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Structural development of bio-active compounds affecting nuclear receptor function

Research Project

Project/Area Number 10470461
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Chemical pharmacy
Research InstitutionThe University of Tokyo

Principal Investigator

HASHIMOTO Yuichi  Institute of Molecular and Cellular Biosciences, The University of Tokyo, professor, 分子細胞生物学研究所, 教授 (90164798)

Co-Investigator(Kenkyū-buntansha) KOBAYASHI Hisayoshi  Institute of Molecularand Cellular Biosciences, The University of Tokyo, assistant professor, 分子細胞生物学研究所, 助手 (80225531)
KOISO Yuikiko  Institute of Molecularand Cellular Biosciences, The University of Tokyo, assistant professor, 分子細胞生物学研究所, 助手 (50092200)
森崎 尚子  東京大学, 分子細胞生物学研究所, 講師 (00092354)
白井 隆一  東京大学, 分子細胞生物学研究所, 助手 (80183838)
Project Period (FY) 1998 – 2001
Project Status Completed (Fiscal Year 2001)
Budget Amount *help
¥13,100,000 (Direct Cost: ¥13,100,000)
Fiscal Year 2001: ¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 2000: ¥2,900,000 (Direct Cost: ¥2,900,000)
Fiscal Year 1999: ¥2,700,000 (Direct Cost: ¥2,700,000)
Fiscal Year 1998: ¥4,300,000 (Direct Cost: ¥4,300,000)
Keywordsnuclear receptor / retioids / thalidomide / androgen / structural development / molecular design / enzyme inhibitors / ligand / 構造活性相関 / ヘシン / アンドロジェン / アンタゴニスト / フタルイミド / ホモフタルイミド / シナージスト / 医薬品化学 / 阻害剤 / 情報伝達物質
Research Abstract

The full-scale commercial appearance of antibiotics in the 1950's caused a shift of the nature of our lethal diseases from infectious/acute to non-infectious/chronic. In this situation, biological response modifiers (BRM's), which are not based on selective toxicity, are expected to be useful. There exist several types of BRM's, including retinoids which act directly on cells at the gene expression level, and thalidomide (and related molecules) which modulate internal circumstances of our body. We have been engaged in medicinal chemical/structural development studies based on these bio-active compounds. Retinoids include all-tarans-retinoic acid (ATRA), a major active form of vitamin A (retinol), and its bio-isosters, which elicit their biological effects by binding to their nuclear receptors, RAR's. ATRA has been used in differentiation therapy [typically for the treatment of acute promyelocytic leukemia (APL)] and the treatment of dermatological diseases. Our structural development studies of retinoids, including computer-assisted molecular design has yielded class/subtype-selective agonists, synergists and antagonists of RAR's and their partner nuclear receptors, RXR's. Thalidomide elicits a wide range of pharmacological effects, including anti-cachexia, anti-angiogenic and antimetastatic activities. We have found that thalidomide is a multi-target drug. Hypothetical target events/molecules of thalidomide include TNF-alpha production, nuclear androgen receptor, aminopeptidases, and alpha-glucosidase. Specific and potent compounds for each of these target phenomena/molecules have been : prepared by appropriate modification of the thalidomide structure, and are expected to be superior lead compounds for novel immunomodulators, anti-angiogenic agents, and anti-tumor promoting agents.

Report

(5 results)
  • 2001 Annual Research Report   Final Research Report Summary
  • 2000 Annual Research Report
  • 1999 Annual Research Report
  • 1998 Annual Research Report
  • Research Products

    (42 results)

All Other

All Publications (42 results)

  • [Publications] Yuichi Hashimoto: "Novel biological response modifiers derived from thalidomide"Currene Medicinal Chemistry. 5. 163-178 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Rumiko Shimazawa: "Novel small molecule nonpeptide aminopeptidase N inhibitors with a oyclic imide skeleton"Journal of Eneyme Inhibiton. 14. 259-275 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Masayuki Ebisawa: "Retinoid X rec"Chemical & Pharmaceutical Bulletin. 47. 1778-1786 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Yuichi Hashimoto: "Bioprobes recogniting Nucleic acids and signal transduction factors"Recent Research Development in Organic Chemistry. 4. 87-120 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Hiroki Kakuta: "Enayme inhibitors derived from thalidomide"Recent Research Development in Medicinal Chemistry. 1. 189-211 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Yuichi Hashimoto: "Structural development of biological response modifiers based on thalidomide"Bioorganic & Medicinal Chemistry. 10. 461-479 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] 橋本 祐一: "がんとくすり"東京化学同人. 172 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Masato Komoda, Hiroki Kakuta, Hiroyasu Takahashi, Yasuyuki Fujimoto, Shizuo Kadoya, Fuminori Kato and Yuichi Hashimoto: "Specific inhibitor of puromycin-sensitive aminopeptidase with a homophthalimide skeleton"Bioorg. Med. chem.. 9(1). 121-131 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Masayuki Ebisawa, Kiminori Ohta, Emiko Kawachi, Hiroshi Fukasawa, Yuichi Hashiraoto and Hiroyuki Kagechika: "Novel retinoidal tropolone derivatives Bioisosteric relationship of tropolone ring with benzoic acid moiety in retinoid structure"Chem. Pharm. Bull.. 49(4). 501-503 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Sonei Sou, Hiroyasu Takahashi, Ryu Yamasaki, Hiroyuki Kagechika, Yasuyuki Endo and Yuichi Hashimoto: "α-Glucosidase inhibitors with a 4,5,6,7-tetrachlorophthalimide skeleton pendanted with a cycloalkyl or dicarba-closo-dodecaborane group"Chem. Pharm. Bull.. 49(6). 791-793 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Tetsuya Kita, Hiroyasu Takahashi and Yuichi Hashimoto*: "Thymidine phosphorylase inhibitors with a homophthalimide skeleton"Biol. Pharm. Bull.. 24(7). 860-862 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Hiroki Kakuta, Yukiko Koiso, Hiroyasu Takahashi, Kazuo Nagasawa and Yuichi Hashimoto*: "Novel specific puromycin-sensitive aminopeptidase inhibitors: 3-(2,6-diethylphenyl)-2,4(1H, 3H)-quinazolinedione and N-(2,6-diethylphenyl)-2-amino-4H-3,1-benzoxazin-4-one"Heterocycles. 55(8). 1433-1438 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Yuichi Hashimoto: "Structural development of biological response modifiers based on thalidomide"Bioorg. Med. chem.. 10(3). 461-479 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Hiroki Kakuta, Hiroyasu Takahashi, Sonei Sou, Tetsuya Kita, Kazuo Nagasawa and Yuichi Hashimoto*: "Enzyme inhibitors derived from thalidomide"Recent Res. Develop. Med. Chem.. (in press). (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Yuichi Hashimoto: "Structural development of biological response modifiers based on retinoids and thalidomide"Mini-Rev. Med. Chem.. (in press). (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Toshiyasu Ishioka, Asako Kubo, Yukiko Koiso, Kazuo Nagasawa, Akiko Itai and Yuichi Hashimoto*: "Novel non-steroidal/non-anilide type androgen antagonists with a isoxazolone moiety"Bioorg. Med. chem.. (in press). (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Toshiyasu Ishioka: "Novel non-steroidal/non-anilide type androgen antagonists with an isoxazolonne moiety"Bioorganic & Medicinal Chemistry. 10・5. 1555-1566 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Yuichi Hashimoto: "Structural devolopment of biological response modifiers based on retinoids and thalidomide"Mini-Reviews in Medicinal Chemistry. (印刷中). (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Yuichi Hashimoto: "Structural development of biological response modifiers based on thalidomide"Bioorganic & Medicinal Chemistry. 10・3. 461-479 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Masayuki Ebisawa: "Novel retinoidal tropolone derwative. Bioisoster relationship of tropolone ring with benzoic acid moiety in retinoid system"Chemical & Pharmaceutical Bulletin. 49・4. 501-503 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Masato Komoda: "Specific inhibitors of puromyein-sensitive aminopeptidase with a homophthalimide skeleton"Bioorganic & Medicinal Chemistry. 9・1. 121-131 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Hiroki Kakuta: "Enzyme inhibitors derived from thalidomide"Recent Researoh Development in Medicinal Chemistry. 1. 189-211 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Hiroyasu Takahashi 他4名: "Anti-androgenic activity of substituted azo-and azoxy-benzene derivatives."Biological & Pharmaceutical Bulletin. 23・11. 1387-1390 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Yuichi Hashimoto: "Bioprobes recognizing nucleic acids and signal transduction factors."Recent Research Development in Organic Chemistry. 4. 87-120 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Sonei Sou 他6名: "Novel α-glucosidase inhibitors with a tetrachlorophthalimide skeleton."Bioorganic & Medicinal Chemistry Letters. 10・10. 1081-1084 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Hiroyas Takahashi 他4名: "α-Glucosidase inhibitors with a phthalimide skeleton : structure-activity relationship study."Chemical & Pharmaceutical Bulletin. 48・10. 1494-1499 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] 高橋裕保 他3名: "環状イミド構造を有する特異的アミノペプチダーゼ阻害剤リードの創製"薬学雑誌. 120・10. 909-921 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kouske Dodo 他5名: "Synthesis of a novel class of cdc 25A inhibitors from vitamin D_3"Bioorganic & Medicinal Chemistry Letters. 10・7. 615-617 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Masayuki Ebisawa 他10名: "Retinoid X receptor-antagonistic diazepinylbenzoic acids"Chemical and Pharmaceutical Bulletin. 47・12. 1778-1786 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Yin Li 他4名: "Identification of a novel class of retinoic acid receptor β- 〜"Journal of Biological Chemistry. 274・22. 15360-15366 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Rumiko Shimazawa 他6名: "Antiangiogenic activity of tumor necrosis factor-α 〜"Biological and Pharmaceutical Bulletin. 22・2. 224-226 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Rumiko Shimazawa 他4名: "Non-peptide small-molecular inhibitor of dipeptidyl 〜"Bioorganic and Medicinal.Chemistry Letters. 9・4. 559-562 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Yukiko Koiso 他4名: "Modification by heme oxygenase inhibitor,tin proto- 〜"Biological and Pharmaceutical Bulletin. 22・4. 439-440 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Rumiko Shimazawa 他12名: "Novel small molecule nonpeptide aminopeptidase N 〜"Journal of Enzyme Inhibition. 14・4. 259-275 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] 橋本祐一: "がんとくすり"東京化学同人. 172 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] 橋本祐一: "臨床腫瘍学 第2版 Part I"癌と化学療法社. 17 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Masayuki Ebisawa 他6名: "Novel thiazolidine dione derivatives with retinoid synergistic activity." Biological and Pharmaceutical Bulletin. 21・5. 547-549 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Asuka Nishikawa 他2名: "Synthesis of 6-amylsalirylic acid from 3-anisalolehyde." Tefrahedron Letters. 39・40. 7307-7308 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Yuichi Hashimoto: "Novel biological response modifiers derived from thnlidomide." Current Medicinal Chemistry. 5・3. 163-178 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Hiroyuki Miyachi 他3名: "Novel potent nonpeptide aminopeptidase N inhibitors with a eyclic〜" Journal of Medicinal Chemistry. 41・3. 263-265 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Kiminori Ohta 他6名: "Potent retinoid syneryists wiht a diphenylamine skeleton." Biological and Pharmaceutical Bulletin. 21・5. 544-546 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] 嶋澤るみ子 他2名: "サリドマイドをリードとした新規生物応答調節剤の創製" 有機合成化学協会誌. 57・2. 92-104 (1999)

    • Related Report
      1998 Annual Research Report

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Published: 1998-04-01   Modified: 2016-04-21  

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