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2006 Fiscal Year Final Research Report Summary

Design and development of biological response modifiers

Research Project

Project/Area Number 14103018
Research Category

Grant-in-Aid for Scientific Research (S)

Allocation TypeSingle-year Grants
Research Field 医薬分子機能学
Research InstitutionThe University of Tokyo

Principal Investigator

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

Co-Investigator(Kenkyū-buntansha) MIYACHI Hiroyuki  The University of Tokyo, Institute of Molecular and Cellular Biosciences, Associate Professor, 分子細胞生物学研究所, 助教授 (20376643)
TANATANI Aya  Ochanomizu Univ., Fac.Sci., Associate Professor, 大学院人間文化研究科, 助教授 (40361654)
NAGASAWA Kazuo  Tokyo Univ.Agr.Tech., Fac.Tech., Associate Prof., 大学院共生科学技術研究院, 助教授 (10247223)
ENDO Yasuyuki  Tohoku Pharm.Univ., Fac.Pharm.Sci., Professor, 薬学部, 教授 (80126002)
KAGECHIKA Hiroyuki  Tokyo Med.Dent.Univ., School Biomed.Sci., Prof., 大学院疾患生命科学研究部, 教授 (20177348)
Project Period (FY) 2002 – 2006
Keywordsnuclear receptor / structural development / steroid hormone / antagonists / enzyme inhibitor / molecular design / bioprobe / thalidomide
Research Abstract

Various biological response modifiers, including nuclear receptor ligands (agonists/antagonists) and enzyme inhibitors, were designed and prepared, aiming development of agents for the treatment of chronic diseases (cancers, diabetes, rheumatoid diseases etc). Methodologically, functional regulation hypothesis of nuclear receptors based on the lingand-dependent conformational change of their substructure, helix 12, and multi-template hypothesis have been proposed. Based on these hypotheses,
(1)ligands (agonists and antagonists) of nuclear receptors [retinoic acid receptors (RARs), retinoid X receptors (RXRs), androgen receptor, progesterone receptor, estrogen receptor, peroxisome proliferators-activated receptors (PPARs), farnsoid X receptor (FXR), liver X receptors (LXRs), and viamine D receptor,
(2)specfic and potent inhibitors of tumor necrosis factor (TNF)-α production, tubulin polymerization, puromycin-sensitive aminopeptidase (PSA), α-glucosidase, dipeptidylpeptidase (DPP) type IV, … More tumor cell invasion, histone deacetylase (HDAC), heparanase, calcineulin, cyclooxygenase (COX), nitrogen oxidase synthase (NOS), μ-calpain, thymidine phosphorylase, and angiogenesis, have been created.
Typical compounds created in this research project includes;
(a)a synthetic retinoid, Am80 (tamibarotene), which has been launched since 2005 as a medicament for the treatment of acute promyelocytic leukemia, and is now under phase II clinical trial for the treatment of Crohn's diseases,
(b)a synthetic retinoid, TAC-101, which is now under phase III clinical trial for the treatment of liver cancer,
(c)non-steroidal/non-anilide type structure of androgen antagonists which are active toward so-called anti-androgen-resistant cells (ex.LNCaP cells) bearing point mutated androgen receptor(s),
(d)novel vitamin D antagonists (DLAMs) containing a nitrogen atom in their structure,
(e)steroid hormone receptor ligands containing a carborane group in their structure.
Our studies suggests the wide utility/applicability of the above-mentioned hypothesis for drug design, and the usefulness of thalidomide-related phthalimide/homophtalimide skeleton and diphenylpentane structure as the scaffold of various biologically active compounds and steroid-related active compounds, respectively. Less

  • Research Products

    (14 results)

All 2006 2005 2004 2002

All Journal Article (12 results) Book (1 results) Patent(Industrial Property Rights) (1 results)

  • [Journal Article] Ligands with a 3,3-diphenylpentane skeleton for nuclear vitamin D and androgen receptors : Dual activities and metabolic activation.2006

    • Author(s)
      Shinnosuke Hosoda, 他7名
    • Journal Title

      Bioorganic & Medicinal Chemistry 14・16

      Pages: 5489-5502

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Practical synthesis and evaluation of the biological activities of 1α,25-dihydroxyvitamin D_3 antagonists, 1α,25-dihydroxyvitamin D_3-26,23-lactams. Designed on the basis of the helix 12-folding inhibition hypothesis.2006

    • Author(s)
      Yusuke Nakano, 他9名
    • Journal Title

      Journal of Medicinal Chemistry 49・8

      Pages: 2398-2406

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Ligands with a 3,3-diphenylpentane skeleton for nuclear vitamin D and androgen receptors : Dual activities and metabolic activation2006

    • Author(s)
      Shinnosuke Hosoda, et al.
    • Journal Title

      Bioorganic & Medicinal Chemistry 14(16)

      Pages: 5489-5502

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Practical synthesis and evaluation of the biological activities of 1α,25-dihydroxyvitamin D_3 antagonists, 1α,25-dihydroxyvitamin D_3-26,23-lactams. Designed on the basis of the helix 12-folding inhibition hypothesis2006

    • Author(s)
      Yusuke Nakano, et al.
    • Journal Title

      Journal of Medicinal Chemistry 49(8)

      Pages: 2398-2406

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Nuclear receptor antagonists designed based on the helix-folding inhibition hypothesis.2005

    • Author(s)
      Yuichi Hashimoto, 他1名
    • Journal Title

      Bioorganic & Medicinal Chemistry 13・17

      Pages: 5080-5093

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Potent androgen antagonists based on carborane as a hydrophobic core structure.2005

    • Author(s)
      Shinya Fujii, 他6名
    • Journal Title

      Journal of Medicinal Chemistry 48・14

      Pages: 4654-4662

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Nuclear receptor antagonists designed based on the helix-folding inhibition hypothesis2005

    • Author(s)
      Yuichi Hashimoto, et al.
    • Journal Title

      Bioorganic & Medicinal Chemistry 13(17)

      Pages: 5080-5093

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Potent androgen antagonists based on carborane as a hydrophobic core structure2005

    • Author(s)
      Shinya Fujii, et al.
    • Journal Title

      Journal of Medicinal Chemistry 48(14)

      Pages: 4654-4662

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Thalidomide as a multi-target drug and its application as a template for drug design.2004

    • Author(s)
      Yuichi Hashimoto, 他3名
    • Journal Title

      Drugs Future 29・4

      Pages: 383-391

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Thalidomide as a multi-target drug and its application as a template for drug design2004

    • Author(s)
      Yuichi Hashimoto, et al.
    • Journal Title

      Drugs Future 29(4)

      Pages: 383-391

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Structural development of biological response modifiers based on retinoids and thalidomide.2002

    • Author(s)
      Yuichi Hashimoto
    • Journal Title

      Mini-Reviews in Medicinal Chemistry 2・6

      Pages: 543-551

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Structural development of biological response modifiers based on retinoids and thalidomide2002

    • Author(s)
      Yuichi Hashimoto
    • Journal Title

      Mini-Reviews in Medicinal Chemistry 2(6)

      Pages: 543-551

    • Description
      「研究成果報告書概要(欧文)」より
  • [Book] ケミカルバイオロジー・ケミカルゲノミクス2005

    • Author(s)
      橋本祐一(分担執筆)
    • Total Pages
      278
    • Publisher
      シュプリンガー・フェアラーク東京
    • Description
      「研究成果報告書概要(和文)」より
  • [Patent(Industrial Property Rights)] 置換イソキサゾール誘導体2006

    • Inventor(s)
      宮地弘幸, 貝沼雅彦, 橋本祐一
    • Industrial Property Rights Holder
      国立大学法人東京大学
    • Industrial Property Number
      特許、特願2006-054501
    • Filing Date
      2006-03-01
    • Description
      「研究成果報告書概要(和文)」より

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Published: 2008-05-27  

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