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西脇 寿ニシワキ ヒサシ

所属部署
大学院農学研究科 生命機能学専攻
職名准教授
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Last Updated :2018/05/25

研究者基本情報

学歴

  • 1996年 - 2001年, 京都大学大学院, 農学研究科
  • 1992年 - 1996年, 京都大学, 農学部, 農芸化学科

学位

  • 京都大学博士(農学)

経歴

  •   2017年,  - 現在, 愛媛大学大学院, 農学研究科
  •   2015年,  - 2016年, Rothamsted Research, visiting researcher
  •   2008年,  - 2017年, 愛媛大学, 農学部
  •   2001年,  - 2008年, 近畿大学, 博士研究員

所属学協会

  • 日本農薬学会
  • 日本農芸化学会
  • 日本応用動物昆虫学会
  • Society for Invertebrate Pathology

研究活動情報

研究キーワード

    生物調節化学 農薬学

MISC

  • Structure-Antifungal Activity Relationship of Fluorinated Dihydroguaiaretic Acid Derivatives and Preventive Activity against Alternaria alternata Japanese Pear Pathotype
    Hisashi Nishiwaki, Shoko Nakazaki, Koichi Akiyama, Satoshi Yamauchi, Satoshi Yamauchi, Journal of Agricultural and Food Chemistry, 65,   2017年08月, © 2017 American Chemical Society. The structure-activity relationship of the antifungal fluorinated dihydroguaiaretic acid derivatives was evaluated. Some of the newly synthesized lignan compounds were found to show higher antifungal activity against phytopathogenic fungi such as Alternaria alternata (Japanese pear and apple pathotypes) and A. citri than the lead compound, 3-fluoro-3′-methoxylignan-4′-ol (3). The broad antifungal spectrum of 3′-hydroxyphenyl derivative 16 was observed, and the 3′-fluoro-4′-hydroxyphenyl derivative 38 was found to show the highest activity against the A. alternata Japanese pear pathotype, with an EC 50 value of 11 μM. The preventive effect of the potent lignan on the infection of A. alternata in the Japanese pear's leaves was also shown.
  • Conversion to purpurogallin, a key step in the mechanism of the potent xanthine oxidase inhibitory activity of pyrogallol
    Sari Honda, Yuya Fukuyama, Hisashi Nishiwaki, Akiko Masuda, Toshiya Masuda, Free Radical Biology and Medicine, 106,   2017年05月01日, © 2017 Elsevier Inc. In this study, the mechanism of the xanthine oxidase (XO) inhibitory activity of pyrogallol, the main inhibitor found in roasted coffee, was investigated. Pyrogallol was unstable and readily converted to purpurogallin in a pH 7.4 solution, a physiological model of human body fluids. The XO inhibitory activity of the produced purpurogallin was higher than that of pyrogallol, as evidenced by comparing their IC 50 values (0.2 µmol L −1 for purpurogallin, 1.6 µmol L −1 for pyrogallol). The XO activity of pyrogallol was enhanced by pre-incubation in pH 7.4 solution. Although the initial XO inhibitory activity of 4-methylpyrogallol was weak (IC 50 33.3 µmol L −1 ), its XO inhibitory activity was also enhanced by pre-incubation in the pH 7.4 solution. In contrast, 5-methylpyrogallol, which could not be transformed into corresponding purpurogallin derivatives, did not show XO inhibitory activity before or after incubation in pH 7.4 solution. Molecular docking simulations clarified that purpurogallins have stronger affinities for XO than corresponding pyrogallols. These results revealed that the potent XO inhibitory activity seemingly observed in pyrogallol is actually derived from its chemical conversion, under alkaline conditions, into purpurogallin.
  • Suppressive effect of ethanol extract from passion fruit seeds on IgE production
    Ai Mizusaki, Kosuke Nishi, Kosuke Nishi, Hisashi Nishiwaki, Momoko Ishida, Takeshi Tamamoto, Takuya Sugahara, Takuya Sugahara, Takuya Sugahara, Journal of Functional Foods, 32,   2017年05月, © 2017 An array of foodstuffs was screened for the suppressive effect on production of IgE, a key molecule in the type I allergic reaction, using U266 cells. An ethanol extract from passion fruit seeds (PFS) has emerged as a food material with the IgE production-suppressive effect as the result of screening. Real-time RT-PCR analysis revealed that the IgE production-suppressive effect was caused by downregulated IgE gene expression. In addition, PFS selectively suppressed IgE production and did not affect the production of IgG, IgA, or IgM by mouse splenocytes. Resveratrol and piceatannol were identified as bioactive ingredients contained in passion fruit seeds. The effect of oral administration of PFS, resveratrol, and piceatannol was evaluated using a mouse model of allergic contact dermatitis. Both stilbenoids significantly suppressed IgE production in orally administered mice. Overall results indicated that passion fruit seeds are a promising candidate with the antiallergy effect for development of functional foods.
  • Syntheses of cytotoxic novel arctigenin derivatives bearing halogen and alkyl groups on aromatic rings
    Satoshi Yamauchi, Tuti Wukirsari, Yoshiaki Ochi, Hisashi Nishiwaki, Kosuke Nishi, Takuya Sugahara, Takuya Sugahara, Koichi Akiyama, Taro Kishida, Taro Kishida, Bioorganic and Medicinal Chemistry Letters, 27,   2017年01月, © 2017 The new lignano-9,9′-lactones (α,β-dibenzyl-γ-butyrolactone lignans), which showed the higher cytotoxicity than arctigenin, were synthesized. The well-known cytotoxic arctigenin showed activity against HL-60 cells (EC 50 = 12 μM), however, it was inactive against HeLa cells (EC 50 > 100 μM). The synthesized (3,4-dichloro, 2′-b utoxy)-derivative 55 and (3,4-dichloro, 4′-butyl)-derivative 66 bearing the lignano-9,9′-lactone structures showed the EC 50 values of 10 μM and 9.4 μM against HL-60 cells, respectively. Against HeLa cells, the EC 50 value of the derivative 66 was 27 μM. By comparing the activities with the corresponding 9,9′-epoxy structure (tetrahydrofuran compounds), the importance of the lactone structure of 55 and 66 for the higher activities was shown. The substituents on the aromatic ring of the lignano-9,9′-lactones affected the cytotoxicity level, observing more than 10-fold difference.
  • Enantioselective syntheses of both enantiomers of 9′-dehydroxyimperanene and 7,8-dihydro-9′-dehydroxyimperanene and the comparison of biological activity between 9-norlignans and dihydroguaiaretic acids
    Satoshi Yamauchi, Ryosuke Tanimura, Hisashi Nishiwaki, Kosuke Nishi, Takuya Sugahara, Takuya Sugahara, Masafumi Maruyama, Yoshitaka Ano, Koichi Akiyama, Taro Kishida, Taro Kishida, Bioorganic and Medicinal Chemistry Letters, 26,   2016年07月, © 2016 Elsevier Ltd. All rights reserved. To estimate the effect of methyl group of dihydroguaiaretic acid, which shows many kinds of biological activities, on biological activity, both enantiomers of 9′-dehydroxyimperanene (5, 6) and 7,8-dihydro-9′-dehydroxyimperanene (7, 8) lacking one of the methyl groups of dihydroguaiaretic acid were synthesized. (S)-7,8-Dihydro-9′-dehydroxyimperanene (7) showed 4-6-fold higher cytotoxic activity than all stereoisomers of dihydroguaiaretic acid (2-4). The IC 50 values of (S)-7,8-dihydro-9′-dehydroxyimperanene (7) against HL-60 and HeLa cells were 6.1 μM and 5.6 μM, respectively. Though only one of three stereoisomers of dihydroguaiaretic acid showed antibacterial activity against a gram negative bacterium, both enantiomers of 5-8 showed antibacterial activity against a gram negative bacterium. This is a Letter on biological activity of 9-norlignan, in which one of methyl groups of lignan is absent.
  • Absorption, Metabolism, and Excretion by Freely Moving Rats of 3,4-DHPEA-EDA and Related Polyphenols from Olive Fruits (Olea europaea)
    Shunsuke Kano, Haruna Komada, Lina Yonekura, Akihiko Sato, Hisashi Nishiwaki, Hirotoshi Tamura, Journal of Nutrition and Metabolism, 2016,   2016年01月, © 2016 Shunsuke Kano et al. Absorption, metabolism, and excretion of 3,4-DHPEA-EDA, oleuropein, and hydroxytyrosol isolated from olive fruits were newly evaluated after oral and intravenous administration in freely moving rats cannulated in the portal vein, jugular vein, and bile duct. Orally administered 3,4-DHPEA-EDA, an important bioactive compound in olive pomace, was readily absorbed and metabolized to hydroxytyrosol, homovanillic acid, and homovanillyl alcohol, as shown by dose-normalized 4 h area under the curve (A U C 0 → 4 h /Dose) values of 27.7, 4.5, and 4.2 M·min·kg/mol, respectively, in portal plasma after oral administration. The parent compound 3,4-DHPEA-EDA was not observed in the portal plasma, urine, and bile after oral and intravenous administration. Additionally, hydroxytyrosol, homovanillic acid, and homovanillyl alcohol in the portal plasma after oral administration of hydroxytyrosol showed 51.1, 22.8, and 7.1 M·min·kg/mol A U C 0 → 4 h /Dose, respectively. When oleuropein, a polar glucoside, was injected orally, oleuropein in the portal plasma showed 0.9 M·min·kg/mol A U C 0 → 4 h /Dose. However, homovanillic acid was detected from oleuropein in only a small amount in the portal plasma. Moreover, the bioavailability of hydroxytyrosol and oleuropein for 4 hours was 13.1% and 0.5%, respectively. Because the amount of 3,4-DHPEA-EDA in olive fruits is about 2-3 times greater than that of hydroxytyrosol, the metabolites of 3,4-DHPEA-EDA will influence biological activities.
  • Effect of the structure of dietary epoxylignan on its cytotoxic activity: Relationship between the structure and the activity of 7,7′-epoxylignan and the introduction of apoptosis by caspase 3/7
    Tuti Wukirsari, Hisashi Nishiwaki, Kosuke Nishi, Takuya Sugahara, Takuya Sugahara, Koichi Akiyama, Taro Kishida, Taro Kishida, Satoshi Yamauchi, Satoshi Yamauchi, Bioscience, Biotechnology and Biochemistry, 80,   2016年01月01日, © 2016 Japan Society for Bioscience, Biotechnology, and Agrochemistry. We compared the cytotoxic activities of dietary epoxylignans and their stereoisomers and found (-)-verrucosin, which is (7S,7′R,8R,8′R)-7,7′-epoxylignan, to be the most cytotoxic epoxylignan against HeLa cells (IC 50 = 6.6 μM). On the other hand, the activity was about a factor of 10 less against HL-60. In this research on the relationship between the structure and cytotoxic activity of (-)-verrucosin 13, the 7-(4-methoxyphenyl)-7′-(3,4-dimethoxyphenyl) derivative 60, for which the activity (IC 50 = 2.4 μM) is three times greater than (-)-verrucosin 13, was discovered. The induction of apoptosis by caspase 3/7 was observed upon treatment with the (-)-verrucosin derivative.
  • New Sesquiterpene Lactone Dimer, Uvedafolin, Extracted from Eight Yacon Leaf Varieties (Smallanthus sonchifolius): Cytotoxicity in HeLa, HL-60, and Murine B16-F10 Melanoma Cell Lines
    Yurika Kitai, Kana Hayashi, Moe Otsuka, Hisashi Nishiwaki, Tatsuya Senoo, Tomohiko Ishii, Genta Sakane, Makoto Sugiura, Hirotoshi Tamura, Hirotoshi Tamura, Journal of Agricultural and Food Chemistry, 63,   2015年12月23日, © 2015 American Chemical Society. Uvedafolin, 1, a new sesquiterpene lactone dimer, was isolated from the leaves of Smallanthus sonchifolius with five related compounds, 2-6, and their cytotoxicity was assessed against three tumor cell lines (HeLa, HL-60, B16-F10 melanoma). The stereostructure of 1 was newly elucidated by ESI-TOF-MS, 1D/2D NMR, and single-crystal X-ray diffraction. Dimers 1 and 2 had the most effective IC 50 values, 0.2-1.9 μM, against the three tumor cell lines when compared with monomers 3-6 (IC 50 values 0.7-9.9 μM) and etoposide (IC 50 values 0.8-114 μM). The ester linkages of two sets of monomers, uvedalin, 5, and sonchifolin, 6, for 1, and enhydrin, 4, and sonchifolin, 6, for 2, as well as the acetyl group at the C-9 position, were essential for the high cytotoxicity. Dimers 1 and 2 would have potential as anticancer agents.
  • Structure-activity relationships of amide-phosphonate derivatives as inhibitors of the human soluble epoxide hydrolase
    In Hae Kim, Yong Kyu Park, Hisashi Nishiwaki, Bruce D. Hammock, Kosuke Nishi, Bioorganic and Medicinal Chemistry, 23,   2015年11月15日, © 2015 Elsevier Ltd. All rights reserved. Structure-activity relationships of amide-phosphonate derivatives as inhibitors of the human soluble epoxide hydrolase (sEH) were investigated. First, a series of alkyl or aryl groups were substituted on the carbon alpha to the phosphonate function in amide compounds to see whether substituted phosphonates can act as a secondary pharmacophore. A tert-butyl group (16) on the alpha carbon was found to yield most potent inhibition on the target enzyme. A 4-50-fold drop in inhibition was induced by other substituents such as aryls, substituted aryls, cycloalkyls, and alkyls. Then, the modification of the O-substituents on the phosphonate function revealed that diethyl groups (16 and 23) were preferable for inhibition to other longer alkyls or substituted alkyls. In amide compounds with the optimized diethylphosphonate moiety and an alkyl substitution such as adamantane (16), tetrahydronaphthalene (31), or adamantanemethane (36), highly potent inhibitions were gained. In addition, the resulting potent amide-phosphonate compounds had reasonable water solubility, suggesting that substituted phosphonates in amide inhibitors are effective for both inhibition potency on the human sEH and water solubility as a secondary pharmacophore.
  • Syntheses of natural 1,3-polyol/α-pyrone and its all stereoisomers to estimate antifungal activities against plant pathogenic fungi
    Satoshi Yamauchi, Yasuyoshi Isozaki, Hisashi Nishiwaki, Koichi Akiyama, Bioorganic and Medicinal Chemistry Letters, 25,   2015年06月, © 2015 Elsevier Ltd. All rights reserved. All stereoisomers of 1,3-polyol/α-pyrone 1-8 with more than 99% ee were synthesized to estimate the effect of stereochemistry on the antifungal activity. The absolute configuration of natural compound was determined as (6R,2′S,4′R)-2. The eight stereoisomers showed the antifungal activity against plant pathogenic Alternaria alternata Japanese pear pathotype and Colletotrichum lagenarium. The large difference of activity level was not observed between stereoisomers, showing 43-72% of growth ratio against control at 0.5 mM. The most potent stereoisomer was (6S,2′S,4′S)-8 and the activity of (6R,2′S,4′S)-1 was weakest against both fungi.
  • Evaluation of plant growth regulatory activity of furofuran lignan bearing a 7,9′:7′,9-diepoxy structure using optically pure (+)- and (-)-enantiomers
    Satoshi Yamauchi, Hiroaki Ichikawa, Hisashi Nishiwaki, Yoshihiro Shuto, Journal of Agricultural and Food Chemistry, 63,   2015年06月, © 2015 American Chemical Society. The plant growth regulatory activity of furofuran lignan (7,9′:7′,9-diepoxylignan) was evaluated by employing optically pure synthesized (+)- and (-)-enantiomers. (+)-Sesamin possessing a 3,4-methylenedioxy group on the aromatic rings and 7-aryl structure showed growth promotion activity against lettuce roots (EC < inf > 50 < /inf > = 0.50 mM); on the other hand, growth inhibitory activity was observed against lettuce shoots (EC < inf > 50 < /inf > = 0.38 mM). Against ryegrass shoots, (-)-sesamolin, which has 3,4-methylenedioxy groups on the aromatic rings and a 7-acetal structure, was effective in showing growth inhibitory activity (EC < inf > 50 < /inf > = 0.23 mM). Different activity levels were observed between (+)- and (-)-enantiomers. It was assumed that the 3,4-methylenedioxy group on the aromatic ring was more potent for the plant growth regulatory activity.
  • Identification and characterization of bifunctional proline racemase/hydroxyproline epimerase from archaea: Discrimination of substrates and molecular evolution
    Seiya Watanabe, Yoshiaki Tanimoto, Hisashi Nishiwaki, Yasuo Watanabe, PLoS ONE, 10,   2015年03月18日, © 2015 Watanabe et al. Proline racemase (ProR) is a member of the pyridoxal 5′-phosphate-independent racemase family, and is involved in the Stickland reaction (fermentation) in certain clostridia as well as the mechanisms underlying the escape of parasites fromhost immunity in eukaryotic Trypanosoma. Hydroxyproline epimerase (HypE), which is in the same protein family as ProR, catalyzes the first step of the trans-4-hydroxy-L-proline metabolism of bacteria. Their substrate specificities were previously considered to be very strict, in spite of similarities in their structures and catalytic mechanisms, and no racemase/epimerase fromthe ProR superfamily has been found in archaea.We here characterized the ProR-like protein (OCC-00372) from the hyperthermophilic archaeon, Thermococcus litoralis (TlProR). This protein could reversibly catalyze not only the racemization of proline, but also the epimerization of 4-hydroxyproline and 3-hydroxyproline with similar kinetic constants. Among the four (putative) ligand binding sites, one amino acid substitution was detected between TlProR (tryptophan at the position of 241) and natural ProR (phenylalanine). TheW241F mutant showed a significant preference for proline over hydroxyproline, suggesting that this (hydrophobic and bulky) tryptophan residue played an importance role in the recognition of hydroxyproline (more hydrophilic and bulky than proline), and substrate specificity for hydroxyproline was evolutionarily acquired separately between natural HypE and ProR. A phylogenetic analysis indicated that such unique broad substrate specificity was derived from an ancestral enzyme of this superfamily.
  • Docking model of the nicotinic acetylcholine receptor and nitromethylene neonicotinoid derivatives with a longer chiral substituent and their biological activities
    Hikaru Nagaoka, Hisashi Nishiwaki, Takuya Kubo, Miki Akamatsu, Satoshi Yamauchi, Yoshihiro Shuto, Bioorganic and Medicinal Chemistry, 23,   2015年02月, © 2014 Elsevier Ltd. All rights reserved. In the present study, nitromethylene neonicotinoid derivatives possessing substituents that contain a sulfur atom, oxygen atom or aromatic ring at position 5 on the imidazolidine ring were synthesized to evaluate their affinity for the nicotinic acetylcholine receptor (nAChR) and their insecticidal activity against adult female houseflies. Comparing the receptor affinity of the alkylated derivative with the receptor affinity of compounds possessing either ether or thioether groups revealed that conversion of the carbon atom to a sulfur atom did not influence the receptor affinity, whereas conversion to an oxygen atom was disadvantageous for the receptor affinity. The receptor affinity of compounds possessing a benzyl or phenyl group was lower than that of the unsubstituted compound. Analysis of the three-dimensional quantitative structure-activity relationship using comparative molecular field analysis demonstrated that steric hindrance of the receptor should exist around the C3 of an n-butyl group attached at position 5 on the imidazolidine ring. A docking study of the nAChR-ligand model suggested that the ligand-binding region expands as the length of the substituent increases by brushing against the amino acids that form the binding region. The insecticidal activity of the compounds was positively correlated with the receptor affinity by considering log P and the number of heteroatoms, including sulfur and oxygen atoms, in the substituents, suggesting that the insecticidal activity is influenced by the receptor affinity, hydrophobicity, and metabolic stability of the compounds.
  • Revised stereochemistry of ficifolidione and its biological activities against insects and cells
    Hisashi Nishiwaki, Satomi Fujiwara, Tuti Wukirsari, Hiroyuki Iwamoto, Shigeki Mori, Kosuke Nishi, Takuya Sugahara, Satoshi Yamauchi, Yoshihiro Shuto, Journal of Natural Products, 78,   2015年01月, © 2014 The American Chemical Society and American Society of Pharmacognosy. Ficifolidione (1), a moderately active insecticidal compound from two species of Myrtaceae, and its derivatives were synthesized to evaluate their insecticidal activity. X-ray crystallographic analyses and specific rotation values of ficifolidione and its C-4 (2) demonstrated that the structure of ficifolidione differs from the reported absolute structure; that is, the C-4 configuration of ficifolidione should have an S configuration. The reported insecticidal activity of ficifolidione (1) and its C-4 epimer (2) against adult houseflies (Musca domestica), mosquito larvae (Culex pipiens), and cutworms (Spodoptera litura) was not observed. The cytotoxicities of ficifolidione and its derivatives (1-4) against four cell lines, Sf9, Colon26, HL60, and Vero, were also measured because ficifolidione has a phloroglucinol-derived moiety, a motif that is often present in the structure of cytotoxic chemicals. Compound 1 exhibited IC 50 values of ca. 32, 9, 3, and 12 μM for Sf9, Colon26, HL60, and Vero cells, respectively, indicating that ficifolidione possesses selective cytotoxicity against the four cell lines. In HL60 cells treated with 1, DNA fragmentation and the activation of procaspase 3 were observed, suggesting that the cytotoxicity is induced by apoptosis.
  • Stereoselective syntheses of cryptocarya diacetate and all its stereoisomers in optically pure forms
    Satoshi Yamauchi, Hiroki Nishimura, Hisashi Nishiwaki, Bioscience, Biotechnology and Biochemistry, 79,   2015年01月, © 2014 Japan Society for Bioscience Biotechnology and Agrochemistry. Cryptocarya diacetate and each of its stereoisomers were stereoselectively synthesized in 8-16 steps. One of the three chiral carbons was converted from the chiral center of a yeast-reduction product. The other two chiral carbons were constructed by employing stereoselective allylation and syn-and anti-1,3-reductions. The enantiomeric excesses of the synthesized cryptocarya diacetate and its stereoisomers were determined to be more than 99%ee using a chiral column.
  • Acute larvicidal activity against mosquitoes and oxygen consumption inhibitory activity of dihydroguaiaretic acid derivatives
    Hisashi Nishiwaki, Yoshimi Tabara, Taro Kishida, Taro Kishida, Kosuke Nishi, Yoshihiro Shuto, Takuya Sugahara, Takuya Sugahara, Satoshi Yamauchi, Satoshi Yamauchi, Journal of Agricultural and Food Chemistry, 63,   2015年01月01日, © 2015 American Chemical Society. (-)-Dihydroguaiaretic acid (DGA) and its derivatives having 3-hydroxyphenyl (3-OH-DGA) and variously substituted phenyl groups instead of 3-hydroxy-4-methoxyphenyl groups were synthesized to measure their larvicidal activity against the mosquito Culex pipiens Linnaeus, 1758 (Diptera: Culicidae). Compared with DGA and 3-OH-DGA (LC 50 (M), 3.52 × 10 -5 and 4.57 × 10 -5 , respectively), (8R,8′R)-lignan-3-ol (3) and its 3-Me (10), 2-OH (12), 3-OH (13), and 2-OMe (15) derivatives showed low potency (ca. 6-8 × 10 -5 M). The 4-Me derivative (11) showed the lowest potency (12.1 × 10 -5 M), and the 2-F derivative (4) showed the highest (2.01 × 10 -5 M). All of the synthesized compounds induced an acute toxic symptom against mosquito larvae, with potency varying with the type and position of the substituents. The 4-F derivative (6), which killed larvae almost completely within 45 min, suppressed the O 2 consumption of the mitochondrial fraction, demonstrating that this compound inhibited mitochondrial O 2 consumption contributing to a respiratory inhibitory activity.
  • Structure-plant phytotoxic activity relationship of 7,7′-epoxylignanes, (+)- and (-)-verrucosin: Simplification on the aromatic ring substituents
    Satoshi Yamauchi, Kumiko Nakayama, Hisashi Nishiwaki, Yoshihiro Shuto, Bioorganic and Medicinal Chemistry Letters, 24,   2014年10月, © 2014 Elsevier Ltd. All rights reserved. The synthesized 7-aryl derivatives of (7R,7′S,8S,8′S)-(+)-verrucosin were applied to growth inhibitory activity test against ryegrass at 1 mM. 7-(3-Ethoxy-4-hydroxyphenyl) derivative 12 and 7-(2-hydroxyphenyl) derivative 4 showed comparable activity to those of (+)-verrucosin against the root (-95%) and the shoot (-60%), respectively. The growth inhibitory activity test against lettuce using synthesized 7-aryl derivatives of (7S,7′R,8R,8′R)-(-)-verrucosin at 1 mM showed that the activities of 7-(3-hydroxyphenyl) derivative 20 and 7-(3-ethoxy-4-hydroxyphenyl) derivative 28 are similar to that of (-)-verrucosin against the root (-95%). Against the shoot, 7-(3-hydroxyphenyl) derivative 20 showed higher activity (-80%) than that of (-)-verrucosin (-60%). As the next step, (7S,7′R,8R,8′R)-7-(3-hydroxyphenyl)-7′-aryl-(-)-verrucosin derivatives, in which the most effective 3-hydroxyphenyl group is employed as 7-aromatic ring, were synthesized for the assay against lettuce. In this experiment, 7′-(2-hydroxyphenyl) derivative 37 and 7′-(3-hydroxyphenyl) derivative 38 showed similar activity to that of derivative 20. The effect of 7- and 7′-aryl structures of 7,7′-epoxylignanes on the plant growth inhibitory activity was clarified. The 7- and 7′-aryl structures were simplified to show comparable activity to or higher activity than that of (-)-verrucosin. The plant growth inhibitory activity of a nutmeg component, (+)-fragransin C 3b , was estimated as -80% inhibition at 1 mM against ryegrass roots.
  • Cytotoxic activity of butane type of 1,7-seco-2,7′-cyclolignanes and apoptosis induction by Caspase 9 and 3
    Tuti Wukirsari, Hisashi Nishiwaki, Kosuke Nishi, Takuya Sugahara, Takuya Sugahara, Koichi Akiyama, Taro Kishida, Taro Kishida, Satoshi Yamauchi, Satoshi Yamauchi, Bioorganic and Medicinal Chemistry Letters, 24,   2014年09月01日, All stereoisomers of methoxybutane and fluorobutane type of 1,7-seco-2,7′-cyclolignane were synthesized and cytotoxic activities of these compounds were compared with those of all stereoisomers of butane and butanol type compounds. Both enantiomers of butane type secocyclolignane showed higher cytotoxic activity (IC 50 = 16-20 μM) than methoxy type compounds, whereas none was observed for all the stereoisomers of butanol type secocyclolignane, however, (-)-Kadangustin J showed stereospecific cytotoxic activity (IC 50 = 47-67 μM). Since (R)-9′-fluoro derivative 23 was most potent (IC 50 = 19 μM) among the corresponding fluoro stereoisomers, (R)-9′-alkyl derivatives were synthesized, hydrophobic 9′-heptyl derivative 27 showing highest activity (IC 50 = 3.7 μM against HL-60, IC 50 = 3.1 μM against HeLa) in this experiment. Apoptosis induction caused by Caspase 3 and 9 for (R)-9′-heptyl derivative 27 was observed in the research on the mechanism. A degradation of DNA into small fragments was also shown by DNA ladder assay. © 2014 Elsevier Ltd. All rights reserved.
  • Cytotoxic activity of dietary lignan and its derivatives: Structure-cytotoxic activity relationship of dihydroguaiaretic acid
    Tuti Wukirsari, Hisashi Nishiwaki, Kosuke Nishi, Takuya Sugahara, Takuya Sugahara, Koichi Akiyama, Taro Kishida, Taro Kishida, Satoshi Yamauchi, Satoshi Yamauchi, Journal of Agricultural and Food Chemistry, 62,   2014年06月11日, Cytotoxic activities of synthesized lignan derivatives were estimated by WST-8 reduction assay against HL-60 and HeLa cells to show the structure-activity relationship. The activities of some effective compounds were examined against Colon 26 and Vero cells. Dietary secoisolariciresinol (SECO, 1) and its metabolite, 9,9′-anhydrosecoisolariciresinol (2), did not show the cytotoxic activity. On the other hand, all stereoisomers of dihydroguaiaretic acid (DGA, 9,9′-dehydroxysecoisolariciresinol, 3-5) exhibited the activity (IC 50 : around 30 μM). The IC 50 value of (8R,8′R)-9-butyl DGA derivative 13 was around 6 μM. This fact means that the hydrophobic group was advantageous for higher activity at 9- and 9′-positions. By the evaluation of the effect of 7and 7′-aryl group on the activity, we discovered the highest activity of (8R,8′R)-7-(3- hydroxy-4-methoxyphenyl)-7′-(2-ethoxyphenyl) DGA derivative 47 showing around 1 μM of IC 50 value, which is about 24-fold higher activity than that of natural (8R,8′R)-DGA. The derivative of dietary lignan showed the high cytotoxic activity. © 2014 American Chemical Society.
  • Structure-activity relationships of substituted oxyoxalamides as inhibitors of the human soluble epoxide hydrolase
    In Hae Kim, In Hee Lee, Hisashi Nishiwaki, Bruce D. Hammock, Kosuke Nishi, Bioorganic and Medicinal Chemistry, 22,   2014年02月01日, We explored both structure-activity relationships among substituted oxyoxalamides used as the primary pharmacophore of inhibitors of the human sEH and as a secondary pharmacophore to improve water solubility of inhibitors When the oxyoxalamide function was modified with a variety of alkyls or substituted alkyls, compound 6 with a 2-adamantyl group and a benzyl group was found to be a potent sEH inhibitor, suggesting that the substituted oxyoxalamide function is a promising primary pharmacophore for the human sEH, and compound 6 can be a novel lead structure for the development of further improved oxyoxalamide or other related derivatives In addition, introduction of substituted oxyoxalamide to inhibitors with an amide or urea primary pharmacophore produced significant improvements in inhibition potency and water solubility In particular, the N,N,O-trimethyloxyoxalamide group in amide or urea inhibitors (26 and 31) was most effective among those tested for both inhibition and solubility The results indicate that substituted oxyoxalamide function incorporated into amide or urea inhibitors is a useful secondary pharmacophore, and the resulting structures will be an important basis for the development of bioavailable sEH inhibitors © 2014 Elsevier Ltd All rights reserved.
  • Rosmarinic acid extract for antioxidant, antiallergic, and α-glucosidase inhibitory activities, isolated by supramolecular technique and solvent extraction from Perilla leaves
    Fengxian Zhu, Takayuki Asada, Akihiko Sato, Yoriko Koi, Hisashi Nishiwaki, Hirotoshi Tamura, Hirotoshi Tamura, Journal of Agricultural and Food Chemistry, 62,   2014年01月29日, Rosmarinic acid extract with potent biological activities was successfully isolated by supramolecular technique and solvent extraction from Perilla leaves. By the supramolecular complex which was formed from flavocommelin and Perilla leaf extract as initial materials, the supernatant containing rosmarinic acid was isolated. Rosmarinic acid extract (62.9 ± 4.5% purity) was partly purified by partitioning ethyl acetate and water. Rosmarinic acid extract exhibited high total phenolic content of 433.9 ± 58.6 μg/mg of gallic acid equivalent, effective DPPH radical scavenging activity (SC 50 of 5.5 ± 0.2 μg/mL), antiallergic activity (IC 50 of 52.9 ± 6.7 μg/mL), and α-glucosidase inhibitory activity (IC 50 of 0.23 ± 0.01 mg/mL). Rosmarinic acid extract shows high potential for diabetes mellitus and allergy treatments by inhibiting α-glucosidase activity and measuring β-hexosaminidase, related to life-style disease. © 2014 American Chemical Society.
  • Synthesis of all stereoisomers of 3,3′-dimethoxy-7,7′- epoxylignane-4,4′-diol and their plant growth inhibitory activity
    Hisashi Nishiwaki, Kumiko Nakayama, Yoshihiro Shuto, Satoshi Yamauchi, Journal of Agricultural and Food Chemistry, 62,   2014年01月22日, All stereoisomers of 3,3′-dimethoxy-7,7′-epoxylignane-4, 4′-diol were synthesized to examine the effect of stereochemistry on their plant growth inhibitory activity using lettuce and Italian ryegrass. The effect of structural modifications such as dehydroxylation, methoxylation and hydroxylation at the 9- and 9′-positions of the lignans on the activity was also studied. Most of the epoxylignanes showed higher plant growth inhibitory potency against ryegrass than against lettuce, and the inhibitory activity varied depending on the configurations of each position of the tetrahydrofuran ring (7-, 7′-, 8-, and 8′-positions of the epoxylignanes). Among the 9,9′-position-modified derivatives, the dehydroxy derivatives showed the highest potency. These results suggested that the plant growth inhibitory activity should be influenced by the structure of the epoxylignanes. © 2013 American Chemical Society.
  • Syntheses of all the stereoisomers of butanol type 1,7-seco-2,7′-cyclolignane
    Satoshi Yamauchi, Chisato Tomiyama, Tuti Wukirsari, Hisashi Nishiwaki, Bioscience, Biotechnology and Biochemistry, 78,   2014年01月, © 2014 Japan Society for Bioscience, Biotechnology, and Agrochemistry. All the stereoisomers of butanol type 1,7-seco-2,7′-cyclolignane were stereoselectively synthesized by employing (S)- and (R)-Evans' auxiliaries to construct the stereochemistry. (+)- and (-)-Kadangustin J and their diastereomers were also prepared. The optical purity of the synthesized butanol type 1,7-seco-2,7′-cyclolignane was more than 99%ee.
  • A new diterpene from Litsea cubeba fruits: Structure elucidation and capability to induce apoptosis in HeLa cells
    Piyapat Trisonthi, Akihiko Sato, Hisashi Nishiwaki, Hirotoshi Tamura, Hirotoshi Tamura, Molecules, 19,   2014年01月01日, A new diterpene, identified as (+)-6-(4-hydroxy-4-methyl-2-pentenoyl)-4,6- dimethyl-5-(3-methyl-2-butenyl)-1,3-cyclohexadienecarbaldehyde (1, cubelin), was isolated from a methanol extract of Litsea cubeba fruits by normal phase column chromatography and purified by preparative HPLC. The structure elucidation was conducted by spectroscopic methods (UV, IR, ESI-TOF-MS, 1-D and 2-D NMR). Cubelin exhibited activity against HeLa cell viability and proliferation. The cells also exhibited changes in nuclear morphology which are hallmarks of apoptotic cell death. The presence of cleaved caspase-3/-7, caspase-8 and caspase-9 in the cubelin treated population indicated the potential of the compound to induce apoptosis in HeLa cells via both intrinsic and extrinsic pathways. © 2014 by the authors.
  • Structure-plant growth inhibitory activity relationship of lariciresinol
    Satoshi Yamauchi, Mitsuko Kumamoto, Yuki Ochi, Hisashi Nishiwaki, Yoshihiro Shuto, Journal of Agricultural and Food Chemistry, 61,   2013年12月, The syntheses of 55 lariciresinol derivatives containing derivatives on the 9-position and an aryl group at both 7- and 7′-positions were successful to examine the effect of structure of (-)-lariciresinol (1) on plant growth regulatory activity. (-)-(7R,8R,8′S)-9-Dehydroxylariciresinol 9 showed activity 2-fold more potent than that of natural (-)-lariciresinol (1) and -95% growth inhibitory activity to negative control against rye grass root at 1 mM. The derivatives bearing hydrophobic and smaller groups at the 9-position showed higher activity. The importance of 4- and 4′-hydroxy groups and 3- and 3′-small hydrophobic groups on 7- and 7′-phenyl groups for higher activity was also suggested. © 2013 American Chemical Society.
  • Quantitative structure-activity relationship analysis of antifungal (+)-dihydroguaiaretic acid using 7-phenyl derivatives
    Ayaka Hasebe, Hisashi Nishiwaki, Koichi Akiyama, Takuya Sugahara, Taro Kishida, Satoshi Yamauchi, Journal of Agricultural and Food Chemistry, 61,   2013年09月11日, The relationship between antifungal activity against Alternaria alternata and structure on the 7-phenyl group of (+)-dihydroguaiaretic acid ((+)-DGA) was clarified by employing 38 synthesized (+)-DGA derivatives. The results were identified by quantitative structure-activity relationship (QSAR) analysis employing the Hansch-Fujita method. Some compounds showed higher activity than (+)-DGA. The compound showing highest activity was 3,5-difluorophenyl derivative 37. It was suggested that the small electron-withdrawing group at the meta-position of the 7-phenyl group is important for the higher activity by antifungal test and Hansch-Fujita analysis. The whitening activity of 3-hydroxy-4-methoxyphenyl derivative 28, 3-hydroxy-4-ethoxyphenyl derivative 29, and 3-hydroxy-4-isopropoxyphenyl derivative 30 against A. alternata Japanese pear pathotype was also discovered. © 2013 American Chemical Society.
  • Structure-cytotoxic activity relationship of sesquilignan, morinol A
    Satoshi Yamauchi, Saya Kawahara, Tuti Wukirsari, Hisashi Nishiwaki, Kosuke Nishi, Takuya Sugahara, Takuya Sugahara, Koichi Akiyama, Taro Kishida, Taro Kishida, Bioorganic and Medicinal Chemistry Letters, 23,   2013年09月, The cytotoxic activities of sesquilignans, (7S,8S,7′R,8′R)- and (7R,8R,7′S,8′S)-morinol A and (7S,8S,7′S,8′S)- and (7R,8R,7′R,8′R)-morinol B were compared, showing no significant difference between stereoisomers (IC 50 = 24-35 μM). As a next stage, the effect of substituents at 7, 7′, and 7″-aromatic ring on the activity was evaluated to find out the higher activity of (7S,8S,7′R,8′R)-7,7′,7″-phenyl derivative 18 (IC 50 = 6-7 μM). In the research on the structure-activity relationship of 7″-position of (7S,8S,7′R,8′R)-7,7′, 7″-phenyl derivative 18, the most potent compounds were 7,7′,7″-phenyl derivative 18 (IC 50 = 6 μM) against HeLa cells. Against HL-60 cells, 7″-(4-nitrophenyl)-7,7′-phenyl derivative 33 and 7″-hexyl-7,7′-phenyl derivative 37 (IC 50 = 5 μM) showed highest activity. We discovered the compounds showed four to sevenfold potent activity than that of natural (7S,8S,7′R,8′R)-morinol A. It was also confirmed that the 7′-benzylic hydroxy group have an important role for exhibiting activity, on the other hand, the resonance system of cinnamyl structure is not crucial for the potent activity. © 2013 Elsevier Ltd. All rights reserved.
  • First discovery of insecticidal activity of 9,9′-epoxylignane and dihydroguaiaretic acid against houseflies and the structure-activity relationship
    Tuti Wukirsari, Hisashi Nishiwaki, Ayaka Hasebe, Yoshihiro Shuto, Satoshi Yamauchi, Journal of Agricultural and Food Chemistry, 61,   2013年05月08日, The insecticidal activity of (-)-(8R,8′R)-3,3′-dimethoxy-9, 9′-epoxylignane-4,4′-diol (1) against houseflies was clarified for the first time. The activities of other stereoisomers were weaker than that of the (8R,8′R)-stereoisomer. In the course of research into structure-activity relationships involving 30 newly synthesized (8R,8′R)-derivatives, 5-fold higher activity (ED 50 = 0.91 nmol/fly) was observed for (-)-(8R,8′R)-3,3′,4-trimethoxy-9, 9′-epoxylignan-4′-ol (21) than for the naturally occurring compound (1). The activity of 1 was weaker than that of (-)-(8R,8′R)- dihydroguaiaretic acid ((-)-DGA) (4); however, compound 21 showed almost the same level of activity as 4. © 2013 American Chemical Society.
  • Synthesis of imidacloprid derivatives with a chiral alkylated imidazolidine ring and evaluation of their insecticidal activity and affinity to the nicotinic acetylcholine receptor
    Hisashi Nishiwaki, Mituhiro Kuriyama, Hikaru Nagaoka, Akira Kato, Miki Akamatsu, Satoshi Yamauchi, Yoshihiro Shuto, Bioorganic and Medicinal Chemistry, 20,   2012年11月01日, A series of imidacloprid (IMI) derivatives with an alkylated imidazolidine ring were asymmetrically synthesized to evaluate their insecticidal activity against adult female housefly, Musca domestica, and affinity to the nicotinic acetylcholine receptor of the flies. The bulkier the alkyl group, the lower was the receptor affinity, but the derivatives methylated and ethylated at the R-5-position of the imidazolidine ring were equipotent to the unsubstituted compound. Quantitative structure-activity relationship (QSAR) analysis of the receptor affinity demonstrated that the introduction of a substituent into the imidazolidine ring was fundamentally disadvantageous, but the introduction of a substituent at the R-5-position was permissible in the case of its small size. The binding model of the synthesized derivatives with the receptor supported the QSAR analysis, indicating the existence of space for a short alkyl group around the R-5-position in the ligand-binding site. In addition, positive correlation was observed between the insecticidal activity and receptor affinity, suggesting that the receptor affinity was the primary factor in influencing the insecticidal activity even if the imidazolidine ring was modified. © 2012 Elsevier Ltd. All rights reserved.
  • Effect of substituents at phenyl group of 7,7′-dioxo-9,9′- epoxylignane on antifungal activity
    Hisashi Nishiwaki, Maya Ouchi, Junko Matsugi, Koichi Akiyama, Takuya Sugahara, Takuya Sugahara, Taro Kishida, Taro Kishida, Satoshi Yamauchi, Bioorganic and Medicinal Chemistry Letters, 22,   2012年11月, Using 21 newly synthesized 7,7′-dioxo-9,9′-epoxylignane derivatives having a modified 7-phenyl group, we examined the relationship between their structure and antifungal activity against plant pathogens such as Bipolaris oryzae to determine the effects of various substituents on the antifungal activity. Compared with the lead compound having a 4-OH-3-CH 3 O-phenyl moiety, several analogs showed higher antifungal activity against B. oryzae, including the compound having an unsubstituted phenyl group and those having either of the following phenyl substituents: 2-OH, 4-CH 3 O, 4-C 2 H 5 O, 4-n-C 3 H 7 O, 4-n-C 4 H 9 O, 4-CF 3 O, 4-C 2 H 5 , or 4-Cl. On the other hand, the activity of compounds having a branched substituent, such as 4-i-C 3 H 7 O or 4-i-C 3 H 7 , on the 7-phenyl group or a multi-substituted phenyl group was equipotent or inferior to that of the lead compound. These results as well as correlations between the antifungal activity of the test compounds and the physicochemical parameters of the varied substituents suggest that the position of substitution on the 7-phenyl group and the incorporation of substituents with optimal physicochemical properties are important for exerting the antifungal activity. © 2012 Elsevier Ltd. All rights reserved.
  • Total syntheses of (-)- and (+)-boronolide and their plant growth-inhibitory activity
    Satoshi Yamauchi, Satoshi Yamauchi, Yasuyoshi Isozaki, Hiroki Nishimura, Tomoko Tsuda, Hisashi Nishiwaki, Yoshihiro Shuto, Bioscience, Biotechnology and Biochemistry, 76,   2012年10月01日, Optically pure (+)- and (-)-boronolides were stereoselectively synthesized from yeast reductive products which had been obtained by yeast reduction of one common racemic substrate. The lactone structure of boronolide was constructed by Baeyer-Villiger oxidation. The stereochemistry of the yeast reduction products was studied to obtain the stereocenters at 5 positions of the dodecanolides of (+)- and (-)-boronolides. The stereochemistry of the 6 and 7 positions was obtained by AD-mix-α or β oxidation. The chiral center at the 8 position was constructed by employing (R)-(+)- or (S)-(-)-2-methyl-CBS- oxazaborolidine reduction or the Mitsunobu reaction. The plant growth-inhibitory activity against Echinochloa crusgalli L. of naturally occurring (+)-boronolide was higher than that of the (-)-boronolide.
  • Identification and characterization of D-hydroxyproline dehydrogenase and δ1-pyrroline-4-hydroxy-2-carboxylate deaminase involved in novel L-hydroxyproline metabolism of bacteria: Metabolic convergent evolution
    Seiya Watanabe, Daichi Morimoto, Fumiyasu Fukumori, Hiroto Shinomiya, Hisashi Nishiwaki, Miyuki Kawano-Kawada, Miyuki Kawano-Kawada, Yuuki Sasai, Yuzuru Tozawa, Yasuo Watanabe, Journal of Biological Chemistry, 287,   2012年09月21日, L-Hydroxyproline (4-hydroxyproline) mainly exists in collagen, and most bacteria cannot metabolize this hydroxyamino acid. Pseudomonas putida and Pseudomonas aeruginosa convert L-hydroxyproline to α-ketoglutarate via four hypothetical enzymatic steps different from known mammalian pathways, but the molecular background is rather unclear. Here, we identified and characterized for the first time two novel enzymes, D-hydroxyproline dehydrogenase and Δ 1 -pyrroline-4-hydroxy-2-carboxylate (Pyr4H2C) deaminase, involved in this hypothetical pathway. These genes were clustered together with genes encoding other catalytic enzymes on t he bacterial genomes. D-Hydroxyproline dehydrogenases from P. putida and P. aeruginosa were completely different from known bacterial proline dehydrogenases and showed similar high specificity for substrate (D-hydroxyproline) and some artificial electron acceptor(s). On the other hand, the former is a homomeric enzyme only containing FAD as a prosthetic group, whereas the latter is a novel heterododecameric structure consisting of three different subunits (α 4 β 4 γ 4 ), and two FADs, FMN, and [2Fe-2S] iron-sulfur cluster were contained in αβγ of the heterotrimeric unit. These results suggested that the L-hydroxyproline pathway clearly evolved convergently in P. putida and P. aeruginosa. Pyr4H2C deaminase is a unique member of the dihydrodipicolinate synthase/N-acetylneuraminate lyase protein family, and its activity was competitively inhibited by pyruvate, a common substrate for other dihydrodipicolinate synthase/N-acetylneuraminate lyase proteins. Furthermore, disruption of Pyr4H2C deaminase genes led to loss of growth on L-hydroxyproline (as well as D-hydroxyproline) but not L- and D-proline, indicating that this pathway is related only to L-hydroxyproline degradation, which is not linked to proline metabolism. © 2012 by The American Society for Biochemistry and Molecular Biology, Inc.
  • Stereoselective syntheses of all stereoisomers of lariciresinol and their plant growth inhibitory activities
    Hisashi Nishiwaki, Mitsuko Kumamoto, Yoshihiro Shuto, Satoshi Yamauchi, Journal of Agricultural and Food Chemistry, 59,   2011年12月28日, All stereoisomers of lariciresinol were synthesized to examine the effect of stereochemistry on plant growth. Configuration of benzylic 7-positions was constructed through S N 1 or S N 2 intramolecular etherification. 8- and 8′-position configurations were established from the starting material except for all cis stereoisomers, the 8-position configurations of which were achieved by employing stereoselective hydroboration. (-)-Lariciresinol and its 7S,8S,8′R stereoisomer inhibited the root growth of Italian ryegrass to 51-55% relative to the negative control, whereas other stereoisomers had less effect. These results demonstrate that the stereochemistry of lignans is one of the important factors influencing their inhibitory activity. © 2011 American Chemical Society.
  • Larvicidal activity of (-)-dihydroguaiaretic acid derivatives against culex pipiens
    Hisashi Nishiwaki, Ayaka Hasebe, Yuya Kawaguchi, Miki Akamatsu, Yoshihiro Shuto, Satoshi Yamauchi, Bioscience, Biotechnology and Biochemistry, 75,   2011年09月, The larvicidal activity against Culex pipiens of all stereoisomers of dihydroguaiaretic acid (DGA) and secoisolariciresinol was measured, and these DGAs were found to be potent. Sixteen (-)-DGA derivatives were then newly synthesized to analyze their structureactivity relationship. Two derivatives monohydroxylated at the 3- or 4-position of the 7-phenyl group of DGA induced acute paralytic activity in the mosquitoes. Derivatives with several hydroxyl groups had lower activity than the natural compound, suggesting that hydrophobicity was probably an important factor for their insecticidal activity.
  • Syntheses of secocyclolignanes and comparative antioxidative activity between secocyclolignane and the dibenzyl type of lignan
    Masao Morita, Hisashi Nishiwaki, Yoshimi Shingai, Aya Fujimoto, Toshiya Masuda, Satoshi Yamauchi, Bioscience, Biotechnology and Biochemistry, 75,   2011年06月, The antioxidative activity of secocyclolignanes was compared with that of the corresponding dibenzyl lignans for the first time. The radical scavenging activity of the secocyclolignanes was weaker than that of the corresponding dibenzyl lignans, the butane diol type showing the highest activity. The butane type of secocyclolignane exhibited the highest antioxidant activity of the unsaturated fatty acid.
  • Immunomodulatory effect of (-)-matairesinol in vivo and ex vivo
    Manami Yamawaki, Kosuke Nishi, Sogo Nishimoto, Satoshi Yamauchi, Koichi Akiyama, Taro Kishida, Masafumi Maruyama, Hisashi Nishiwaki, Takuya Sugahara, Bioscience, Biotechnology and Biochemistry, 75,   2011年06月, Matairesinol is one of the lignan compounds found in a variety of plant foodstuffs. We investigated the immunomodulatory effects of (-)-matairesinol in vivo and ex vivo by using mice. Although we found no significant differences in the IgG, IgA and IgM levels in the serum, the IgE level was strongly suppressed by the uptake of (-)-matairesinol in both intact and ovalbumin-immunized mice. The immunoglobulin produced by lymphocytes from the spleen was not activated by the intake of (-)-matairesinol. However, lymphocytes in such gut-associated lymphatic tissues as Peyer's patches and mesenteric lymph nodes were activated by the administration of (-)-matairesinol.
  • Affinity to the nicotinic acetylcholine receptor and insecticidal activity of chiral imidacloprid derivatives with a methylated imidazolidine ring
    Hisashi Nishiwaki, Hikaru Nagaoka, Mituhiro Kuriyama, Satoshi Yamauchi, Yoshihiro Shuto, Bioscience, Biotechnology and Biochemistry, 75,   2011年05月16日, Four imidacloprid derivatives with an asymmetrically methylated imidazolidine ring were synthesized. Their affinity to the nicotinic acetylcholine receptor of housefly Musca domestica and insecticidal activity against the housefly were measured. The compound with a 5R-methylated imidazolidine ring demonstrated intrinsic activity comparable to that of the unsubstituted compound. Most of the compounds were synergized by oxygenase inhibitors.
  • Antifungal activity of morinol B derivatives of tetrahydropyran sesquilignan
    Kenta Masuda, Hisashi Nishiwaki, Koichi Akiyama, Satoshi Yamauchi, Masafumi Maruyama, Takuya Sugahara, Taro Kishida, Bioscience, Biotechnology and Biochemistry, 74,   2010年11月, The relationship between the structure of naturally occurring (7R,70R,8R,80R)-morinol B and its antifungal activity was examined. 3-Demethoxy morinol B showed much higher activity than the natural compound. The activity of the 4-butoxy-3-demethoxy derivative was higher than that of 3-demethoxy morinol B.
  • IgE-suppressive activity of (-)-Matairesinol and its structure-activity relationship
    Saya Kawahara, Ipei Iwata, Eriko Fujita, Manami Yamawaki, Hisashi Nishiwaki, Takuya Sugahara, Satoshi Yamauchi, Koichi Akiyama, Taro Kishida, Bioscience, Biotechnology and Biochemistry, 74,   2010年10月, The IgE-suppressive activity of (-)-matairesinol is demonstrated, and the structure-activity relationship of (-)-matairesinol clarified. 3',4-Dihydroxy-3,4'-dime-thoxylignano-9,9'-lactone showed higher IgE-suppressive activity than (-)-matairesinol without any cytotoxic activity. Some derivatives bearing a longer and more bulky alkoxy group at the 3 or 4 position showed IgE-accelerative activity.
  • Antimicrobial activity of stereoisomers of butane-type lignans
    Yuya Kawaguchi, Satoshi Yamauchi, Kenta Masuda, Hisashi Nishiwaki, Koichi Akiyama, Masafumi Maruyama, Takuya Sugahara, Taro Kishida, Yojiro Koba, Bioscience, Biotechnology and Biochemistry, 73,   2009年09月, The relationship between the stereochemistry and antimicrobial activity of butane-type lignans was clarified. All stereoisomers of dihydroguaiaretic acid (DGA) showed both antibacterial and antifungal activity. The (+)- and (-)-7,7'-dioxodihydroguaiaretic acid (ODGA) also showed both antibacterial and antifungal activity, while meso-ODGA did not show antibacterial activity, but showed antifungal activity. No activity of any stereoisomer of secoisolariciresinol (SECO) was apparent.
  • A Role for Leu118 of loop E in agonist binding to the α7 nicotinic acetylcholine receptor
    Shiva Amiri, Masaru Shimomura, Ranjit Vijayan, Hisashi Nishiwaki, Miki Akamatsu, Kazuhiko Matsuda, Andrew K. Jones, Mark S.P. Sansom, Philip C. Biggin, David B. Sattelle, David B. Sattelle, Molecular Pharmacology, 73,   2008年06月01日, Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels mediating fast cholinergic synaptic transmission in the brain and at neuromuscular junctions. We used the structure of the acetylcholine binding protein from Lymnaea stagnalis to model the chicken α7 agonist-binding domain. The initial models and a preliminary docking study suggested that position Leu118 may play an important role in determining agonist actions on α7. A prediction from these in silico studies, that L118E and L118D would retain binding to acetylcholine but L118K and L118R would not, was confirmed in electrophysiological studies on functional recombinant mutant receptors expressed in Xenopus laevis oocytes. The functional studies also demonstrated that residues at position 118 have a dramatic effect on the actions of imidacloprid (a partial agonist of wild-type α7 receptors) and its des-nitro derivative. Molecular dynamics simulations confirmed that Leu118 can strongly influence agonist binding and that the model was robust in terms of its prediction for acetylcholine binding. Together, the results indicate a role for Leu118 in influencing agonist actions on α7 nAChRs. Copyright © 2008 The American Society for Pharmacology and Experimental Therapeutics.
  • Crystal structures of Lymnaea stagnalis AChBP in complex with neonicotinoid insecticides imidacloprid and clothianidin
    Makoto Ihara, Toshihide Okajima, Atsuko Yamashita, Takuma Oda, Koichi Hirata, Hisashi Nishiwaki, Takako Morimoto, Miki Akamatsu, Yuji Ashikawa, Shun'Ichi Kuroda, Ryosuke Mega, Seiki Kuramitsu, David B. Sattelle, Kazuhiko Matsuda, Invertebrate Neuroscience, 8,   2008年06月01日, Neonicotinoid insecticides, which act on nicotinic acetylcholine receptors (nAChRs) in a variety of ways, have extremely low mammalian toxicity, yet the molecular basis of such actions is poorly understood. To elucidate the molecular basis for nAChR-neonicotinoid interactions, a surrogate protein, acetylcholine binding protein from Lymnaea stagnalis (Ls-AChBP) was crystallized in complex with neonicotinoid insecticides imidacloprid (IMI) or clothianidin (CTD). The crystal structures suggested that the guanidine moiety of IMI and CTD stacks with Tyr185, while the nitro group of IMI but not of CTD makes a hydrogen bond with Gln55. IMI showed higher binding affinity for Ls-AChBP than that of CTD, consistent with weaker CH-π interactions in the Ls-AChBP-CTD complex than in the Ls-AChBP-IMI complex and the lack of the nitro group-Gln55 hydrogen bond in CTD. Yet, the NH at position 1 of CTD makes a hydrogen bond with the backbone carbonyl of Trp143, offering an explanation for the diverse actions of neonicotinoids on nAChRs. © 2008 The Author(s).
  • Insecticidal bacteria isolated from predatory larvae of the antlion species Myrmeleon bore (Neuroptera: Myrmeleontidae)
    Hisashi Nishiwaki, Katsuhiko Ito, Masaru Shimomura, Kenta Nakashima, Kazuhiko Matsuda, Journal of Invertebrate Pathology, 96,   2007年09月01日, Various bacterial species were isolated from the crop (digestive organ) of the antlion species Myrmeleon bore and tested for their insecticidal activity against caterpillars by injection. Sixty-eight isolates from the antlion crop were grouped into twenty-four species based on homologies of 16S rRNA gene sequences and biochemical properties. Isolated Bacillus cereus, Bacillus sphaericus, Morganella morganii, Serratia marcescens and a Klebsiella species killed 80% or more cutworms when injected at a dose of 5 × 10 5 cells per insect. In addition, cutworms killed by these isolates resembled observations made of caterpillars attacked by antlions. A culture-independent analysis showed that the isolated bacterial species are likely to be frequently present in the antlion crop. These results suggest that insecticidal microorganisms associate with antlions, and may promote the death of prey. © 2007 Elsevier Inc. All rights reserved.
  • Cloning, functional characterization, and mode of action of a novel insecticidal pore-forming toxin, sphaericolysin, produced by Bacillus sphaericus
    Hisashi Nishiwaki, Kenta Nakashima, Chiharu Ishida, Tadayuki Kawamura, Kazuhiko Matsuda, Applied and Environmental Microbiology, 73,   2007年05月01日, An insecticidal protein produced by Bacillus sphaericus A3-2 was purified to elucidate its structure and mode of action. The active principle purified from the culture broth of A3-2 was a protein with a molecular mass of 53 kDa that rapidly intoxicated German cockroaches (Blattela germanica) at a dose of about 100 ng when injected. The insecticidal protein sphaericolysin possessed the undecapeptide motif of cholesterol-dependent cytolysins and had a unique N-terminal sequence. The recombinant protein expressed in Escherichia coli was equally as potent as the native protein. Sphaericolysin-induced hemolysis resulted from the protein's pore-forming action. This activity as well as the insecticidal activity was markedly reduced by a Y159A mutation. Also coapplication of sphaericolysin with cholesterol abolished the insecticidal action, suggesting that cholesterol binding plays an important role in insecticidal activity. Sphaericolysin-lysed neurons dissociated from the thoracic ganglia of the German cockroaches. In addition, sphaericolysin's activity in ganglia was suppressed by the Y159A mutation. The sphaericolysin-induced damage to the cockroach ganglia was greater than the damage to the ganglia of common cutworms (Spodoptera litura), which accounts, at least in part, for the higher sensitivity to sphaericolysin displayed by the cockroaches than that displayed by cutworms. Copyright © 2007, American Society for Microbiology. All Rights Reserved.
  • A hypothesis to account for the selective and diverse actions of neonicotinoid insecticides at their molecular targets, nicotinic acetylcholine receptors: Catch and release in hydrogen bond networks
    Makoto Ihara, Masaru Shimomura, Chiharu Ishida, Hisashi Nishiwaki, Miki Akamatsu, David B. Sattelle, Kazuhiko Matsuda, Invertebrate Neuroscience, 7,   2007年03月01日, The low mammalian toxicity of neonicotinoid insecticides has been shown to be attributable, at least in part, to their selective actions on insect nicotinic acetylcholine receptors (nAChRs). There are multiple nAChR s in insects and a wealth of neonicotinoid chemicals. Studies to date have discribed a wide range of effects on nAChRs, notably partial agonist, super agonist and antagonist actions. Both the diversity of the neonicotinoid actions and their selectivity for insect over vertebrate nAChRs are the result of physicochemical and steric interactions at their molecular targets (nAChRs). In such interactions, the formation and breakage of hydrogen bond (HB) networks plays a key role. Therefore the loss or gain of even a single HB resulting from either structural changes in neonicotinoids, or the amino acid sequence of a particular nAChR subunit, could result in a drastic modification of neonicotinoid actions. In addition to the amino acid residues, the backbone carbonyl of nAChRs may also be involved in the formation of HB networks with neonicotinoids. © 2007 Springer-Verlag.
  • Studies on the structure-activity relationship and mode of actions of neonicotinoid insecticides
    Hisashi Nishiwaki, Journal of Pesticide Science, 29,   2004年12月01日, The binding affinity of neonicotinoids for housefly head membranes was evaluated to elucidate the physicoehemical features of the compounds involved in the ligand-nicotinic acetylcholine receptor (nAChR) interactions. Both steric and electrostatic factors of the substituents on the aromatic and imidazolidine rings were found to influence the binding affinity. [ 14 C]Imidacloprid was employed to clarify the metabolism of imidacloprid in the flies. It was found that the compound was degraded and the metabolites were then excreted from the flies in a short period after administration. Agonist actions of neonicotinoids on nAChRs were evaluated to examine their relationships with the binding and insecticidal activities. High correlations were observed among these activities, suggesting that the channel opening of nAChRs resulting from the neonicotinoid binding is likely to cause the insecticidal actions.
  • Metabolism of imidacloprid in houseflies
    Hisashi Nishiwakl, Kazuyuki Sato, Yoshiaki Nakagawa, Masahiro Miyashlta, Hisashi Miyagawa, Journal of Pesticide Science, 29,   2004年08月26日, Metabolism of imidacloprid in the housefly Musca domestica was investigated. After the injection of 14 C-labeled imidacloprid, radioactivity decreased to approximately 20% of the initial level within 24 hr. Most of the 14 C in the excreta as well as that in the insect body was accounted for by an olefin derivative of imidacloprid. The pre-application of piperonyl butoxide or propargyl propyl phenylphosphonate as a synergist suppressed the degradation of imidacloprid and delayed the excretion of insecticidal components from houseflies. These results suggested that the insecticidal activity of imidacloprid was affected by oxidative metabolic processes.
  • Purification and functional characterization of insecticidal sphingomyelinase C produced by Bacillus cereus
    Hisashi Nishiwaki, Katsuhiko Ito, Katsuhiko Otsuki, Hiroyuki Yamamoto, Koichiro Komai, Kazuhiko Matsuda, Kazuhiko Matsuda, European Journal of Biochemistry, 271,   2004年02月01日, Bacillus cereus isolated from the larvae of Myrmeleon bore was found to secrete proteins that paralyze and kill German cockroaches, Blattela germanica, when injected. One of these active proteins was purified from the culture broth of B. cereus using anion-exchange and gel-filtration chromatography. The purified toxin, with a molecular mass of 34 kDa, was identified as sphingomyelinase C (EC 3.1.4.12) on the basis of its N-terminal and internal amino-acid sequences. A recombinant sphingomyelinase C expressed in Escherichia coli was as potent as the native protein in killing the cockroaches. Site-directed mutagenesis (His151Ala) that inactivated the sphingomyelinase activity also abolished the insecticidal activity, suggesting that the rapid insect toxicity of sphingomyelinase C results from its phospholipid-degrading activity.
  • Insecticidal activity and nicotinic acetylcholine receptor binding of dinotefuran and its analogues in the housefly, Musca domestica
    Kazuhisa Kiriyama, Hisashi Nishiwaki, Yoshiaki Nakagawa, Keiichiro Nishimura, Keiichiro Nishimura, Pest Management Science, 59,   2003年10月01日, The insecticidal activity of dinotefuran and 23 related compounds against the housefly, Musca domestica (L) was measured by injection with metabolic inhibitors. Dinotefuran was less active than imidacloprid and clothianidin by a factor of 10 in molar concentrations. Their binding activities to the fly-head membrane preparation were measured by using [ 125 I]α -bungarotoxin ([ 125 I]α-BGTX) and [ 3 H]imidacloprid ([ 3 H]IMI) as radioligands. The activity of some selected compounds measured with [ 3 H]IMI was 10 4 -fold higher than that measured with [ 125 I]α-BGTX. With [ 3 H]IMI as a radioligand, dinotefuran was 13-fold less active than imidacloprid. The inhibitory effect of dinotefuran on the binding of [ 3 H]IMI to the membrane preparation was in a competitive manner. Quantitative analysis of the insecticidal activity of the test compounds with the binding activity measured with [ 3 H]IMI showed that the higher the binding activity, the higher was the insecticidal activity. © 2003 Society of Chemical Industry.
  • Correlations of the electrophysiological activity of neonicotinoids with their binding and insecticidal activities
    Hisashi Nishiwaki, Yoshiaki Nakagawa, Morihiko Kuwamura, Kazuyuki Sato, Miki Akamatsu, Kazuhiko Matsuda, Koichiro Komai, Hisashi Miyagawa, Pest Management Science, 59,   2003年09月01日, The electrophysiological actions of various neonicotinoids, including substituted benzyl derivatives, against recombinant Drosophila SAD/chicken β2 hybrid nicotinic acetylcholine receptor (nAChR) were measured to analyze the relationships between the in vivo (insecticidal) and in vitro (binding and agonist) activities. Most of the neonicotinoids tested were capable of inducing inward currents by activating the hybrid nAChRs expressed in Xenopus laevis oocytes, whereas some compounds had no agonist activity and only blocked the acetylcholine-induced currents. Variations in the agonist activity were well correlated with those in the binding potency evaluated using [ 3 H]imidacloprid as well as insecticidal activities. © 2003 Society of Chemical Industry.
  • Asymmetric Chloronicotinyl Insecticide, 1-[1-(6-Chloro-3-pyridyl)ethyl]- 2-nitroiminoimidazolidine: Preparation, Resolution and Biological Activities toward Insects and Their Nerve Preparations
    Shinzo Kagabu, Kazuhisa Kiriyama, Hisashi Nishiwaki, Yuko Kumamoto, Toshiji Tada, Keiichiro Nishimura, Bioscience, Biotechnology and Biochemistry, 67,   2003年01月01日, The asymmetric chloronicotinyl insecticide, 1-[1-(6-chloro-3-pyridyl)ethyl]-2-nitroiminoimidazolidine, was prepared, and the absolute configurations of the enantiomers were determined by an X-ray analysis. The insecticidal activity against the housefly measured with metabolic inhibitors showed the (S) enantiomer to be slightly more active than the (R) isomer. Electrophysiological measurements on the American cockroach central nerve cord showed the compounds to elicite the impulses and subsequently blocked them. The neuroblocking potency of the (S) isomer was 5.9 μM, while that of the (R) isomer was as high as 73 μM. The molar concentrations required for 50% inhibition of the specific binding of [ 3 H]imidacloprid to the housefly head membrane preparation were respectively 0.19 μM and 0.95 μM for the (S) and (R) isomers. This enatioselectivity ratio was smaller than 35 for nicotine isomers but greater than 2 for epibatidine isomers. © 2003 by Japan Society for Bioscience, Biotechnology, and Agrochemistry.
  • Nicotinic acetylcholine receptor binding of imidacloprid-related diaza compounds with various ring sizes and their insecticidal activity against Musca domestica
    Shinzo Kagabu, Shinzo Kagabu, Hisashi Nishiwaki, Kazuyuki Sato, Manabu Hibi, Nahato Yamaoka, Yoshiaki Nakagawa, Pest Management Science, 58,   2002年05月09日, Fifteen 5-substituted 1-(6-chloro-3-pyridylmethyl)-2-nitromethylene-1,3-diazacyclohexanes and three other related compounds having a five- or seven-membered ring were synthesized and their biological activities were measured in vivo and in vitro. The insecticidal (in vivo) activity was evaluated against houseflies Musca domestica L under synergistic conditions with propargyl propyl phenyl phosphonate and piperonyl butoxide. The binding activity of each compound to nicotinic acetylcholine receptor in vitro was measured using [ 125 I]α-bungarotoxin. The insecticidal activities of the unsubstituted diazacyclohexane analogues were slightly higher than those of the imidazolidine analogues, but the enlargement of ring size to diazacycloheptane lowered the activity. Substitution of 1,3-diazacyclohexane or imidazolidine rings was not generally favourable for the activity, but the unsubstituted 1,3-diazacyclohexane analogue showed the highest binding activity. Ring substitutions and ring enlargement decreased the activity 100-30000-fold. © 2002 Society of Chemical Industry.
  • Effects of synergists on the insecticidal activity of chloronicotinyl-related benzyl compounds against houseflies
    Hisashi Nishiwaki, Yoshiaki Nakagawa, Tamio Ueno, Keiichiro Nishimura, Keiichiro Nishimura, Journal of Pesticide Sciences, 26,   2001年12月01日
  • Insecticidal and binding activities of N3-substituted imidacloprid derivatives against the housefly Musca domestica and the α-bungarotoxin binding sites of nicotinic acetylcholine receptors
    Hisashi Nishiwaki, Yoshiaki Nakagawa, Tamio Ueno, Shinzo Kagabu, Keiichiro Nishimura, Pest Management Science, 57,   2001年09月17日, N3-substituted imidacloprid congeners containing C 1 -C 6 alkyl groups or various analogous groups, and their corresponding nitromethylene analogues, were used in this study. Their insecticidal activity against the housefly, Musca domestica, and their binding activity toward the nicotinic acetylcholine receptor were determined. The insecticidal test was conducted using the synergists piperonyl butoxide and propargyl propyl phenylphosphonate. The binding assay was performed with housefly head membrane preparations using radio-labelled α-bungarotoxin. Both insecticidal and binding activities were drastically lowered by the introduction of alkyl/allyl groups at the imidazolidine NH sites of both nitroimino and nitromethylene compounds. The binding activity of N3-substituted nitromethylene analogues was much higher than that of the corresponding nitroimino analogues. However, the insecticidal activity of both series of compounds with a given substituent was nearly identical. The insecticidal activity correlated positively with the binding activity after taking into account the structural difference of the nitroimino and nitromethylene moieties and a structural feature of the N3-substituents. © 2001 Society of Chemical Industry.
  • Binding activity of substituted benzyl derivatives of chloronicotinyl insecticides to housefly-head membranes, and its relationship to insecticidal activity against the housefly Musca domestica
    Hisashi Nishiwaki, Yoshiaki Nakagawa, Yoshiaki Nakagawa, David Y. Takeda, Atsushi Okazawa, Miki Akamatsu, Hisashi Miyagawa, Tamio Ueno, Keiichiro Nishimura, Pest Management Science, 56,   2000年10月14日, Variously substituted benzyl derivatives of chloronlcotinyl insecticides were synthesized with a wide range of substituents including halogens, NO 2 , CN, CF 3 and small alkyl and alkoxy groups at the ortho, meta and para positions, as well as multiple-substituted benzyl analogues. Their binding activity to the α-bungarotoxin binding site in housefly (Musca domestica) head membrane preparations was measured. Among the compounds tested, the activity of the meta-CN derivative was the highest, being 20-100 times higher than those of imidacloprid, acetamiprid and nitenpyram. The synergized insecticidal activity against houseflies was also measured for selected compounds with the metabolic inhibitor, NIA16388 (propargyl propyl phenylphosphonate). For the nitromethylene analogues, including both benzyl and pyridylmethyl analogues, higher binding activity usually resulted in higher insecticidal activity. (C) 2000 Society of Chemical Industry.
  • Three-dimensional quantitative structure-activity relationship analysis of acyclic and cyclic chloronicotinyl insecticides
    Atsushi Okazawa, Miki Akamatsu, Miki Akamatsu, Hisashi Nishiwaki, Yoshiaki Nakagawa, Hisashi Miyagawa, Keiichiro Nishimura, Tamio Ueno, Pest Management Science, 56,   2000年06月01日, The binding activity of chloronicotinyl insecticides, including acetamiprid, nitenpyram and related compounds, to the nicotinic acetylcholine receptors (nAChR) of houseflies was measured. These compounds were defined as 'acyclic' compounds. Variations in the binding activity were analysed using comparative molecular field analysis (CoMFA) which is a technique for the analysis of three-dimensional quantitative structure-activity relationships. The CoMFA results showed that steric interactions were more significant for the acyclic compounds than for imidacloprid and its derivatives (cyclic compounds). It was also shown that the acyclic compounds could bind to housefly-nAChR in a similar manner to the cyclic compounds, and that the electrostatic natures of the acyclic amino- and cyclic imdazolidine-moieties affected their binding activity. (C) 2000 Society of Chemical Industry.
  • Prediction of the binding mode of imidacloprid and related compounds to house-fly head acetylcholine receptors using three-dimensional QSAR analysis
    A. Okazawa, M. Akamatsu, A. Ohoka, H. Nishiwaki, W. J. Cho, Y. Nakagawa, K. Nishimura, T. Ueno, Pesticide Science, 54,   1998年01月01日, The binding activity of imidacloprid and related compounds to nicotinic acetylcholine receptors (nAChR) of house flies was measured by use of radioactive α-bungarotoxin as a ligand. Variations in the activity were examined three-dimensionally using comparative molecular field analysis (CoMFA). The CoMFA results suggest that one conformer among the four stable ones is active and provide support for one of the proposed binding models for this class of compound, in which the nitrogen atom of the pyridine ring and the nitrogen atom at the 1-position of the imidazolidine ring interact with the hydrogendonating and electron-rich sites of nAChR, respectively. The CoMFA field map showed that the nitroimino moiety and a portion of the imidazolidine ring were mainly surrounded by a sterically and electrostatically sensitive region of nAChR.

受賞

  •   2004年, 日本農薬学会奨励賞


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