Multi-functionality and structure development of thalidomide

• Project/Area Number: 21790107
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Drug development chemistry
• Research Institution: The University of Tokyo
• Principal Investigator: YACHIDE Tomomi 東京大学, 分子細胞生物学研究所, 技術職員 (20401284)
• Project Period (FY): 2009 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2012: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2011: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2010: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2009: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: ケミカルバイオロジー / サリドマイド / 構造展開 / 構造活性相関 / マルチテンプレート / 肝臓Ｘ受容体 / 核内受容体 / ヒダントイン誘導体 / ピューロマイシン感受性アミノペプチダーゼ / 肝臓X受容体 / エストロゲン受容体 / ペルオキシソーム増殖剤応答性受容体 / α-グルコシダーゼ / グリコーゲンホスホリラーゼ / 糖尿病 / 分化誘導 / チューブリン / シクロオキシゲナーゼ / 血管新生

Research Abstract

I investigated the molecular mechanism of action of thalidomide andits metabolites, and cell signaling of biologically active derivatives of thalidomide. In addition, some biologically active compounds, such as nuclear receptor agonists/antagonists and enzyme inhibitors, have been created by structural development ofthalidomide and its derivatives. Based on these studies, I proved that thalidomide is usefulas a novel multi-template for development of various kinds of biologically activecompounds.

Research Products

• [Journal Article] Sructure-activity relationship of benzodiazepine derivatives as LXXLL peptide mimetics that inhibit the interaction of vitamin D receptor with (2013)
  • Author(s): Noguchi- Yachide, Yuichi Hashimoto and Minoru Ishikawa
  • Journal Title: Bioorg. Med. Chem Volume: 21 Pages: 993-1005
  • Peer Reviewed
• [Journal Article] Small-molecular, non-peptide, non-ATP-competitive polo-like kinase 1 (Plk1) inhibitors with a terphenyl skeleton (2013)
  • Author(s): Yusuke Mita, Tomomi Noguchi- Yachide, Minoru Ishikawa and Yuichi Hashimoto
  • Journal Title: Bioorg. Med. Chem Volume: 21 Pages: 608-617
  • Peer Reviewed
• [Journal Article] Small-molecular, non-peptide, non-ATP-competitive polo-like kinase 1 (Plk1) inhibitors with a terphenyl skeleton (2013)
  • Author(s): Mita, Y., Noguchi-Yachide, T., Ishikawa, M. and Hashimoto, Y.
  • Journal Title: Bioorg. Med. Chem. Volume: 21 Issue: 3 Pages: 608-617
  • DOI: 10.1016/j.bmc.2012.11.054
  • Peer Reviewed
• [Journal Article] Structure-activity relationship of benzodiazepine derivatives as LXXLL peptide mimetics that inhibit the interaction of vitamin D receptor with coactivators (2013)
  • Author(s): Mita, Y., Dodo, K., Noguchi-Yachide, T., Hashimoto, Y. and Ishikawa, M.
  • Journal Title: Bioorg. Med. Chem. Volume: 21 Issue: 4 Pages: 993-1005
  • DOI: 10.1016/j.bmc.2012.11.042
  • Peer Reviewed
• [Journal Article] Specific Inhibitors of Puromycin-Sensitive Aminopeptidase with a 3-(Halogenated Phenyl)-2,4(1H,3H)-quinazolinedione Skeleton. (2012)
  • Author(s): Yotaro Matsumoto, Tomomi Noguchi- Yachide, Masaharu Nakamura, Yusuke Mita, Akiyoshi Numadate, and Yuichi Hashimoto.
  • Journal Title: Heterocycles Volume: 86 Pages: 1449-1463
  • Peer Reviewed
• [Journal Article] Small-molecular inhibitors of Ca2+-induced mitochondrial permeability transition (MPT) derived from muscle relaxant dantrolene. (2012)
  • Author(s): Shunpei Murasawa, Katsuya Iuchi, Shinichi Sato, Tomomi Noguchi- Yachide, Mikiko Sodeoka, Tsutomu Yokomatsu, Kosuke Dodo, Yuichi Hashimoto, Y. and Hiroshi Aoyama
  • Journal Title: Bioorg. Med. Chem. Volume: 20 Pages: 6384-6393
  • Peer Reviewed
• [Journal Article] Design, synthesis, and biological evaluation of novel transrepression-selective liver X receptor (LXR) ligands with 5,11-dihydro-5-methyl-11-methylene-6 Hdibenz[b,e]azepin-6-one skeleton. (2012)
  • Author(s): Atsushi Aoyama, Kaori Endo-Umeda, Kenji Kishida, Kenji Ohgane, Tomomi Noguchi- Yachide, Hiroshi Aoyama, Minoru Ishikawa, Hiroyuki Miyachi, Makoto Makishima and Yuichi Hashimoto
  • Journal Title: J. Med. Chem Volume: 55 Pages: 7360-7377
  • Peer Reviewed
• [Journal Article] Design, synthesis, and biological evaluation of novel transrepression-selective liver X receptor (LXR) ligands with 5,11-dihydro-5-methyl-11-methylene-6H-dibenz[b,e]-azepin-6-one skeleton. (2012)
  • Author(s): Atsushi Aoyama
  • Journal Title: Journal of Medicinal Chemistry Volume: 55 Issue: 17 Pages: 7360-7377
  • DOI: 10.1021/jm3002394
  • Peer Reviewed
• [Journal Article] Small-molecular inhibitors of Ca2+-induced mitochondrial permeability transition (MPT) derived from muscle relaxant dantrolene. (2012)
  • Author(s): Shinpei Murasawa
  • Journal Title: Bioorganic & Medicinal Chemistry Volume: 20 Issue: 21 Pages: 6384-6393
  • DOI: 10.1016/j.bmc.2012.08.062
  • Peer Reviewed
• [Journal Article] Specific Inhibitors of Puromycin-Sensitive Aminopeptidase with a 3-(Halogenated Phenyl)-2,4(1H,3H)-quinazolinedione Skeleton (2012)
  • Author(s): Matsumoto, Y., Noguchi-Yachide, T., Nakamura, M., Mita, Y., Numadate, A. and Hashimoto, Y.
  • Journal Title: Heterocycles Volume: 86 Issue: 2 Pages: 1449-1463
  • DOI: 10.3987/com-12-s(n)109
  • Peer Reviewed
• [Journal Article] Estrogen receptor α/β ligands derived from thalidomide. (2011)
  • Author(s): Tomomi Noguchi - Yachi de, Kazuyuki Sugita and Yuichi Hashimoto.
  • Journal Title: Heterocycles Volume: 83 (9) Pages: 2137-2147
  • Peer Reviewed
• [Journal Article] Further Application of the Multi-Templ ate Approach f or Creati on of Biological Response Modifiers: Discovery of a New Class of Multifunctional Anti-Diabetic Agents. (2011)
  • Author(s): Kazunori Motoshima, Tomomi Noguchi- Yachi de, Minoru Ishikawa, Yui chi Hashi moto, and Kazuyuki Sugita
  • Journal Title: Heterocycles Volume: 82 (2) Pages: 1083-1101
  • Peer Reviewed
• [Journal Article] Estrogen receptor α/β ligands derived from thalidomide (2011)
  • Author(s): Tomomi Noguchi-Yachide, 他2名
  • Journal Title: Heterocycles Volume: 83 Pages: 2137-2147
  • Peer Reviewed
• [Journal Article] Further Application of the Multi-Template Approach for Creation of Biological Response Modifiers : Discovery of a New Class of Multifunctional Anti-Diabetic Agents (2011)
  • Author(s): Kazunori Motoshima, Tomomi Noguchi-Yachide, 他3名
  • Journal Title: Heterocycles Volume: 82 Pages: 1083-1101
  • Peer Reviewed
• [Journal Article] Novel Selective Anti-androgens with a Diphenylpentane Skeleton (2010)
  • Author(s): Keisuke Maruyama, Tomomi Noguchi- Yachi de, Kazuyuki Sugita, Yui chi Hashi moto and Mi noru Ishikawa
  • Journal Title: Bioorg. Med. Chem. Lett. Volume: 20 Pages: 6661-6666
  • Peer Reviewed
• [Journal Article] LXXLL peptide mimetics as inhibitorsof the interaction of vitamin D receptorwith coactivators (2010)
  • Author(s): Noguchi- Yachi de, Hiroyuki Miyachi, Makoto Makishima, Yuichi Hashimoto and Minoru Ishikawa
  • Journal Title: Bioorg. Med. Chem. Lett. Volume: 20 Pages: 1712-1717
  • Peer Reviewed
• [Journal Article] b-Naphthoflavone analogs as potentand soluble aryl hydrocarbon receptoragonists: Improvement of solubility bydisruption of molecular planarity (2010)
  • Author(s): Yuj i Fuj i ta, Mi tsuhi ro Yonehara, Masashi Tetsuhashi, Tomomi Noguchi- Yachi de, Yuichi Hashimotoand Minoru Ishikawa
  • Journal Title: Bioorg. Med. Chem. Volume: 18 Pages: 1194-1203
  • Peer Reviewed
• [Journal Article] Identification of Binding Proteins of Fusarielin A as Actin and Tubulin (2010)
  • Author(s): T.Noguchi-Yachide, 他6名
  • Journal Title: Chemical & Pharmaceutical Bulletin 58・1 Pages: 129-134
  • Peer Reviewed
• [Journal Article] β-Naphthoflavone analogs as potent and soluble aryl hydrocarbon receptor agonists : Improvement of solubility by disruption of molecular planarity (2010)
  • Author(s): Y.Fujita, M.Yonehara, M.Tetsuhashi, T.Noguchi-Yachide, 他2名
  • Journal Title: Bioorganic & Medicinal Chemistry 18 Pages: 1194-1203
  • Peer Reviewed
• [Journal Article] LXXLL peptide mimetics as inhibitors of the interaction of vitamin Dreceptor with coactivators (2010)
  • Author(s): Y.Mita, K.Dodo, T.Noguchi-Yachide, 他4名
  • Journal Title: Bioorganic & Medicinal Chemistry Letters 20 Pages: 1712-1717
  • Peer Reviewed
• [Journal Article] Separation of α-glucosidase-inhibitoryand liver X receptor-antagonistic activities of phenethylphenyl phthalimide analogs and generation of LXR-selective antagonists. (2009)
  • Author(s): Kazunori Motoshima, Tomomi Noguchi- Yachide, Kazuyuki Sugita,Yuichi Hashimoto and Minoru Ishikawa.
  • Journal Title: Bioorg. Med. Chem. Volume: 17 Pages: 5001-5014
  • Peer Reviewed
• [Journal Article] Enhancement of Chemically-induced HL-60 Cell Differentiation by 3,3'-Diindolylmethane (DIM) Derivatives. (2009)
  • Author(s): Tomomi Noguchi - Yachi de, Masashi Tetsuhashi , Hi roshi Aoyama and Yui chi Hashimoto.
  • Journal Title: Chem. Pharm. Bull. Volume: 57(5) Pages: 536-540
  • Peer Reviewed
• [Journal Article] Separation of α-glucosidase-inhibitory and liver X receptor-antagonistic activities of phenethylphenyl phthalimide analogs and generation of LXRα-selective antagonists (2009)
  • Author(s): K.Motoshima, T.Noguchi-Yachide, 他3名
  • Journal Title: Bioorganic & Medicinal Chemistry 17 Pages: 5001-5014
  • Peer Reviewed
• [Presentation] 免疫調節作用選択的な肝臓X受容体(LXR)リガンドの創製 (2012)
  • Author(s): 青山惇、梅田(遠藤)香織、岸田健治、大金賢司、谷内出(野口)友美、青山洋史、石川稔、宮地弘幸、槇島誠、橋本祐一
  • Organizer: 日本レチノイド研究会第23回学術集会
  • Place of Presentation: 鳥取県米子市
  • Year and Date: 2012-10-19
• [Presentation] サリドマイド由来エストロゲン受容体リガンドの創製 (2012)
  • Author(s): 谷内出友美、松本洋太郎、杉田和幸、橋本祐一
  • Organizer: 日本薬学会132年会
  • Place of Presentation: 北海道札幌市
• [Presentation] LiverXReceptor(LXR)リガンドの構造展開によるTransrepression作用選択的リガンドの創製 (2012)
  • Author(s): 青山惇、梅田(遠藤)香織、谷内出(野口)友美、石川稔、宮地弘幸、槇島誠、橋本祐一
  • Organizer: 日本薬学会132年会
  • Place of Presentation: 北海道札幌市
• [Presentation] 虚血性細胞死抑制活性を有する低分子化合物の創製 (2012)
  • Author(s): 村澤慎平、青山洋史、どど孝介、谷内出友美、橋本祐一
  • Organizer: 日本薬学会132年会
  • Place of Presentation: 北海道札幌市
• [Presentation] LXXLL配列を模倣したVDR-コアクチベーター相互作用阻害物質の構造活性相関 (2012)
  • Author(s): 三田裕介、どど孝介、谷内出友美、橋本祐一、石川稔
  • Organizer: 日本薬学会132年会
  • Place of Presentation: 北海道札幌市
• [Presentation] サリドマイド由来エストロゲン受容体リガンドの創製 (2012)
  • Author(s): 谷内出友美, 他3名
  • Organizer: 日本薬学会132年会
  • Place of Presentation: 北海道大学
• [Presentation] Improvement in aqueous solubility of biocyclic molecules by disruption of molecular planarity and symmetry (2011)
  • Author(s): M. Ishikawa, Y. Fujita, J. Kasuga, M. Yonehara, T. Noguchi - Ychide, H. Miyachi and Y. Hashimoto
  • Organizer: AIMECS11, 8th AFMC International Medicinal Chemistry Symposium "Frontier of Medicinal Science"
  • Place of Presentation: Tokyo
• [Presentation] LXXLL peptide mimetics as inhibitors ofthe interaction of vitamin D receptor (2011)
  • Author(s): Y. Mita, K. Dodo, T. Noguchi- Yachide, H. Miyachi and Y. Hashimoto.
  • Organizer: AIMECS11, 8th AFMC International Medicinal Chemistry Symposium "Frontier of Medicinal Science"
  • Place of Presentation: Tokyo
• [Presentation] Further application of the multi-template approach for creation of biologically active compounds: discovery of a new class of multifunctional anti-diabetic agents. (2011)
  • Author(s): K. Sugita, K. Motoshima, T. Noguchi- Yachide, M. Ishikawa and Y. Hashimoto.
  • Organizer: AIMECS11, 8th AFMC International Medicinal Chemistry Symposium "Frontier of Medicinal Science"
  • Place of Presentation: Tokyo
• [Presentation] LXR依存的なTransrepression作用選択的リガンドの創製 (2011)
  • Author(s): 青山惇、遠藤香織、谷内出友美、青山洋史、石川稔、槇島誠、宮地弘幸、橋本祐一
  • Organizer: 日本薬学会第131年会
  • Place of Presentation: 静岡
• [Presentation] ジフェニルペンタン骨格を有する選択的抗アンドロゲン物質の創製研究 (2011)
  • Author(s): 丸山慶輔、谷内出友美、杉田和幸、橋本祐一、石川稔
  • Organizer: 日本薬学会第131年会
  • Place of Presentation: 静岡
• [Presentation] Further application of the multi-template approach for creation of biologically active compounds : discovery of a new class of multifunctional anti-diabetic agents (2011)
  • Author(s): Kazuyuki Sugita, 他4名(3番目)
  • Organizer: AIMECS11, 8th AFMC International Medicinal Chemistry Symposium "Frontier of Medicinal Science"
  • Place of Presentation: Tokyo
• [Presentation] LXRを介した抗炎症作用を有する選択的リガンドの創製 (2010)
  • Author(s): 青山惇, 他6名(2番目)
  • Organizer: 日本薬学会第130年会
  • Place of Presentation: 岡山桃太郎アリーナ
  • Year and Date: 2010-03-29
• [Presentation] LXXLL配列を模倣した核内受容体-コアクチベーター阻害物質の創製 (2010)
  • Author(s): 三田裕介, 他5名(3番目)
  • Organizer: 日本薬学会第130年会
  • Place of Presentation: 岡山大学津島キャンパス
  • Year and Date: 2010-03-28
• [Presentation] 難溶性を改善したAhRリガンドの創製 (2010)
  • Author(s): 藤田優史, 他5名(4番目)
  • Organizer: 日本薬学会第130年会
  • Place of Presentation: 岡山大学津島キャンパス
  • Year and Date: 2010-03-28
• [Presentation] Design, synthesis and evaluation of transrepression-selective ligands, bearing anti-inflammatory activity mediated by LXR. (2010)
  • Author(s): A. Aoyama, T. Yachi de, H. Aoyama, M. Ishikawa, M. Makishima, H. Miyachi and Y. Hashimoto
  • Organizer: The International Chemical Congress of Pacific Basin Societies
  • Place of Presentation: Hawaii
• [Presentation] ss-Naphthoflavone analogs as potent and soluble aryl hydrocarbon receptor agonists: Improvement of solubility by disruption of molecular planarity. (2010)
  • Author(s): Y. Fuj i t a, M. Yonehara, M. Tetsuhashi, T. Noguchi - Yachi de, Y. Hashimoto and M. Ishikawa
  • Organizer: The International Chemical Congress of Pacific Basin Societies
  • Place of Presentation: Hawaii
• [Presentation] Selective anti-androgens with a 3,3-diphenylpentane skeleton . (2010)
  • Author(s): K. Maruyama, M. Ishikawa, T. Noguchi- Yachi de and Y. Hashimoto
  • Organizer: The International Chemical Congress of Pacific Basin Societies
  • Place of Presentation: Hawaii
• [Presentation] LXXLL peptide mimetics as inhibitors of the interaction of vitamin D receptor with coactivators. (2010)
  • Author(s): Yachi de, H. Miyachi, Y. Hashimoto and M. Ishikawa
  • Organizer: The International Chemical Congress of Pacific Basin Societies
  • Place of Presentation: Hawaii
• [Presentation] 難溶性を改善したAhRリガンドの創製 (2010)
  • Author(s): 藤田優史、米原光拡、鉄橋正士、谷内出友美、橋本祐一、石川稔
  • Organizer: 第29回メディシナルケミストリーシンポジウム
  • Place of Presentation: 京都テレサ
• [Presentation] LXXLL配列を模倣したビタミンD受容体-コアクチベーター相互作用阻害物質の創製- (2010)
  • Author(s): 三田裕介、どど孝介、谷内出友美、宮地弘幸、橋本祐一、石川稔
  • Organizer: 第29回メディシナルケミストリーシンポジウム
  • Place of Presentation: 京都テレサ
• [Presentation] LXRを介した抗炎症作用を有する選択的リガンドの創製 (2010)
  • Author(s): 青山惇、谷内出友美、青山洋史、石川稔、槇島誠、宮地弘幸、橋本祐一
  • Organizer: 日本薬学会第130年会
  • Place of Presentation: 岡山
• [Presentation] LXXLL配列を模倣した核内受容体-コアクチベーター阻害物質の創製 (2010)
  • Author(s): 三田裕介、どど孝介、谷内出友美、宮地弘幸、橋本祐一、石川稔
  • Organizer: 日本薬学会第130年会
  • Place of Presentation: 岡山
• [Presentation] 難溶性を改善したAhRリガンドの創製 (2010)
  • Author(s): 藤田優史、米原光拡、鉄橋正士、谷内出友美、橋本祐一、石川稔
  • Organizer: 日本薬学会第130年会
  • Place of Presentation: 岡山
• [Presentation] 環状イミドを有するヒダントイン類の合成と活性評価 (2009)
  • Author(s): 山口淳一, 他4名(2番目)
  • 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: 東京大学安田講堂
  • Year and Date: 2009-11-26
• [Presentation] サリドマイド誘導体におけるα-glucosidase とLXR活性の作用分離、および glycogen phosphorylase 阻害活性 (2009)
  • Author(s): 本島和典, 他4名(3番目)
  • 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: 東京大学安田講堂
  • Year and Date: 2009-11-26
• [Presentation] 環状イミドを有するヒダントイン類の合成と活性評価 (2009)
  • Author(s): 山口淳一、谷内出友美、坂口由佳、柴田千秋、橋本祐一
  • 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
• [Presentation] サリドマイド誘導体におけるα-glucosidaseとLXR活性の作用分離、およびglycogenphosphorylase阻害活性 (2009)
  • Author(s): 島和典、石川稔、谷内出友美、杉田和幸、橋本祐一
  • 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
• [Presentation] 免疫調節作用選択的な肝臓Ｘ受容体（ＬＸＲ）リガンドの創製
  • Author(s): 青山惇
  • Organizer: 日本レチノイド研究会第23回学術集会
  • Place of Presentation: 米子（鳥取県）
• [Remarks]
  • URL: http://www.iam.u-tokyo.ac.jp/chem/IMCB-8ken-HP/Index.html
• [Remarks] 東京大学 分子細胞生物学研究所 生体有機化学研究分野
  • URL: http://www.iam.u-tokyo.ac.jp/chem/IMCB-8ken-HP/Index.html