL derivatives, we developed new synthetic routes with flexibility to incorporate a range of substituents at a late stage. The synthesized IL derivatives were evaluated for activity to inhibit necrotic cell death induced by hydrogen peroxide. Among them, IL-12 showed the most potent activity (IC50=49 nM) among the IL and indolylmaleimide (IM) derivatives examined.
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  • Asymmetric Synthesis of Multisubstituted Dihydrobenzofurans by Intramolecular Conjugate Addition of Short-Lived C–O Axially Chiral Enolates
    Keisuke Tomohara, Koji Kasamatsu, Tomoyuki Yoshimura, Takumi Furuta, T ...
    2016 Volume 64 Issue 7 Pages 899-906
    Published: July 01, 2016
    Released on J-STAGE: July 01, 2016
    Advance online publication: May 03, 2016
    DOIhttps://doi.org/10.1248/cpb.c16-00272
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    Enantioselective intramolecular conjugate addition reactions of short-lived C–O axially chiral enolates have been developed. The reactions proceeded with inversion of the configuration and provided dihydrobenzofurans with contiguous tetra- and trisubstituted carbon centers in up to 96% enantiomeric excess (ee).
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