Takashi Takahashi

Yokohama College Of Pharmacy, Chigaraki, Kanagawa, Japan

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Publications (280)927.19 Total impact

  • ChemInform 12/2014; 45(49).
  • Tetrahedron 11/2014; 70(45):8690–8695. · 2.82 Impact Factor
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    ABSTRACT: Toll-like receptors (TLRs) play a key role in linking pathogen recognition with the induction of innate immunity. They have been implicated in the pathogenesis of chronic inflammatory diseases, representing potential targets for prevention/treatment. Vegetable-rich diets are associated with the reduced risk of several inflammatory disorders. In the present study, based on an extensive screening of vegetable extracts for the TLR-inhibiting activity in the HEK293 cells co-expressing TLR together with the NF-κB reporter gene, we found the cabbage and onion extracts as the richest sources of a TLR signaling inhibitor. To identify the active substances, we performed the activity-guiding separation of the principal inhibitors and identified 3-methylsulfinylpropyl isothiocyanate (iberin) from the cabbage and quercetin and quercetin-4'-O-β-glucoside from the onion, among which iberin showed the most potent inhibitory effect. It was revealed that iberin specifically acted on the dimerization step of TLRs in the TLR signaling pathway. To gain an insight into the inhibitory mechanism of the TLR dimerization, we developed a novel probe, combining an isothiocyanate-reactive group and an alkyne functionality, for click chemistry and detected the probe bound to the TLRs in living cells, suggesting that iberin disrupts dimerization of the TLRs via covalent binding. Furthermore, we designed a variety of iberin analogues and found that the inhibition potency was influenced by the oxidation state of the sulfur. Modeling studies of the iberin analogues showed that the oxidation state of sulfur might influence the global shape of the isothiocyanates. These findings establish the TLR dimerization step as a target of food-derived anti-inflammatory compounds.
    Journal of Biological Chemistry 10/2014; · 4.60 Impact Factor
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    ABSTRACT: The elucidation of the structure-property relationship is an important issue in the development of organic electronics. Combinatorial synthesis and the evaluation of systematically modified compounds is powerful tool in the work of elucidating structure-property relationships. In this manuscript, D-π-A structure, 32 p-type organic semiconductors were rapidly synthesized via a one-pot, Suzuki-Miyaura coupling with subsequent Knoevenagel condensation. Evaluation of the solubility and photovoltaic properties of the prepared compounds revealed that the measured solubility was strongly correlated with the solubility parameter (SP), as reported by Fedors. In addition, the SPs were correlated with the Jsc of thin-film organic solar cells prepared using synthesized compounds. Among the evaluated photovoltaic properties of the solar cells, Jsc and Voc had strong correlations with the photoconversion efficiency (PCE).
    ACS Combinatorial Science 08/2014; · 3.40 Impact Factor
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    ABSTRACT: A sequential diversification approach for the synthesis of various multi‐substituted β‐keto amide derivatives based on a simple and readily available dioxinone scaffold was developed. The process involves: (1) nucleophilic addition of the scaffold to an aldehyde, and a subsequent one‐pot dehydration; (2) palladium‐catalysed cross‐coupling of the scaffold with either an arylboronic acid pinacol ester, or CO and an aliphatic amine; and (3) nucleophilic addition of either an aliphatic amine or an arylamine, or a hetero‐Diels–Alder reaction of isocyanate/isothiocyanate, with an acylketene generated in situ from the dioxinone scaffold. Multi‐substituted β‐keto amides were synthesized in a sequential four‐component coupling process based on a dioxinone scaffold. The sequence consists of three steps: (1) nucleophilic addition of the scaffold to R1–CHO followed by a one‐pot dehydration; (2) Pd‐catalysed coupling of the scaffold with either R2–[B] or CO and R2–NH2; (3) nucleophilic addition of R3–NH2 to an in situ generated acyl ketene.
    European Journal of Organic Chemistry 08/2014; 2014(22). · 3.15 Impact Factor
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    ABSTRACT: Development of efficient methods for preparation of bioactive nonribosomal peptides, containing densely functionalized nonproteinogenic amino acids, is an important task in organic synthesis. We have employed a concise synthesis for such amino acids by asymmetric aldol addition coupled with an isomeric resolution via diastereoselective cyclization. This approach is successfully applied to the first total synthesis of the cyclic hexapeptide aglycone of the mannopeptimycins, a group of glycopeptides known for potent activity against drug-resistant bacteria. The facile preparation of the key amino acid residues and the synthesis of the aglycone pave the way for further studies on this class of antibiotics and the development of new lead compounds with therapeutic potential. In addition, our studies have led to the revision of the stereochemistry of the β-methylphenylalanine residue in the mannopeptimycin aglycone.
    Journal of the American Chemical Society 07/2014; · 11.44 Impact Factor
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    ABSTRACT: Aggregations of both amyloid-β (Aβ) and hyper-phosphorylated tau proteins are recognized as key pathological manifestations of Alzheimer's disease (AD). Agents that inhibit both those forms of aggregation show promise as drug candidates. Seventeen oligo heteroaromatic compounds were rapidly synthesized via a one-pot, 3- or 4-component coupling procedure. Evaluations showed that compounds E16 and E18 were the most potent inhibitors of Aβ and tau aggregations (E16: IC50s = 0.38, 0.29 μM against Aβ, tau, respectively, E18: IC50s = 0.55, 0.30 μM against Aβ, tau, respectively).
    European Journal of Medicinal Chemistry 07/2014; 85C:228-234. · 3.43 Impact Factor
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    ABSTRACT: In this report, a synthetic study of landomycinone via Masamune–Bergmann cyclization is described. A 10-membered 1,2-dialkynylbenzene derivative was designated as a key intermediate in the formation of an angular tetracyclic core via Masamune–Bergmann cyclization. Cyclization was expected to proceed under mild heating conditions based on a DFT transition state analysis of the 10-membered enediyne. The enediyne was successfully prepared by intramolecular NHK cyclization in good yield and underwent Masamune–Bergman cyclization at 70 °C for 2 h. However, an undesired β-elimination of the secondary alcohol was involved in the cyclization. In addition, iodination at the 12 position did not occur due to the steric hindrance of two methyl groups. This methodology should be widely applicable to the synthesis of various types of highly oxy-functionalized anthraquinone derivatives as well as landomycinone, and should be a useful way to clarify structure–activity relationships.
    RSC Advances 07/2014; 4(61). · 3.71 Impact Factor
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    ABSTRACT: The creation of organic dyes with excellent high power conversion efficiency (PCE) is important for the further improvement of dye-sensitized solar cells. We wish to describe the rapid synthesis of a 112-membered donor-π-acceptor dye library by a one-pot procedure, evaluation of PCEs, and elucidation of structure-property relationships. No obvious correlations between ε, and the η were observed, whereas the HOMO and LUMO levels of the dyes were critical for η. The dyes with a more positive EHOMO , and with an ELUMO <-0.80 V, exerted higher PCEs. The proper driving forces were crucial for a high Jsc , and it was the most important parameter for a high η. The above criteria of EHOMO and ELUMO should be useful for creating high PCE dyes; nevertheless, that was not sufficient for identifying the best combination of donor, π, and acceptor blocks. Combinatorial synthesis and evaluation was important for identifying the best dye.
    Chemistry - A European Journal 06/2014; · 5.93 Impact Factor
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    ABSTRACT: A straightforward and convergent total synthesis of (+)-antimycin A3b is reported. Four fragments were assembled on a solid support and the fully functionalized seco acid was cyclized in the solution phase. This synthetic route minimized the number of manipulations in the solution phase and is useful for a combinatorial library synthesis.
    Annalen der Chemie und Pharmacie 06/2014; · 3.15 Impact Factor
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    Shinichiro Fuse, Yuto Mifune, Takashi Takahashi
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    ABSTRACT: The development of highly efficient amide bond forming methods which are devoid of side reactions, including epimerization, is important, and such a method is described herein and is based on the concept of rapid and strong activation of carboxylic acids. Various carboxylic acids are rapidly (0.5 s) converted into highly active species, derived from the inexpensive and less-toxic solid triphosgene, and then rapidly (4.3 s) reacted with various amines to afford the desired peptides in high yields (74 %-quant.) without significant epimerization (≤3 %). Our process can be carried out at ambient temperature, and only CO2 and HCl salts of diisopropylethyl amine are generated. In the long history of peptide synthesis, a significant number of active coupling reagents have been abandoned because the highly active electrophilic species generated are usually susceptible to side reactions such as epimerization. The concept presented herein should renew interest in the use of these reagents.
    Angewandte Chemie International Edition 01/2014; 53(3):851-855. · 11.34 Impact Factor
  • European Journal of Medicinal Chemistry. 01/2014; 85:228–234.
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    ABSTRACT: β(1-3)-Glucans, abundant in fungi, have the potential to activate the innate immune response against various pathogens. Although part of the action is exerted through the C-type lectin-like receptor Dectin-1, details of the interaction mechanism with respect to glucan chain-length remain unclear. In this study, we investigated a set of short β(1-3)-glucans with varying degree of polymerization (DP); 3, 6, 7, 16, and laminarin (average DP; 25), analyzing the relationship between the structure and interaction with the C-type lectin-like domain (CTLD) of Dectin-1. The interaction of short β(1-3)-glucans (DP6, DP16, and laminarin) with the CTLD of Dectin-1 was systematically analyzed by (1)H-NMR titration as well as by saturation transfer difference (STD)-NMR. The domain interacted weakly with DP6, moderately with DP16 and strongly with laminarin, the latter plausibly forming oligomeric protein-laminarin complexes. To obtain structural insights of short β(1-3)-glucans, the exchange rates of hydroxy protons were analyzed by deuterium induced (13)C-NMR isotope shifts. The hydroxy proton at C4 of laminarin has slower exchange with the solvent than those of DP7 and DP16, suggesting that laminarin has a secondary structure. Diffusion ordered spectroscopy revealed that none of the short β(1-3)-glucans including laminarin forms a double or triple helix in water. Insights into the interaction of the short β(1-3)-glucans with Dectin-1 CTLD provide a basis to understand the molecular mechanisms of β-glucan recognition and cellular activation by Dectin-1.
    Glycoconjugate Journal 11/2013; · 1.88 Impact Factor
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    ABSTRACT: Oligo/polysialic acids consisting of consecutive α(2,8)-linkages on gangliosides and glycoproteins play a role in cell adhesion and differentiation events in a manner that is dependent on the degree of polymerization (DP). Anti-oligo/polysialic acid antibodies often have DP-dependent antigenic specificity, and such unique antibodies are often used in biological studies for the detection and differentiation of oligo/polysialic acids. However, molecular mechanisms remain unclear. We here use NMR techniques to analyze the binding epitopes of the anti-oligo/polysialic acid monoclonal antibodies (mAb) A2B5 and 12E3. The mAb A2B5, which has a preference for trisialic acid, recognizes sialic acid residues at the non-reducing terminus and those in nascent units. On the other hand, mAb 12E3, which prefers oligo/polysialic acids of more than six sugar units, recognizes inner sialic acid residues. In both structural complexes, the interresidue transferred NOE correlations are significantly different from those arising from analogs of the free states, indicating that the bound and free sugar conformations are distinct. The ability of the two mAbs to distinguish the chain lengths comes from different binding epitopes and possibly from the conformational differences in the oligo/polysialic acids. Information on the recognition modes is needed for the structural design of immunoreactive antigens for the development of high-affinity anti-polysialic acid antibodies and of related vaccines against pathogenic, polysialic acid-coated bacteria.
    Bioorganic & medicinal chemistry 07/2013; · 2.82 Impact Factor
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    ABSTRACT: The spirocycle is a key structure found in many bioactive compounds. From the cytotoxic and spirocyclic natural product, spiromamakone A (1) and its analogues, a more synthetically accessible spiroacetal template 4 was designed based on structural similarity analysis. A total of 50 compounds were rapidly synthesized in only one or two synthetic steps from the starting compound, and their cytotoxicity was evaluated. As a result, (±)-(2R*,5R*)-2-(4-iodophenyl)-7-chloro-1,4-dioxa-spiro[4.5]deca-6,9-dien-8-one (7d-II) was discovered and found to be fifteen-fold more cytotoxic than 1. The easily accessible spiroacetal 7d-II appeared to act in a manner similar to the highly oxidized natural product, spiromamakone A (1).
    European Journal of Medicinal Chemistry 06/2013; 66C:180-184. · 3.43 Impact Factor
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    ABSTRACT: The synthesis and biological evaluation of the Forssman antigen pentasaccharide and derivatives thereof by using a one-pot glycosylation and polymer-assisted deprotection is described. The Forssman antigen pentasaccharide, composed of GalNAcα(1,3)GalNAcβ(1,3)Galα(1,4)Galβ(1,4)Glc, was recently identified as a ligand of the lectin SLL-2 isolated from an octocoral Sinularia lochmodes. The chemo- and α-selective glycosylation of a thiogalactoside with a hemiacetal donor by using a mixture of Tf(2) O, TTBP and Ph(2) SO, followed by activation of the remaining thioglycoside, provided the trisaccharide at the reducing end in a one-pot procedure. The pentasaccharide was prepared by the α-selective glycosylation of the N-Troc-protected (Troc=2,2,2-trichloroethoxycarbonyl) thioglycoside with a 2-azide-1-hydroxyl glycosyl donor, followed by glycosidation of the resulting disaccharide at the C3 hydroxyl group of the trisaccharide acceptor in a one-pot process. We next applied the one-pot glycosylation method to the synthesis of pentasaccharides in which the galactosamine units were partially and fully replaced by galactose units. Among the three possible pentasaccharides, Galα(1,3)GalNAc and Galα(1,3)Gal derivatives were successfully prepared by the established method. An assay of the binding of the synthetic oligosaccharides to a fluorescent-labeled SLL-2 revealed that the NHAc substituents and the length of the oligosaccharide chain were both important for the binding of the oligosaccharide to SLL-2. The inhibition effect of the oligosaccharide relative to the morphological changes of Symbiodinium by SLL-2, was comparable to their binding affinity to SLL-2. In addition, we fortuitously found that the synthetic Forssman antigen pentasaccharide directly promotes a morphological change in Symbiodinium. These results strongly indicate that the Forssman antigen also functions as a chemical mediator of Symbiodinium.
    Chemistry - A European Journal 01/2013; · 5.93 Impact Factor
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    ABSTRACT: Yariv phenylglycosides, 1,3,5-tri-(p-glycosyloxyphenylazo)-2,4,6-trihydroxybenzene, are a group of chemical compounds, which selectively bind to arabinogalactan-proteins (AGPs), a type of plant proteoglycan. Yariv phenylglycosides are widely used as cytochemical reagents to perturb the molecular functions of AGPs, as well as for the detection, quantification, purification, and staining of AGPs. However, the target structure in AGPs to which Yariv phenylglycosides bind has so far not been determined. Here, we identify the structural element of AGPs required for the interaction with Yariv phenylglycosides by stepwise trimming of the arabinogalactan moieties using combinations of specific glycoside hydrolases. Whereas the precipitation with Yariv phenylglycosides (Yariv reactivity) of radish root AGP was not reduced after enzyme treatment to remove alpha-L-arabinofuranosyl and beta-glucuronosyl residues and beta-1,6-galactan side chains, it was completely lost after degradation of the beta-1,3-galactan main chains. In addition, Yariv reactivity of gum arabic, a commercial product of acacia AGPs, increased rather than decreased during the repeated degradation of beta-1,6-galactan side chains by Smith degradation. Among various oligosaccharides corresponding to partial structures of AGPs, beta-1,3-galactooligosaccharides longer than beta-1,3-galactoheptaose exhibited significant precipitation with Yariv in a radial diffusion assay on agar. A pull-down assay using oligosaccharides crosslinked to hydrazine beads detected interaction of beta-1,3-galactooligosaccharides longer than beta-1,3-galactopentaose with Yariv phenylglycoside. To the contrary no interactaction with Yariv was detected for beta-1,6-galactooligosaccharides of any length. Therefore we conclude that Yariv phenylglycosides should be considered specific binding reagents for beta-1,3-galactan chains longer than five residues, and seven residues are sufficient for crosslinking, leading to precipitation of the Yariv phenylglycosides.
    Plant physiology 01/2013; · 7.39 Impact Factor
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    ABSTRACT: Sterically crowded diimine ligands with five aryl rings were prepared in one step in good yields using a micro-flow technique. X-ray crystallographic analysis revealed the detailed structure of the bulky ligands. The nickel complexes prepared from the ligands exerted high polymerization activity in the ethylene homopolymerization and copolymerization of ethylene with polar monomers.
    Beilstein Journal of Organic Chemistry 01/2013; 9:2336-43. · 2.80 Impact Factor
  • Hiroshi Tanaka, Yusuke Tateno, Takashi Takahashi
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    ABSTRACT: In this paper, we describe an effective method for the elongation of a GlcNα(1,4)GlcAβ(1,4) sequence using a GlcNTrocα(1,4)GlcA disaccharide unit and the synthesis of the N- and/or O-sulfated GlcNα(1,4)GlcAβ(1,4) oligosaccharides. N-Troc protection of GlcNα(1,4)GlcA units was effective for the synthesis of the GlcNα(1,4)GlcAβ(1,4) oligosaccharides in comparison with the azido substituent. The GlcNα(1,4)GlcAβ(1,4) dodecasaccharide was successfully prepared by the direct β-selective glycosidation of glucuronate in the GlcNα(1,4)GlcAβ(1,4)GlcNα(1,4)GlcAβ(1,4) tetrasaccharide. In addition, the synthesis of the N- and/or O-sulfated GlcNα(1,4)GlcAβ(1,4) oligosaccharides was accomplished by fluorous-assisted deprotection and sulfation. The fluorous-assisted synthetic technology applied to the highly polar sulfated oligosaccharide permits it to be more easily separated from the highly polar reagents, such as SO(3)·NEt(3).
    Organic & Biomolecular Chemistry 11/2012; · 3.49 Impact Factor
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    ABSTRACT: A sequential multicomponent coupling approach is a powerful method for the construction of combinatorial libraries because structurally complex and diverse molecules can be synthesized from simple materials in short steps. In this paper, an efficient synthesis of nickel(II) complexes with N-aryl-2-amino phenols via a sequential three-step coupling approach is described, for potential use in nonlinear optical materials, bioinspired catalytic systems, and near-infrared absorbing filters. Seventeen N-aryl-2-amino phenolates were successfully synthesized in high yields based on the coupling of 3,5-di-tert-butylbenzene-1,2-diol with a pivotal aromatic scaffold, 4-bromo-2-iodo-aniline, followed by sequential Suzuki-Miyaura coupling with aryl boronates. A total of 16 analytically pure nickel(II) complexes with N-aryl-2-amino phenolates were obtained from 17 complexation trials. The procedure allowed us to assemble 4 components in high yields without protection, deprotection, oxidation or reduction steps. Various building blocks that included electron-donating, electron-withdrawing, and basic were used, and readily available, nontoxic and environmentally benign substrates and reagents were employed with no generation of toxic compounds. No strict anhydrous or degassed conditions were required. Absorption spectroscopic measurement of the synthesized nickel(II) complexes revealed that the ortho-substituent Ar(1) exerted more influence on the absorption wavelength of the complexes than the para-substituent Ar(2). On the other hand, both substituents Ar(1) and Ar(2) influenced the molar absorptivity values. These observations should be useful for the design of new and useful nickel(II) complexes as near-infrared chromophores.
    ACS combinatorial science. 08/2012;

Publication Stats

2k Citations
927.19 Total Impact Points


  • 2014
    • Yokohama College Of Pharmacy
      Chigaraki, Kanagawa, Japan
  • 1977–2014
    • Tokyo Institute of Technology
      • • Department of Applied Chemistry
      • • Department of Chemical Engineering
      Edo, Tōkyō, Japan
  • 2010
    • Tohoku University
      • Graduate School of Pharmaceutical Sciences
      Sendai-shi, Miyagi-ken, Japan
    • National Institute of Advanced Industrial Science and Technology
      • Biomedicinal Information Research Center
  • 2006–2008
    • Kitasato University
      Edo, Tōkyō, Japan
    • Nagoya University
      • Graduate School of Bio-Agricultural Sciences
      Nagoya, Aichi, Japan
  • 2007
    • Tokyo University of Agriculture and Technology
      Edo, Tōkyō, Japan
  • 2003
    • Purdue University
      West Lafayette, Indiana, United States
  • 1998
    • Kyoto University
      Kioto, Kyōto, Japan
    • Science University of Tokyo, Yamaguchi
      Yamaguti, Yamaguchi, Japan
  • 1987
    • Hamamatsu University School of Medicine
      Hamamatu, Shizuoka, Japan