Study toward Development Ionotropic Glutamate Receptore Subytpe Selective Ligand

• Project Area: Chemical Biology using bioactive natural products as specific ligands: identification of molecular targets and regulation of bioactivity
• Project/Area Number: 23102009
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Science and Engineering
• Research Institution: Osaka City University
• Principal Investigator: Shianda Tetsuro 大阪市立大学, 大学院理学研究科, 教授 (30271513)
• Co-Investigator(Kenkyū-buntansha): Ohfune Yasufumi 大阪市立大学, 大学院理学研究科, 名誉教授 (20142078)
• Co-Investigator(Renkei-kenkyūsha): Shimamoto Keiko (公益財団法人)サントリー生命科学財団, 主幹研究員 (70235638) ; Sakaguchi Kazuhiko 大阪市立大学, 大学院理学研究科, 准教授 (80264795)
• Project Period (FY): 2011-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥43,290,000 (Direct Cost: ¥33,300,000、Indirect Cost: ¥9,990,000); Fiscal Year 2015: ¥9,230,000 (Direct Cost: ¥7,100,000、Indirect Cost: ¥2,130,000); Fiscal Year 2014: ¥9,230,000 (Direct Cost: ¥7,100,000、Indirect Cost: ¥2,130,000); Fiscal Year 2013: ¥9,750,000 (Direct Cost: ¥7,500,000、Indirect Cost: ¥2,250,000); Fiscal Year 2012: ¥9,620,000 (Direct Cost: ¥7,400,000、Indirect Cost: ¥2,220,000); Fiscal Year 2011: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
• Keywords: グルタミン酸受容体 / 天然物 / カイトセファリン / アクロメリン酸 / リガンド / 超活性 / ケミカルバイオロジー / アンタゴニスト / ＮＭＤＡ型受容体 / ＫＡ型受容体 / グルタミン酸 / カイノイド / アナログ合成 / 受容体 / 天然リガンド / 標的分子探索

Outline of Final Research Achievements

Chemical biology of natural products focusing on naturally occurring ionotropic glutamte receptor ligands, acromelic acid A and kaitocephalin was studied. Studies involving total synthesis of these natural products, their analog synthesis, ionotropic glutamate receptor binding assay, and structure analysis of ligand-protein complexes of these natural products bound to ionotropic glutamate receptors were conducted. As a result, the target receptor subtype of kaitocephalin was identified. Moreover, (7S)-kaitocephalin was discovered as a more potent NMDA receptor selective ligand than kaitocephalin.

Research Products

• [Journal Article] (7S)-Kaitocephalin as a potent NMDA receptor selective ligand (2016)
  • Author(s): Y. Yasuno, M. Hamada, M. Kawasaki, K. Shimamoto, Y. Shigeri, T. Akizawa, M. Konishi, Y. Ohfune, T. Shinada
  • Journal Title: Org. Biomol. Chem. Volume: 14 Issue: 4 Pages: 1206-1210
  • DOI: 10.1039/c5ob02301g
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] The stereoselective construction of E- and Z-Δ-Ile from E-dehydroamino acid ester: the synthesis of the phomopsin A tripeptide side chain (2016)
  • Author(s): Y. Yasuno, A. Nishimura, Y. Yasukawa, Y. Karita, Y. Ohfune, T. Shinada
  • Journal Title: Chem. Commun Volume: 52 Issue: 7 Pages: 1478-1481
  • DOI: 10.1039/c5cc08458j
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] A facile synthesis of (5-siloxymethy)pyrrolidine-2-carboxylic acid ester (2015)
  • Author(s): Y. Yasuno, Y. Yoshida, A. Nishimura, Y. Ohfune, T. Shinada
  • Journal Title: Heterocycles Volume: 91 Issue: 12 Pages: 2377-2385
  • DOI: 10.3987/com-15-13347
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Cyclopropanation of E-dehydroaspartic acid esters with furan derivatives: The synthesis of highly functionalized α-2,3-methanoamino acid esters (2015)
  • Author(s): A. Manabe, R. Matsumoto, T. Shinada
  • Journal Title: Synlett Volume: 26 Issue: 12 Pages: 1710-1714
  • DOI: 10.1055/s-0034-1380812
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Short Total Synthesis of (-)-Kainic Acid, (2014)
  • Author(s): K. Oe, Y. Ohfune T. Shinada,
  • Journal Title: Org. Lett. Volume: 16 Issue: 9 Pages: 2550-2553
  • DOI: 10.1021/ol5009526
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Solid Phase Synthesis of α-Amino Squaric Acid-containing Peptides (2014)
  • Author(s): K. Maeda, Y. Kiniwa, Y. Ohfune, S. Ishiguro, K. Suzuki, K. Murata, H. Matsuda T. Shinada
  • Journal Title: RSC Adv. Volume: 4 Issue: 92 Pages: 50639-50643
  • DOI: 10.1039/c4ra10442k
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Toward the Total Synthesis of Tetrodotoxin: Stereoselective Construction of the 7-Oxanorbornane Intermediate (2014)
  • Author(s): A. Manabe, Y. Ohfune T. Shinada
  • Journal Title: Tetrahedron Lett. Volume: 55 Issue: 44 Pages: 6077-6080
  • DOI: 10.1016/j.tetlet.2014.09.036
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Stereoselective Synthesis of (E)-α,β-Dehydroamino Acid Esters (2013)
  • Author(s): Y. Yasuno, M. Hamada, T. Yamada, T. Shinada, Y. Ohfune
  • Journal Title: Eur. J. Org. Chem. Volume: 2013 Issue: 10 Pages: 1884-1888
  • DOI: 10.1002/ejoc.201300112
  • Peer Reviewed
• [Journal Article] Identification of Novel Sesterterpene/Triterpene Synthase from Bacillus clausii (2013)
  • Author(s): T. Sato, H. Yamaga, S. Kashima, Y. Murata, T. Shinada, C. Nakano, T. Hoshino
  • Journal Title: ChemBioChem Volume: 14 Issue: 7 Pages: 822-825
  • DOI: 10.1002/cbic.201300035
  • Peer Reviewed
• [Journal Article] Using​ Stable​ Radicals​ To​ Protect​ Pentacene​ Derivatives​ from​ Photodegradation (2013)
  • Author(s): Y. Kawanaka, A. Shimizu, T. Shinada, R. Tanaka, Y. Teki
  • Journal Title: Angew. Chem. Int. Ed. Engl. Volume: 52 Issue: 26 Pages: 6643-6647
  • DOI: 10.1002/anie.201300595
  • Peer Reviewed
• [Journal Article] Efficient Total Synthesis of Manzacidin B (2012)
  • Author(s): K.Oe
  • Journal Title: Tetrahedron Lett. Volume: 53 Issue: 26 Pages: 3250-3253
  • DOI: 10.1016/j.tetlet.2012.04.042
  • Peer Reviewed
• [Journal Article] The Structure of (-)-Kaitocephalin Bound to the Ligand Binding Domain of the (S)-α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA)/Glutamate Receptor, GluA2 (2012)
  • Author(s): A. H. Ahmed
  • Journal Title: J. Biol. Chem. Volume: 287 Issue: 49 Pages: 41007-41013
  • DOI: 10.1074/jbc.m112.416362
  • Peer Reviewed
• [Journal Article] Efficient Synthesis of Anhydrorhodovibrin and Analogues (2012)
  • Author(s): T. Yamada ,K. Okada,T. Shinada ,Y. Ohfune , H. Hashimoto
  • Journal Title: Syn. Lett. Volume: 23 Issue: 20 Pages: 2980-2984
  • DOI: 10.1055/s-0032-1317678
  • Peer Reviewed
• [Journal Article] Total Synthesis of Manzacidins. An Overview and Perspective (2012)
  • Author(s): Y. Ohfune
  • Journal Title: Heterocycles Volume: 85 Issue: 11 Pages: 2617-2649
  • DOI: 10.3987/contents-12-85-11
  • Peer Reviewed
• [Journal Article] Total synthesis of (-)-funebrine via Au-catalyzed regio- and stereoselective γ-butyrolactonization of allenylsilane (2011)
  • Author(s): T.Okada, K.Sakaguchi, T.Shinada, Y.Ohfune
  • Journal Title: Tetrahedron Lett. Volume: 52 Issue: 44 Pages: 5744-5746
  • DOI: 10.1016/j.tetlet.2011.08.050
  • Peer Reviewed
• [Journal Article] Au-catalyzed cyclization of allenylsilanes. Regioselective conversion to 2-amino-4-silylmethylene-γ-butyrolactone (2011)
  • Author(s): T.Okada, K.Sakaguchi, T.Shinada, Y.Ohfune
  • Journal Title: Tetrahedron Lett. Volume: 52 Issue: 44 Pages: 5740-5743
  • DOI: 10.1016/j.tetlet.2011.07.144
  • Peer Reviewed
• [Journal Article] 天然神経毒アミノ酸類の全合成 (2011)
  • Author(s): 大船泰史、品田哲郎
  • Journal Title: 化学工業 Volume: 62 Pages: 642-648
• [Presentation] Synthetic Study of Fluorescent-Labelled Kaitocephalin (2016)
  • Author(s): Y. Yoshida, Y. Yasuno, Y. Ohfune, T. Shinada
  • Organizer: 日本化学会第96春季年会
  • Place of Presentation: 同志社大学、京都府京田辺市
  • Year and Date: 2016-03-24
• [Presentation] Synthetic Study of SF-2132 (2016)
  • Author(s): A. Sawai, A. Nishimura, Y. Yasuno, T. Shinada
  • Organizer: 7th OCARINA International Symposium in conjunction with Symposium in honor of Distinguished Professor Michael Nobel
  • Place of Presentation: 大阪市立大学、大阪府大阪市
  • Year and Date: 2016-03-17
  • Int'l Joint Research
• [Presentation] Synthetic Study of Phomopsin A (2016)
  • Author(s): Y. Karita, Y. Yasuno, T. Shinada
  • Organizer: 7th OCARINA International Symposium in conjunction with Symposium in honor of Distinguished Professor Michael Nobel
  • Place of Presentation: 大阪市立大学、大阪府大阪市
  • Year and Date: 2016-03-17
  • Int'l Joint Research
• [Presentation] Synthesis of fluorescent ligand for visualization of native ionotropic glutamate receptors (2015)
  • Author(s): T. Shinada
  • Organizer: The 2015 International Chemical Congress of Pacific Basin Societies
  • Place of Presentation: Honolulu, Hawaii, USA
  • Year and Date: 2015-12-15
  • Int'l Joint Research
• [Presentation] Structure-Activity Relationship Study of Kaitocephalin: Effect of the Aromatic Ring Moiety (2015)
  • Author(s): Y. Yasuno, Y. Yoshida, T. Shinada
  • Organizer: The 19th Osaka City University International Workshop on Advanced Molecular Materials Science
  • Place of Presentation: 大阪市立大学、大阪府大阪市
  • Year and Date: 2015-11-12
  • Int'l Joint Research
• [Presentation] Synthetic Study of Tetrodotoxin (2015)
  • Author(s): A. Manabe, Y. Ohfune, T. Shinada
  • Organizer: The 13th International Kyoto Conference on New Aspects of Organic Chemistry
  • Place of Presentation: リーガロイヤルホテル、京都府京都市
  • Year and Date: 2015-11-09
  • Int'l Joint Research
• [Presentation] カイトセファリンの蛍光プローブ化に向けた構造活性相関研究 (2015)
  • Author(s): 保野陽子、品田哲郎
  • Organizer: 新学術領域研究「天然物ケミカルバイオロジー?分子標的と活性制御」第７回若手研究者ワークショップ
  • Place of Presentation: 東北大学青葉サイエンスホール、宮城県仙台市
  • Year and Date: 2015-06-09
• [Presentation] Synthetic Study of Kainoid Analogs via Intramolecular Radical Cyclization Reaction (2015)
  • Author(s): T. Shinada
  • Organizer: 新学術領域研究「天然物ケミカルバイオロジー～分子標的と活性制御～」第8回公開シンポジウム
  • Place of Presentation: 東北大学片平キャンパス、宮城県仙台市
  • Year and Date: 2015-06-08
• [Presentation] Synthesis of Dihydrokainic Acid by an Intramolecular Cyclization (2015)
  • Author(s): A. Yamada, T. Shinada,
  • Organizer: 日本化学会第95春季年会
  • Place of Presentation: 日大船橋キャンパス（千葉県船橋市）
  • Year and Date: 2015-03-26 – 2015-03-29
• [Presentation] Synthetic Study of Kaitocephalin Analogs toward Fluorescent Labeling (2015)
  • Author(s): Y. Yoshida, Y. Yasuno, Y. Ohfune, T. Shinada
  • Organizer: 日本化学会第95春季年会
  • Place of Presentation: 日大船橋キャンパス（千葉県船橋市）
  • Year and Date: 2015-03-26 – 2015-03-29
• [Presentation] Synthetic Study of Substituted Pyridone Carboxylates using Cross Coupling Reaction (2015)
  • Author(s): K. Misaki, T. Shinada,
  • Organizer: The 18th Osaka City University International Conference
  • Place of Presentation: Osaka City University (Sugimoto, Osaka, Japan )
  • Year and Date: 2015-03-09 – 2015-03-10
• [Presentation] Synthesis Bioactivity of Kaitocephalin Analog Bearing an Alkyl Side Chain on the Aromatic Ring (2015)
  • Author(s): Y. Yoshida, Y. Yasuno, T. Shinada
  • Organizer: The 18th Osaka City University International Conference
  • Place of Presentation: Osaka City University (Sugimoto, Osaka, Japan )
  • Year and Date: 2015-03-09 – 2015-03-10
• [Presentation] イオンチャネル型グルタミン酸受容体結合活性試験法 (2014)
  • Author(s): 保野陽子
  • Organizer: 新学術領域研究「天然物ケミカルバイオロジー：分子標的と活性制御」 第５回若手研究者ワークショップ
  • Place of Presentation: 名古屋大学理学研究科 (愛知県名古屋市)
  • Year and Date: 2014-05-29
• [Presentation] 高親和性イオンチャネル型グルタミン酸受容体リガンドの創製に向けた天然物ケミカルバイオロジー (2014)
  • Author(s): 品田哲郎
  • Organizer: 新学術領域研究「天然物ケミカルバイオロジー～分子標的と活性制御～」 第6回公開シンポジウム
  • Place of Presentation: 名古屋大学、坂田・平田ホール(愛知県名古屋市)）
  • Year and Date: 2014-05-28 – 2014-05-29
• [Presentation] Exploration of Neew Juvenile Hormone of Heteropteran Insects (2014)
  • Author(s): T. Shinada
  • Organizer: Nakanishi Shimposium 2014
  • Place of Presentation: 名古屋大学
  • Invited
• [Presentation] 分子内ラジカル環化を用いたカイノイド類の合成研究 (2014)
  • Author(s): 山田梓紗、大船泰史、品田哲郎
  • Organizer: 日本化学会第９４年会
  • Place of Presentation: 名古屋大学
• [Presentation] 芳香環上に側鎖を持つカイトセファリンアナログの合成研究 (2014)
  • Author(s): 吉田侑矢、保野陽子、大船泰史、品田哲郎
  • Organizer: 日本化学会第９４年会
  • Place of Presentation: 名古屋大学
• [Presentation] アクロメリン酸類の合成研究 (2014)
  • Author(s): 御前公美、品田哲郎
  • Organizer: 日本化学会第９４年会
  • Place of Presentation: 名古屋大学
• [Presentation] シクロプロパン環を導入した2，6-ジアミノピメリン酸誘導体 (2014)
  • Author(s): 安尾望、島本啓子、大船泰史
  • Organizer: 日本化学会第９４年会
  • Place of Presentation: 名古屋大学
• [Presentation] シクロプロパン環を導入したジアミノピメリン酸の合成研究 (2013)
  • Author(s): 若林由華
  • Organizer: 日本化学会第93春季年会
  • Place of Presentation: 立命館大学びわこ・くさつキャンパス
  • Year and Date: 2013-03-22
• [Presentation] 電子不足オレフィンとフラン誘導体を用いたシクロプロパン化反応 (2013)
  • Author(s): 松本遼太郎
  • Organizer: 日本化学会第93春季年会
  • Place of Presentation: 立命館大学びわこ・くさつキャンパス
  • Year and Date: 2013-03-22
• [Presentation] クロスカップリング反応を利用した3 位置換-2-ピリドン-6-カルボン酸の合成研究 (2013)
  • Author(s): 御前公美
  • Organizer: 日本化学会第93春季年会
  • Place of Presentation: 立命館大学びわこ・くさつキャンパス
  • Year and Date: 2013-03-22
• [Presentation] デヒドロアミノ酸の立体制御に基づく生物活性天然有機化合物の全合成研究 (2013)
  • Author(s): 品田哲郎
  • Organizer: 関学化学フォーラム
  • Place of Presentation: 関西学院大学神戸三田キャンパス
  • Year and Date: 2013-01-28
  • Invited
• [Presentation] Total Synthesis of Natural Products Exhibiting Glutamate Receptor Binding Activities (2013)
  • Author(s): T. Shinada
  • Organizer: The 15th Asian Chemical Congress (ACC), (15th ACC 2013)
  • Place of Presentation: Sentosa, Singapore
  • Invited
• [Presentation] Synthetic Study of Conformationally Restricted Pimelic Acid Derivatives (2013)
  • Author(s): Nozomi Yasuo, Yuuka Wakabayashi, Yasufumi Ohfune, and Tetsuro Shinada
  • Organizer: 13th International Conference on the Chemistry of Antibiotics and other bioactive compounds: ICCA
  • Place of Presentation: Yamanashi, Japan
• [Presentation] アクロメリン酸Ａの合成研究 (2013)
  • Author(s): 御前公美、大船泰史、品田哲郎
  • Organizer: 第43回複素環化学討論会
  • Place of Presentation: 長良川国際センター
• [Presentation] Synthesis of Kainoid Analogs and Their Affinities to Glutamate Receptors (2013)
  • Author(s): T. Shinada
  • Organizer: The 2st International Symposium on Chemical Biology of Natural products: Target ID and Regulation of Bioactivity
  • Place of Presentation: Ｙｏｋｏｈａｍａ， Ｊａｐａｎ
• [Presentation] Synthetic Study of Tetrodotoxin (2012)
  • Author(s): A.Manabe
  • Organizer: the Twelfth International Kyoto Conference on New Aspects of Organic Chemistry (IKCOC-12)
  • Place of Presentation: Kyoto
  • Year and Date: 2012-11-12
• [Presentation] Synthesis of Diaminopimelic Acid Derivatives and Their Biological Activity (2012)
  • Author(s): Y. Wakabayashi
  • Organizer: the Twelfth International Kyoto Conference on New Aspects of Organic Chemistry (IKCOC-12)
  • Place of Presentation: Kyoto
  • Year and Date: 2012-11-12
• [Presentation] 置換ピリドンカルボン酸類の新規合成法の開発 (2012)
  • Author(s): 品田 哲郎
  • Organizer: 第42回複素環化学討論会
  • Place of Presentation: 京都テルサ
  • Year and Date: 2012-10-11
• [Presentation] 光学活性ピロリンの簡便な合成法の開発 (2012)
  • Author(s): 大江健太郎
  • Organizer: 第42回複素環化学討論会
  • Place of Presentation: 京都テルサ
  • Year and Date: 2012-10-11
• [Presentation] スクアリン酸含有アミノ酸を組み込んだ新規ペプチドアナログ合成 (2012)
  • Author(s): 前田健太郎
  • Organizer: 第54回天然有機化合物討論会
  • Place of Presentation: 東京農業大学世田谷キャンパス
  • Year and Date: 2012-09-18
• [Presentation] 立体配座を固定した2,6-ジアミノピメリン酸誘導体の合成研究 (2012)
  • Author(s): 若林由華
  • Organizer: 第39回有機反応懇談会
  • Place of Presentation: 関西大学吹田キャンパス
  • Year and Date: 2012-08-03
• [Presentation] 非天然型アミノ酸構造を有する天然有機化合物の全合成研究 (2012)
  • Author(s): 品田哲郎
  • Organizer: 第39回有機反応懇談会
  • Place of Presentation: 関西大学吹田キャンパス
  • Year and Date: 2012-08-03
  • Invited
• [Presentation] Synthetic Study of 2,6-Diaminopimeric Acid Derivatives as a Cystine Isostere (2011)
  • Author(s): Y.Wakabayashil, K.Shimamoto, T.Shinada, Y.Ohfune
  • Organizer: The 16th Osaka City University International Symposium on Dynamic Molecular Devices
  • Place of Presentation: 大阪市立大学学術情報センター
  • Year and Date: 2011-11-09
• [Presentation] 新規置換ピリドンカルボン酸の合成研究 (2011)
  • Author(s): 白井和光、品田哲郎、大船泰史
  • Organizer: 第38回有機反応懇談会主催有機反応懇談会
  • Place of Presentation: 大阪府立大学
  • Year and Date: 2011-08-03
• [Presentation] 炭素鎖連結型シスチン誘導体の合成研究 (2011)
  • Author(s): 若林由華、品田哲郎、大船泰史
  • Organizer: 第38回有機反応懇談会主催有機反応懇談会
  • Place of Presentation: 大阪府立大学
  • Year and Date: 2011-08-03
• [Presentation] 生物活性天然物の全合成 (2011)
  • Author(s): 大船泰史
  • Organizer: 第43回有機合成セミナー(2011)
  • Place of Presentation: 大阪市立工業研究所(招待講演)
• [Presentation] Structure Activity Relationship of Kaitocephalin: Binding Structure of Kaitocephalin to Ionotropic Glutamate Receptor
  • Author(s): 品田哲郎
  • Organizer: 新学術領域研究「天然物ケミカルバイオロジー～分子標的と活性制御～」第4回公開シンポジウム
  • Place of Presentation: つくば国際会議場
• [Presentation] カイトセファリンのケミカルバイオロジー研究
  • Author(s): 品田哲郎
  • Organizer: 工学院大学工学部 セミナー
  • Place of Presentation: 工学院大学
  • Invited
• [Book] 「藻類ハンドブック」 (2012)
  • Author(s): 大船泰史
  • Total Pages: 768
  • Publisher: ＮＴＳ inc.
• [Remarks] 大阪市立大学理学研究科物質分子系専攻 分子変換学研究室
  • URL: http://www.sci.osaka-cu.ac.jp/chem/henkan/
• [Remarks] Molecular Conversion Laboratory
  • URL: http://www.sci.osaka-cu.ac.jp/chem/henkan/
• [Remarks] 大阪市立大学大学院理学研究科物質分子系専攻
  • URL: http://www.sci.osaka-cu.ac.jp/grad/MOLMS/
• [Remarks] 大阪市立大学大学院理学研究科物質分子系専攻分子変換学研究室
  • URL: http://www.sci.osaka-cu.ac.jp/chem/henkan/
• [Remarks] 大阪市立大学大学院理学研究科物質分子系専攻分子変換学研究室
  • URL: http://www.sci.osaka-cu.ac.jp/chem/henkan/index.html
• [Remarks]
  • URL: http://chembiochem.jp/
• [Remarks]
  • URL: http://www.sci.osaka-cu.ac.jp/chem/henkan/index.html