Studies on the interactions between ATR and its inhibitor Gomisin N and its application to a potentiator of antitumor agents.

• Project/Area Number: 25293029
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Drug development chemistry
• Research Institution: Nigata University of Phermacy and Applied Life Sciences
• Principal Investigator: Ishiguro Masaji 新潟薬科大学, 応用生物科学部, 教授 (10280687)
• Co-Investigator(Kenkyū-buntansha): NISHIDA Hiroshi 新潟薬科大学, 応用生物科学部, 教授 (60322541) ; TAKAKU Hiroaki 新潟薬科大学, 応用生物科学部, 教授 (70350717) ; TAMIYA Minoru 新潟薬科大学, 応用生物科学部, 助教 (10468960) ; YAMAZAKI Harutake 新潟薬科大学, 応用生物科学部, 助教 (20456776)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥19,240,000 (Direct Cost: ¥14,800,000、Indirect Cost: ¥4,440,000); Fiscal Year 2015: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2014: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2013: ¥10,660,000 (Direct Cost: ¥8,200,000、Indirect Cost: ¥2,460,000)
• Keywords: グミシンN / 五味子 / ATR / Phosphokinase / リグナン / 抗がん活性増強 / チェックポイント / ゴミシンN / ATR阻害 / 癌 / 生体分子 / 分子モデリング

Outline of Final Research Achievements

radioactive Gomisin N was prepared for examining the interaction site of Gomisin N in the binding at ATR.
A binding mode of Gomisin N at the substrate-binding site of phosphokinase domain of ATR was examined by constructing the phosphokinase domain using a few crystal structures of phosphokinase-related proteins by homology modeling. Docking study of Gomisin N at the substrate binding site of of the domain suggested a characteristic site and new Gomisin-related new liganan derivatives were designed based on the interactions.

Research Products

• [Journal Article] Amino acid residues of bitter taste receptor TAS2R16 that determine sensitivity in primates to β-glycosides (2016)
  • Author(s): Imai H, Suzuki-Hashido N, Ishimaru Y, Sakurai T, Yin W, Pan W, Ishiguro M, Masuda K, Abe K, Misaka T, and Hirai H.
  • Journal Title: Biophysics and Physicobiology Volume: in press
  • NAID: 130005165371
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Structural Basis of pH Dependence of Neoculin, a Sweet Taste-Modifying Protein. (2015)
  • Author(s): Ohkubo T, Tamiya M, Abe K, Ishiguro M.
  • Journal Title: PLoS One Volume: 10
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Synthesis of the aglycon of pentalinoside (2015)
  • Author(s): Isaka, N. Kawada, S.; Ishiguro, M.; Tamiya, M.
  • Journal Title: Heterocycles Volume: 91 Pages: 1715-1721
• [Journal Article] Metabolism and cytotoxic effects of phosphatidylcholine hydroperoxide in human hepatoma HepG2 cells (2015)
  • Author(s): Y. Suzuki, K. Nakagawa, S. Kato, N. Tatewaki, S. Mizuochi, J. Ito, T. Eitsuka, H. Nishida, T. Miyazawa
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 458 Issue: 4 Pages: 920-927
  • DOI: 10.1016/j.bbrc.2015.02.063
  • Peer Reviewed / Open Access
• [Journal Article] Mode-of-action and evolution of methylenedioxy bridge forming P450s in plant specialized metabolism (2014)
  • Author(s): Akio Noguchi, Manabu Horikawa, Jun Murata, Masayuki Tera, Yosuke Kawai, Masaji Ishiguro, Toshiaki Umezawa, Masaharu Mizutani, Eii
  • Journal Title: Plant Biotechnology Volume: 31 Issue: 5 Pages: 493-503
  • DOI: 10.5511/plantbiotechnology.14.0828a
  • NAID: 130004721162
  • ISSN: 1342-4580, 1347-6114
  • Peer Reviewed / Open Access
• [Journal Article] Total Synthesis of 2,6-Dideoxy-3-methylpyranosylillustrol, a Seco-norpregnaneglycoside from Mandevilla illustris. (2014)
  • Author(s): Minoru Tamiya, Nobuhisa Isaka, Kazuya Ishizawa, Mayu Ikda, Masaji Ishiguro
  • Journal Title: Chemistry Letters Volume: 43 Issue: 11 Pages: 1704-1706
  • DOI: 10.1246/cl.140632
  • NAID: 130004677591
  • Peer Reviewed
• [Journal Article] Synergistic inhibition of cancer cell proliferation with a combination of δ-tocotrienol and ferulic acid. (2014)
  • Author(s): Eitsuka T, Tatewaki N, Nishida H, Kurata T, Nakagawa K, Miyazawa T.
  • Journal Title: Biochem Biophys Res Commun. Volume: 453 Issue: 3 Pages: 606-611
  • DOI: 10.1016/j.bbrc.2014.09.126
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Synthesis of the Aglycon of the Argelosides: Antiprolierative 14,15-seco-Pregnane Glycosides (2014)
  • Author(s): Minoru Tamiya, Nobuhisa Isaka, Takaki Kitazawa, Masaji Ishiguro
  • Journal Title: Asian Journal of Organic Chemistry Volume: 3 Issue: 3 Pages: 265-268
  • DOI: 10.1002/ajoc.201300219
  • Peer Reviewed
• [Journal Article] Effects of Acute and Chronic Boysenberry Intake on Blood Pressure and Endothelial Function in Spontaneous Hypertensive Rats (2014)
  • Author(s): Matsusima A, Furuuchi R, Shirai M, Nagai S, Yokoyama T, Nishida H, Hirayama M.
  • Journal Title: Journal of Nutritional Science and Vitaminology Volume: 60 Issue: 1 Pages: 43-51
  • DOI: 10.3177/jnsv.60.43
  • NAID: 130003393764
  • ISSN: 0301-4800, 1881-7742
  • Peer Reviewed
• [Journal Article] Antifungal activity of plant defensin AFP1 in Brassica juncea involves the recognition of the methyl residue in glucosylceramide of target pathogen Candida albicans (2014)
  • Author(s): Oguro Y, Yamazaki H, Takagi M, Takaku H
  • Journal Title: Curr. Genet Volume: 60 Issue: 2 Pages: 89-97
  • DOI: 10.1007/s00294-013-0416-8
  • Peer Reviewed
• [Journal Article] Persimmon Leaf Flavonols Enhance the Anti-Cancer Effect of Heavy Ion Radiotherapy on Murine Xenograft Tumors (2013)
  • Author(s): Kawakami K, Nishida H, Tatewaki N, Eguchi-Kasai E, Anzai K, Eitsuka T, Konishi T, Hirayama M
  • Journal Title: Journal of Cancer Therapy Volume: 4 Issue: 07 Pages: 1150-1157
  • DOI: 10.4236/jct.2013.47133
  • Peer Reviewed
• [Journal Article] Differential Effect of Schisandrin B Stereoisomers on ATR-Mediated DNA Damage Checkpoint Signaling (2013)
  • Author(s): Tatewaki N, Nishida H, Yoshida M, Ando H, Kondo S, Sakamaki T, Konishi T.
  • Journal Title: Journal of Pharmacological Sciences Volume: 122 Issue: 2 Pages: 138-148
  • DOI: 10.1254/jphs.13048FP
  • NAID: 10031185406
  • ISSN: 1347-8613, 1347-8648
  • Peer Reviewed
• [Presentation] 特殊な骨格をもったセコプレグナンの合成に関する研究 (2015)
  • Author(s): 田宮 実
  • Organizer: 有機合成化学協会関東支部シンポジウム
  • Place of Presentation: 長岡市
  • Year and Date: 2015-11-21
• [Presentation] Velutinol A及び関連天然物の合成研究 (2015)
  • Author(s): 井坂修久, 田宮 実, 北澤貴明, 石澤和也, 長谷川篤志, 池田舞由, 石黒正路
  • Organizer: 日本薬学会第135年会
  • Place of Presentation: 神戸学院大学
  • Year and Date: 2015-03-25 – 2015-03-28
• [Presentation] 2,6-Dideoxy-3-O-methylpyranosylillustrolの全合成 (2014)
  • Author(s): 井坂修久, 田宮 実, 石澤和也, 池田舞由, 石黒正路
  • Organizer: 有機合成化学協会関東支部 新潟シンポジウム
  • Place of Presentation: 新潟大学
  • Year and Date: 2014-11-29
• [Presentation] ATR阻害剤ゴミシンNの全合成 (2014)
  • Author(s): 田宮 実, 眞柄良平, 近 恵, 土屋裕徳, 熊倉美佳, 五十嵐久未, 中川悠貴, 石黒正路
  • Organizer: 有機合成化学協会関東支部 新潟シンポジウム
  • Place of Presentation: 新潟大学
  • Year and Date: 2014-11-29
• [Presentation] 味覚修飾タンパク質の酸による甘味発現機構の解析 (2014)
  • Author(s): 大久保崇之, 中嶋健一朗, 伊藤啓祐, 三坂 巧, 阿部啓子, 田宮 実, 石黒正路
  • Organizer: 第42回構造活性相関シンポジウム
  • Place of Presentation: くまもと森都心プラザ
  • Year and Date: 2014-11-14
• [Presentation] Candida albicansにおける植物ディフェンシンAFP1の作用機序解析 (2014)
  • Author(s): 小黒 芳史、山崎 晴丈、高木 正道、高久 洋暁
  • Organizer: 日本農芸化学会２０１４年度大会
  • Place of Presentation: 明治大学
• [Presentation] Strawberry polyphenols attenuate the production of inflammatory mediators in U937 cells (2013)
  • Author(s): M. Saito, M. Nishida, M. Kokubo, T. Eitsuka, H. Nishida
  • Organizer: American Society for Cell Biology, Annual Meeting
  • Place of Presentation: New Orleans
• [Presentation] The effect of Schisandrin on DNA damage checkpoint induced by heavy ion (2013)
  • Author(s): N. Tatewaki, T. Eitsuka, T. Konishi, H. Nishida
  • Organizer: American Society for Cell Biology, Annual Meeting
  • Place of Presentation: New Orleans
• [Presentation] Up-regulation of cellular telomerase activity by Amadori-glycated phosphatidyl- ethanolamine: A link between diabetes and cancer. (2013)
  • Author(s): T. Eitsuka, K. Nakagawa, H. Nishida, T. Miyazawa
  • Organizer: The Conference of Diet and Optimum Health 2013
  • Place of Presentation: Corvallis
• [Presentation] Illustrol の合成研究 (2013)
  • Author(s): 井坂修久、池田舞由、北澤貴明、田宮 実、石黒正路
  • Organizer: 第65回有機合成化学協会関東支部シンポジウム
  • Place of Presentation: 新潟薬科大学
• [Presentation] DOI合成酵素変異体における変異と活性の相関解析 (2013)
  • Author(s): 大久保崇之、佐藤雅人、田宮 実、高久洋暁、岩澤裕喜、石黒正路
  • Organizer: 第41回構造活性相関シンポジウム
  • Place of Presentation: 関西学院
• [Book] Comprehensive Organic Synthesis II (Second Edition), 3.11 Pinacol Coupling Reactions (2014)
  • Author(s): Keisuke Suzuki, Minoru Tamiya
  • Total Pages: 40
  • Publisher: エルゼビア
• [Book] 膜タンパク質構造研究２５章受容体分子とリガンドのモデリング (2013)
  • Author(s): 石黒 正路 （編者：岩田 想）
  • Publisher: 化学同人