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Development of Phthalimide-type Novel Tumor Necrosis Factor (TNF) Production-regulators

Research Project

Project/Area Number 07457548
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field 医薬分子機能学
Research InstitutionTHE UNIVERSITY OF TOKYO

Principal Investigator

HASHIMOTO Yuichi  THE UNIVERSITY OF TOKYO,Insititute of Molecular and Cellular Biosciences, Professor, 分子細胞生物学研究所, 教授 (90164798)

Co-Investigator(Kenkyū-buntansha) MORISAKI Naoko  THE UNIVERSITY OF TOKYO,Assistant Proffesor, 分子細胞生物学研究所, 助手 (00092354)
SHIRAI Ryuichi  THE UNIVERSITY OF TOKYO,Assistant Professor, 分子細胞生物学研究所, 助手 (80183838)
岩崎 成夫  東京大学, 分子細胞生物学研究所, 教授 (00013326)
Project Period (FY) 1995 – 1997
Project Status Completed (Fiscal Year 1997)
Budget Amount *help
¥6,300,000 (Direct Cost: ¥6,300,000)
Fiscal Year 1997: ¥2,100,000 (Direct Cost: ¥2,100,000)
Fiscal Year 1996: ¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 1995: ¥2,400,000 (Direct Cost: ¥2,400,000)
Keywordstumor necrosis factor / phthalimide / cytokine / thalidomide / cell type / bidirectional regulation / enantio-dependence / biological response modifier / 光学異性体 / 医薬品化学 / 生物応答調節剤
Research Abstract

Thalidomide (N-alpha-phthalimidoglutarimide) was used widely as a hypnotic/sedative agent in the late 1950s and the early 1960s, but had to be withdrawn from the market because of its severe teratogenicity. In spite of this, there has been a resurgence of interest in the drug in recent years due to its potential usefulness for the treatment of various deseases, including acquired immunodeficiency syndrome (AIDS), leprosy, malaria, and graft-versus-host desease (GVHD). It has been also attracting attention because of its efficient antiangiogenetic activity. The effectiveness of the drug in these deseases has been attributed to its specific inhibitory activity on tumor necrosis factor (TNF), -alpha production. Because TNF-alpha, a cytokine medating host defense and immune regulation, with a wide range of activities, has deletorious pathophysiological effects in various deseases, including AIDS,tumors, theumatoid arthritis, and diabetes, its production-regulators are are attracative lead … More compounds for novel biological response modifiers. The regulatory effect of thalidomide on TNF-alpha production has been found to be bidirectional, depending on both the cell-type and the TNF-alpha production-inducer ; i.e., thalidomide possesses both enhancing and inhibiting activities on TNF-alpha production. Structural modification of thalidomide aiming at the creation of superior TNF-alpha production-regulators has a afforded a number of pheny1- and benzylphthalimide analogs possessing more potent activity than thalidomide itself. The structure-activity relationships of these analogs has been investigated. The bidirectional TNF-alpha production-regulating activity is electronic state- and enantio-dependent, and both pure potent inhibitors and pure potent enhancers of TNF-alpha production has been obatined. Further structural development of the phthalimide analogs has yielded potent non-steroidal androgen antagonists (much more potent than flutamide) and potent aminopeptidase N-inhibitors (more potent than bestatin). Less

Report

(4 results)
  • 1997 Annual Research Report   Final Research Report Summary
  • 1996 Annual Research Report
  • 1995 Annual Research Report
  • Research Products

    (29 results)

All Other

All Publications (29 results)

  • [Publications] Y.Shibataら: "Pheny Lphthalimides with tumor necrosis factor α produetion-enhancing〜." Chem.Pharm.Bull.44・1. 156-162 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] H.Miyachiら: "Inducer-specific bidirectional regulation by thalidomide and〜." Biochem.Biophys.Res.Commun.244・2. 426-430 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] H.Miyachiら: "Cell type-/inducer-specific bidirectional regulation by thaliclomide〜." Biochem.Biophys.Res.Commun.226・2. 439-444 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] 宮地 弘幸ら: "新しい生物学的応答調節剤:TNF-α産生調節活性を持つフタルイミド誘導体." 薬学雑誌. 166・2. 91-104 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] H.Miyachiら: "Novel biological response modifiers:Phthalimides with tumor necrosis〜" J.Med.Chem.40.18. 2858-2865 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] H.Miyachiら: "Tumor necrosis factor-α production-inhibiting activity of〜." Bioorg.Med.Chem.5・11. 2095-2102 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Y.Shibata, K.Sasaki, Y.Hashimoto, S.Iwasaki: "Phenylphthalimides with tumor necrosis factor alpha production-enhancing activity." Chem.Pharm.Bull.44. 156-162 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] H.Miyachi, A.Azuma, E.Hioki, S.Iwasaki, Y.Kobayashi, Y.Hashimoto: "Inducer-specific bidirectional regulation by thalidomide and phenyl-phthalimides of tumor necrosis factor-alpha production." Biochem.Biophys.Res.Commun.224. 426-430 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] H.Miyachi, A.Azuma, E.Hioki, S.Iwasaki, Y.Kobayashi, Y.Hashimoto: "Cell type-/inducer-specific bidirectional regulation by thalidomide and phenylphthalimides of tumor necrosis factor-alpha production, and its inantio-dependence." Biochem.Biophys.Res.Commun.226. 439-444 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] H.Miyachi, A.Azuma, A.Ogasawara, E.Uchimura, N.Watanabe, Y.Kobayashi, F.Kato, M.Kato, Y.Hashimoto: "Novel biological response modifiers, phthalimides with tumor necrosis factor-alpha production-regulating activity." J.Med.Chem.40. 2858-2865 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] H.Miyachi, A.Ogasawara, A.Azuma, Y.Hashimoto: "Tumor necrosis factor-alpha production-inhibiting activity of phthalimide analogs on human leukemia THP-1 cells and a structure-activity relationship study." Bioorg.Med.Chem.5. 2095-2102 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] 宮地弘幸, 我妻昭彦, 橋本祐一: "新しい生物学式応答調節剤:TNF-α産生調節活性を持つフタルイミド誘導体" 薬学雑誌. 116・2. 91-104 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] H.Miyachiら: "Novel biological response modifiers : Phthalimides with tumor necrosis 〜." J.Med.Chem.40・18. 2858-2865 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] H.Miyachiら: "Tumor necrosis factor-alpha production-inhibiting activity of 〜." Bioorg.Med.Chem.5・11. 2095-2102 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] 橋本 祐一: "サリドマイドによる TNF-αの産生抑制" 臨床免疫. 29・11. 1403-1408 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] H.Miyachiら: "Potent novel nonsteroidal androgen antagonists with α 〜." Bioorg.Med.Chem.Lett.7・11. 1483-1488 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] H.Umemiyaら: "Action mechanism of retinoid-synergistic dibenzodiazepines." Biochem.Biophys.Res.Commun.233・1. 121-125 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Yoshihiro Shibata ら: "Phenylphthalimides with tumor necrosis factor alpha prodution-enhencing activity." Chemical and Pharmaceutical Bulletin. 44・1. 156-162 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Akihiko Azuma ら: "Augmentation by phthalimides of phorbol ester-induced expression of tumor necrosis〜." Biological and Pharmaceutical Bulletin. 19・7. 1001-1003 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Hiroyuki Miyachi ら: "Inducer-specific bidirectional regulation by thalidomide and phenylphthalimides of〜." Biochemical and Biophysical Research Communications. 224・2. 426-430 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Hiroyuki Miyachi ら: "Cell type-/inducer-specific bidirectional regulation by thalidomide and〜." Biochemical and Biophysical Research Communications. 226・2. 439-444 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Hiroyuki Miyachi ら: "Inducer-specific regulutors of tumor necrosis alpha production." Chemical and Pharmaceutical Bulletin. 44・10. 1980-1982 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Hiroyuki Miyachi ら: "Enantio-dependence of inducer-specific bidirectional regulation of tumor〜." Bioorganic and Medicinal Chemistry Letters. 6・19. 2293-2298 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Yoshihiro Shibata ら: "N-AlkyLphthalimides: Structural requirement of thalidomidal action on 12-0-retradecanoyl-phorbol-13-acetate-induced tumor necrosis factor α production by human leukemia HL-60 cells." Chemical and Pharmaceutical Bulletin. 43. 177-179 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Keizo Sasaki ら: "BenzyLphthalimides and phenylphthalimides with thalidomid-like activity on the production of tumor necrosis factor α." Biological and Pharmaceutical Bulletin. 18. 1228-1233 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Yoshihiro Shibata ら: "Phenylphthalimides with tumor necrosis factor alpha production-enhancing activity." Chemical and Parmaceutical Bulletin. 44. 156-162 (1996)

    • Related Report
      1995 Annual Research Report
  • [Publications] Osamu Nakajima ら: "Possible involvement of peripheral-type benzodiazepine receptor in erythroid differentiation of human leukemia cell line, K562" Biological and Pharmaceutical Bulletin. 18. 903-906 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Osamu Nakajima ら: "Possible involvement of retinoid-like cofactor in serum in hemin/protoporphyrin IX-induced differentiation of human leukemia K562 cells." Biochemical and Biophysical Research Communications. 207. 444-451 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Hiroki Umemiya ら: "Synergists for retinoid in cellular differentiation of human promyelorytic leukemia cells HL-60" Chemical and Pharmaceutical Bulletin. 43. 1827-1829 (1995)

    • Related Report
      1995 Annual Research Report

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Published: 1995-04-01   Modified: 2016-04-21  

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