Useful β-turn mimetics having three-dimensional diversity

• Project/Area Number: 21390028
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Drug development chemistry
• Research Institution: Hokkaido University
• Principal Investigator: SHUTO Satoshi 北海道大学, 大学院・薬学研究院, 教授 (70241346)
• Co-Investigator(Kenkyū-buntansha): ARISAWA Mitsuhiro 北海道大学, 大学院・薬学研究院, 准教授 (40312962)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥18,070,000 (Direct Cost: ¥13,900,000、Indirect Cost: ¥4,170,000); Fiscal Year 2011: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000); Fiscal Year 2010: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000); Fiscal Year 2009: ¥8,190,000 (Direct Cost: ¥6,300,000、Indirect Cost: ¥1,890,000)
• Keywords: βターン / ペプチドミメティック / シクロプロパン / MC4 / Grb2 / メラノコルチン受容体 / ペプチドミメティックス / 活性配座 / 配座制御 / 三次元的多様性 / 分子設計

Research Abstract

The stereochemical diversity-oriented b-turn mimetics were designed and efficient and stereoselective synthetic method of them have been developed. Applying the mimetics to the development of melanocortin receptor ligands, we discovered a highly potent non-peptidic lead. Thus, the stereochemical diversity-oriented b-turn mimetics were shown to be useful in developing a non-peptidic lead, especially in cases where the binding conformation of the ligand and the structural data of the receptors are lacking or are poorly documented.

Research Products

• [Journal Article] Cyclopropane-Based Stereochemical Diversity-Oriented Conformational Restriction Strategy : Histamine Analog swith the4-Amino-2, 3-methano-1-(1H-imidazol-4-yl) butane Structure as Highly PotentHistamine H_3 and/or H4 Receptor Ligands. Org (2012)
  • Author(s): M. Watanabe, T. Kobayashi, T. Hirokawa, A. Yoshida, Y. Ito, S. Yamada, N. Orimoto, Y. Yamasaki, M. Arisawa, S. Shuto
  • Journal Title: Biomol. Chem Volume: 10 Issue: 4 Pages: 736-745
  • DOI: 10.1039/c1ob06496g
  • Peer Reviewed
• [Journal Article] Cyclopropane-Based Stereochemical Diversity-Oriented Conformational Restriction Strategy : Histamine Analogs with the 4-Amino-2,3-methano-1-(1H-imidazol-4-y1) butane Structure as Highly Potent Histamine H3 and/or H4 Receptor Ligands (2012)
  • Author(s): M.Watanabe, T.Kobayashi, T.Hirokawa, A.Yoshida, Y.Ito, S.Yamada, N.Orimoto, Y.Yamasaki, M.Arisawa, S.Shuto
  • Journal Title: Org.Biomol.Chem Volume: 10 Pages: 736-745
  • Peer Reviewed
• [Journal Article] Synthesis and discovery of N-carbonylpyrrolidine- or N-sulfonylpyrrolidine-containing uracil derivatives as potent human deoxyuridine triphosphatase inhibitors (2012)
  • Author(s): H.Miyakoshi, S.Miyahara, T.Yokogawa, K.T.Chong, J.Taguchi, K.Endoh, W.Yano, T.Wakasa, H.Ueno, Y.Takao, M.Nomura, S.Shuto, H.Nagasawa, M.Fukuoka
  • Journal Title: J.Med.Chem. Volume: 55 Pages: 2960-2969
  • Peer Reviewed
• [Journal Article] Discovery of a novel class of potent human deoxyuridine triphosphatase inhibitors remarkably enhancing the antitumor activity of thymidylate synthase inhibitors (2012)
  • Author(s): S.Miyahara, H.Miyakoshi, T.Yokogawa, K.T.Chong, J.Taguchi, T.Muto, K.Endoh, W.Yano, T.Wakasa, H.Ueno, Y.Takao, A.Fujioka, A.Hashimoto, K.Itou, K.Yamamura, M.Nomura, H.Nagasawa, S.Shuto, M.Fukuoka
  • Journal Title: J.Med.Chem. Volume: 55 Pages: 2970-2980
  • Peer Reviewed
• [Journal Article] Synthesis of a series of 3,4-methanoarginines as side-chainconformationally restricted analogues of arginine (2011)
  • Author(s): M. Watanabe, K. Yamaguchi, W. Tang, K. Yoshida, R. B. Silverman, M. Arisawa, S. Shuto
  • Journal Title: Bioorg. Med. Chem Volume: 19 Pages: 5984-5988
  • URL: http://www.ncbi.nlm.nih.gov/pubmed/21917467
  • Peer Reviewed
• [Journal Article] Alkene isomerization/enamide-ene and diene metathesis for the construction of indoles, quinolines, benzofurans and chromenes with a chiral cyclopropane substituent (2011)
  • Author(s): Kobayashi, T., Arisawa, M., Shuto, S.
  • Journal Title: Organic & Biomolecular Chemistry Volume: 9 Issue: 4 Pages: 1219-1224
  • DOI: 10.1039/c0ob00597e
  • Peer Reviewed
• [Journal Article] Alkene isomerization/enamide-ene and diene metathesis for the construction of indoles, quinolines, benzofurans and chromenes with a chiral cyclopropane substituent (2011)
  • Author(s): T.Kobayashi, M.Arisawa, S.Shuto
  • Journal Title: Org.Biomol.Chem Volume: 9 Pages: 1219-1224
  • Peer Reviewed
• [Journal Article] Design and synthesis of conformationally restricted indomethacin analogues that enhance doxorubicin cytotoxicity in multidrug resistant cells without cyclooxygenase inhibitory activity (2011)
  • Author(s): M.Arisawa, Y.Kasaya, T.Obata, T.Sasaki, M.Ito, H.Abe, Y.Ito, A.Yamano, S.Shuto
  • Journal Title: ACS Med.Chem.Lett Volume: 2 Pages: 353-357
  • Peer Reviewed
• [Journal Article] Synthesis and characterization of a series of highly fluorogenic substrates for glutathione transferases, a general strategy (2011)
  • Author(s): J.Zhang, A.Shibata, M.Ito, S.Shuto, Y.Ito, B.Mannervik, H.Abe. R.Morgenstern
  • Journal Title: J.Am.Chem.Soc Volume: 133 Pages: 14109-14119
  • Peer Reviewed
• [Journal Article] Characterization of new potential anti-cancer drugs designed to overcome glutathione transferase mediated resistance (2011)
  • Author(s): K.Johansson, M.Ito, C.M.S.Schophuizen, S.Mathew, V.Heuser, J.Zhang, M.Shimoji, M.E.Vahter, W.H.Ang, P.J.Dyson, A.Shibate, S.Shuto, Y.Ito, H.Abe, R.Morgenstern
  • Journal Title: Mol.Pharmaceut Volume: 8 Pages: 1698-1708
  • Peer Reviewed
• [Journal Article] Synthesis of a series of 3,4-methanoarginines as side-chain conformationally restricted analogues of arginine (2011)
  • Author(s): M.Watanabe, K.Yamaguchi, W.Tang, K.Yoshida, R.B.Silverman, M.Arisawa, S.Shuto
  • Journal Title: Bioorg.Med.Chem Volume: 19 Pages: 5984-5988
  • Peer Reviewed
• [Journal Article] One-pot ring-closing metathesis(RCM)/oxidation by an assisted tandem rutheniumcatalysis for the synthesis of 2-quinolones (2011)
  • Author(s): H.Kato, T.Ishigame, N.Oshima, K.Shimawaki, M.Arisawa, S.Shuto
  • Journal Title: Adv.Synth.Cat Volume: (in press)
  • Peer Reviewed
• [Journal Article] Alkene isomerization/enamide-ene and diene metathesis for the construction of indoles, quinolines, benzofurans and chromenes with a chiral cyclopropane substituent. (2011)
  • Author(s): T.Kobayashi., et ai.
  • Journal Title: Org.Biomol.Chem. Volume: 9 Pages: 1219-1224
  • Peer Reviewed
• [Journal Article] Design and Synthesis of Conformationally Restricted Indomethacin Analogues that Enhance Doxorubicin Cytotoxicity in Multidrug Resistant Cells without Cyclooxygenase Inhibitory Activity. (2011)
  • Author(s): M.Arisawa., et ai.
  • Journal Title: ACS Med.Chem.Lett. Volume: in press
  • Peer Reviewed
• [Journal Article] Investigation of the Bioactive Conformation of Histamine H_3 ReceptorAntagonists by the Cyclopropylic Strain-Based Conformational Restriction Strategy (2010)
  • Author(s): M. Watanabe, T. Hirokawa, T. Kobayashi, A. Yoshida, Y. Ito, S. Yamada, N. Orimoto, Y. Yamasaki, M. Arisawa, S. Shuto
  • Journal Title: J. Med. Chem Volume: 53 Issue: 9 Pages: 3585-3593
  • DOI: 10.1021/jm901848b
  • Peer Reviewed
• [Journal Article] Synthesis and Structural and Pharmacological Properties of cyclopropane-based conformationally restricted analogs of 4-methylhistamine as histamine H_3/H_4 receptor ligands. Bioorg (2010)
  • Author(s): T. Kobayashi, M. Watanabe, A. Yoshida, S. Yamada, M. Ito, H. Abe, Y. Ito, M. Arisawa, S. Shuto
  • Journal Title: Med. Chem Volume: 18 Pages: 1076-1082
  • URL: http://www.ncbi.nlm.nih.gov/pubmed/20045649
  • Peer Reviewed
• [Journal Article] Design and Synthesis of Indole Derivatives of Adenophostin A. A Entry into Subtype-Selective IP_3 Receptor Ligands. (2010)
  • Author(s): T.Mochizuki., et ai.
  • Journal Title: Tetrahedron Lett. Volume: 51 Pages: 977-979
  • Peer Reviewed
• [Journal Article] Synthesis and Structural and Pharmacological Properties of Cyclopropane-Based Conformationally Restricted Analogs of 4-Methylhistamine as Histamine H_3/H_4 Receptor Ligands. (2010)
  • Author(s): T.Kobayashi., et ai.
  • Journal Title: Bioorg.Med.Chem. Volume: 18 Pages: 1076-1082
  • Peer Reviewed
• [Journal Article] Investigation of the Bioactive Conformation of Histamine H_3 Receptor Antagonists by the Cyclopropylic Strain-Based Confo rmational Restriction Strategy. (2010)
  • Author(s): M.Watanabe., et ai.
  • Journal Title: J.Med.Chem. Volume: 53 Pages: 3585-3593
  • Peer Reviewed
• [Journal Article] Sulfur Modification of Au via Treatment with Piranha Solution Provides Low-Pd releasing and recyclable Pd Material, SAPd. (2010)
  • Author(s): N.Hoshiya., et ai.
  • Journal Title: J.Am.Chem.Soc. Volume: 132 Pages: 7270-7271
  • Peer Reviewed
• [Journal Article] Structure determination of Pd-catalyst supported on S-terminated GaAs(001) using DFT calculation. (2010)
  • Author(s): A.Ishii., et ai.
  • Journal Title: Physica Status Solidi C : Current Topics in Solid State Physics Volume: 7 Pages: 359-361
  • Peer Reviewed
• [Journal Article] Hard x-ray photoemission spectroscopic investigation of palladium catalysts immobilized on a GaAs(001)surface (2010)
  • Author(s): M.Shimoda., et ai.
  • Journal Title: J.Appl.Phy. Volume: 108 Pages: 24309-24309
  • Peer Reviewed
• [Journal Article] Synthesis and Structural and Pharmacological Properties of Cyclopropane-Based Conformationally Restricted Analogs of 4-Methyl histamine as Histamine H_3/H_4 Receptor Ligands. (2010)
  • Author(s): T.Kobayashi., et al.
  • Journal Title: Bioorg.Med.Chem. 18 Pages: 1076-1082
  • Peer Reviewed
• [Journal Article] Three-dimensional structure-activity relationship study of belactosin A and its stereo and regioisomers : development of potent proteasome inhibitors by the stereochemical diversity-oriented strategy. Org (2009)
  • Author(s): K. Yoshida, K. Yamaguchi, A. Mizuno, Y. Unno, A. Asai, T. Sone, H. Yokosawa, A. Matsuda, M. Arisawa, S. Shuto
  • Journal Title: Biomol. Chem Volume: 7 Pages: 1868-1877
  • URL: http://www.ncbi.nlm.nih.gov/pubmed/19590782
  • Peer Reviewed
• [Journal Article] Three-dimensional structure-activity relationship study of belactosin A and its stereo- and regioisomers : development of potent proteasome inhibitors by the stereochemical diversity-oriented strategy. (2009)
  • Author(s): K.Yoshida., et al.
  • Journal Title: Org.Biomol.Chem. 7 Pages: 1688-1877
  • Peer Reviewed
• [Journal Article] Investigation of the Bioactive Conformation of Histamine H_3 Receptor Antagonists by the Cyclopropylic Strain-Based Conformational Restriction Strategy.
  • Author(s): M.Watanabe., et al.
  • Journal Title: J.Med.Chem. (in press)
  • Peer Reviewed
• [Presentation] Structure-Activity Relationship Study of Unnatural cis-Isomer of Belactosin A, a Potent Proteasome Inhibitor (2011)
  • Author(s): Shuhei, Kawamura, Yuka, Unno, Motohiro, Tanaka, Takuma, Sasaki, Akira, Asai, Mitsuhiro, Arisawa, and Satoshi, Shuto
  • Organizer: AIMECS 11 8t AFMC International Medicinal Chemistry Symposium Frontier of Medicinal Science
  • Place of Presentation: 京王プラザホテル東京(東京都)
• [Presentation] 三次元多様型配座制御法に基づくペプチドミメティックの設計.メラノコルチン受容体リガンドの創製- (2011)
  • Author(s): 水野彰、三浦志帆、渡辺瑞貴、小田上剛直、小上裕二、有澤光弘、周東智
  • Organizer: 第37回反応と合成の進歩シンポジウム
  • Place of Presentation: 徳島大学(徳島市)
• [Presentation] Investigation of the bioactive conformation of Histamine H3/H4 receptor antagonists by the conformational restriction strategy (2011)
  • Author(s): Kobayashi, T. , Watanabe, M., Hirokawa, T., Yamada, S., Arisawa, M., Shuto, S.
  • Organizer: 8th AFMC International Medicinal Chemistry Symposium (AIMECS11)
  • Place of Presentation: 京王プラザホテル東京(東京都)
• [Presentation] Design of Stereochemical Diversity-Oriented Cyclopropane-Based Peptidomimetics : Development of Potent Melanocortin Receptor Ligands (2011)
  • Author(s): Mizuno, A.; Miura, S.; Watanabe, M.; Uchida, S.; Yamada, S.; Arisawa, M.; Shuto, S.
  • Organizer: Otsu Conference 2011
  • Place of Presentation: 大津プリンスホテル(滋賀県)
• [Presentation] Stereochemical Diversity-Oriented Design of Cyclopropane-Based Peptidomimetics : Synthesis of Melanocortin Receptor Ligands (2011)
  • Author(s): Mizuno, A.; Miura, S.; Watanabe, M.; Uchida, S.; Yamada, S.; Arisawa, M.; Shuto, S.
  • Organizer: 28th Herbert C. Brown Lectures
  • Place of Presentation: Purdue University (USA)
• [Presentation] 制がん性プロテアソーム阻害剤ベラクトシンAシス型立体異性体の構造活性相関研究 (2011)
  • Author(s): 川村周平、海野雄加、田中基裕、佐々木磨、浅井章良、有澤光弘、周東智
  • Organizer: 第131年会日本薬学会
  • Place of Presentation: グランシップツインメッセ静岡(静岡県)
• [Presentation] Enamide-ene methasesis for constructing chiral 2-cyclopropylheterocycles : Indole, quinoline, benzofuran and chromene (2010)
  • Author(s): Kobayashi, T., Arisawa, M., Shuto, S.
  • Organizer: 240th American Chemical Society National Meeting
  • Place of Presentation: Boston Convention & Exposition Center (USA)
• [Presentation] 光学活性シクロプロパンを有する複素環化合物合成法の開発 (2010)
  • Author(s): 小林嵩明、有澤光弘、周東智
  • Organizer: 日本薬学会第130年会
  • Place of Presentation: 岡山コンベンションセンター(岡山県)、岡山大学(岡山市)
• [Presentation] シクロプロパン歪みに基づくヒスタミンH3受容体リガンドの設計と活性配座解析 (2009)
  • Author(s): 小林嵩明、渡辺瑞貴、広川貴次、吉田徳、伊東由彦、山田静雄、有澤光弘、周東智
  • Organizer: 第28回メディシナルケミストリーシンポジウム
  • Place of Presentation: 東京大学(文京区)
• [Presentation] 立体多様性を鍵とするシクロプロパン型ペプチドミメティック-メラノコルチン受容体リガンドの創製研究- (2009)
  • Author(s): 水野彰、梶原浩気、三浦志帆、渡辺瑞貴、吉田徳、内田信也、山田静雄、小田上剛直、小上裕二、有澤光弘、周東智
  • Organizer: 第7回次世代を担う有機化学シンポジウム
  • Place of Presentation: 大阪大学(吹田市)
• [Book] 有機医薬分子論 (2011)
  • Author(s): 周東智
  • Total Pages: 320
  • Publisher: 京都廣川書店出版