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Studies on the conformation of active form of vitamin D responsible for binding to the receptor and for expression of the activities

Research Project

Project/Area Number 06453192
Research Category

Grant-in-Aid for General Scientific Research (B)

Allocation TypeSingle-year Grants
Research Field 医薬分子機能学
Research InstitutionTokyo Medical and Dental University

Principal Investigator

YAMADA Sachiko  Tokyo Medical and Dental University, Professor Institute for Medical and Dental Engineering, 医用器材研究所, 教授 (10014078)

Co-Investigator(Kenkyū-buntansha) YAMAMOTO Keiko  Tokyo Medical and Dental University, Research Associate Institute for Medical an, 医用器材研究所, 助手 (90147017)
SHIMIZU Masato  Tokyo Medical and Dental University, Associate Professor Institute for Medical a, 医用器材研究所, 助教授 (50126231)
Project Period (FY) 1994 – 1995
Project Status Completed (Fiscal Year 1995)
Budget Amount *help
¥2,100,000 (Direct Cost: ¥2,100,000)
Fiscal Year 1995: ¥2,100,000 (Direct Cost: ¥2,100,000)
KeywordsVitamin D / Receptor / Synthesis / Analogs / Conformation analysis / Fluorination / Vitamin D binding protein / Photoisomerization / 生理活性 / コンフォメーション / 構造活性相関
Research Abstract

To clarify the stereochemical structure of the active form of vitamin D responsible for binding to the receptor (VDR), we analyzed the conformation of vitamin D by molecular mechanics method, designed and synthesized analogs of vitamin D whose conformations are restricted, and tested their affinity for VDR.
1) The analysis of the side chain conformation of 1,25 (OH) _2D_3 (1) and its 20-epi analog (2), showed that the side chains of these compounds occupies different spatial regions that are further separated in two areas.
2) Four analogs whose side chain are restricted to occupy each of these four spatial regions were designed and synthesized : They are four diastereomers at C (20) and C (22) of 22-methylated 1,25 (OH) _2D_3 (3,4,5, and 6).
3) The affinities of these four analogs for VDR and vitamin D binding protein (DBP) were examined. The 20R,22S-and 20S,22R-analogs 4 and 5 showed significant binding affinity for VDR.It should be noted that especially the potency of 5 was nearly 20 times higher than 1. The results indicate these spatial regions responsible for binding of 1 and 2 to VDR.For DBP only 4 showed significant affinity.
4) Analogs of 1,25 (OH) _2D_3 (1) which have a substituent at C (1) were synthesized to investigate the conformation and activity relationship of the A-ring. Introduction of only a methyl group at 1B-position of 1 reduced the affinity to VDR to 1/50 indicating the importance of the 1alpha-hydroxyl group.
5) We found for the first time a new photochemical isomerization of provitamin D which is caused by a substituent at C (1).
6) The method for synthesizing 19-Fluorovitamin D analogs via vitamin D-SO_2 adduct was developed.

Report

(3 results)
  • 1995 Annual Research Report   Final Research Report Summary
  • 1994 Annual Research Report
  • Research Products

    (42 results)

All Other

All Publications (42 results)

  • [Publications] 清水正人・岩崎由紀子・山田幸子: "Reaction of Geometrical Isomers of retinoic Acid with 1,2,4-Triazoline-3,5-dione Having Fluorescent Chromophore." Tetrahedron Lett.35. 1917-1920 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] 今江優子・山田幸子: "Biological activities of 24-fluoro-1 α,25-dihydroxyvitamin D_2 and its 24-epimer." Biochim. Biophys. Acta. 60. 202-308 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] 富山茂巳・山田幸子: "Gas chromatography/mass spectrometric analysis of 24R,25-dihydroxyvitamin D_3 using 24R,25-dihydroxy〔6,19,19-^2H〕vitamin D_3 as internal standard." Steroids. 59. 559-563 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] 清水正人・山田幸子: "共役ジエンを標的とする新蛍光標識試薬の開発ならびに同試薬のビタミンDおよびA代謝物定量への応用。" ビタミン. 68. 15-30 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] 山田幸子・高山浩明: "ビタミンDと亜硫酸ガス(SO2)との反応および同反応のビタミンDの化学修飾への応用。" ビタミン. 68. 135-144 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] 山田幸子・石田博基・山本恵子: "Introduction of 1α-hydroxy1 group to provitamin D causes new photoisomerization reactions." Vitamin D,a Pluripotent Steroid Hormone:Structural Studies,Molecular Endocrinology and Clinical Application. 31-32 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] 山本恵子・山田幸子: "Active vitamin D analogs with side chain hydroxyl group occupying diverse spatial region." Vitamin D,a Pluripotent Steroid Hormone:Structural Studies,Molecular Endocrinology and Clinical Application. 91-92 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] 石田博基・清水正人・山本恵子・山田幸子: "Syntheses and biological activity of 1β-substituted active vitamin D_3 analogs." Vitamin D,a Pluripotent Steroid Hormone:Structural Studies,Molecular Endocrinology and Clinical Application. 101-102 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] 清水正人・岩崎由紀子・山田幸子: "メタクリル酸メチル(MMA)の犬静脈内投与によるビタミンD代謝への影響" 医用器材研究所報告. 28. 46-50 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] 清水正人・岩崎由紀子・山田幸子: "新しい蛍光標識求ジエン試薬:合成ならびにビタミンD、A、およびマイクロシスチンとの反応と高感度定量分析への応用" 医用器材研究所報告. 28. 11-27 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] 山田幸子・石田博基・山本恵子: "New photoisomerization of provitamin D caused by hydroxylation at C(1)" J.Chem.Soc.,Chem.Commun.423-424 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] 石田博基・山本恵子・岩崎由紀子・山田幸子: "Syntheses of 1-alkyl-1,25-dihydroxyvitamin D" J.Org.Chem.60. 1828-1833 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] 山本恵子・DzLucaHF・山田幸子: "On the side chain conformation of 1α,25-dihydroxyvitamin D_3 responsible for binding to the receptor" Bioorg.Med.Chem.Lett.5. 979-984 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] 堀内登・山田幸子: "Synthesis of 25-hydroxyvitamin D_3 26,23-lactone but not 24,25-dihydroxyvitamin D_3 from 25-hydroxyvitamin D_3 in opossum kidney cells treated with 1α,25-dihydroxyvitamin D_3" Horm.metab.Res.27. 83-89 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] 清水正人・岩崎由紀子・山田幸子: "新蛍光性ジエノフィルの合成並びにビタミンD、ビタミンA及びマイクロシスチンとの反応と蛍光分析への応用" 薬学雑誌. 115. 584-602 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] 山田幸子: "ビタミンD代謝産物およびアナログの有機合成とその臨床応用" ビタミン. 70. 43-55 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] 1. Shimizu M,Yaguchi K,Iwasaki Y,Yamada S: "Reaction of Geometrical Isomers of retinoic Acid with 1,2,4-Triazoline 3,5-dione Having Fluorescent Chromophore." Tetrahedron Lett.35. 1917-1920 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] 2. Imae Y,Manaka A,Yoshida N,Ishimi Y,Shinki T,Abe E,Suda T,Konno K,Takayama H,Yamada S: "Biological activities of 24-fluoro-1alpha, 25-dihydroxyvitamin D_2 and its 24-epimer." Biochim. Biophys. Acta. 1213. 302-308 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] 3. Tomiyama S,Nitta T,Yamada S: "Gas chromatography/mass spectrometric analysis of 24R,25-dihydroxyvitamin D_3 using 24R,25-dihydroxy [6,19,19-^2 H] vitamin D_3 as internal standard." Steroids. 59. 559-563 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] 4. Yamada S,Ishizaka H,Ishida H,Yamamoto K: "Introduction of 1^<alpha> -hydroxyl group to provitamin D causes new photoisomerization reactions." Vitamin D, a Pluripotent Steroid Hormone : Structural Studies, Molecular Endocrinology and Clinical Application. 31-32 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] 5. Yamamoto K,Yamada S,Ohta M: "Active vitamin D analogs with side chain hydroxyl group occupying diverse spatial region." Vitamin D, a Pluripotent Steroid Hormone : Structural Studies, Molecular Endocrinology and Clinical Application. 91-92 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] 6. Ishida H,Shimizu M,Yamamoto K,Yamaguchi K,Yamada S: "Syntheses and biological activity of 1^<beta> -substituted active vitamin D_3 analogs." Vitamin D, a Pluripotent Steroid Hormone : Structural Studies, Molecular Endocrinology and Clinical Application. 101-102 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] 7. Yamada S,ISHIZAKA H,Ishida H,Yamamoto K: "New photoisomerization of provitamin D caused by hydroxylation at C (1)." J.Chem.Soc.Chem.Commun. 423-424 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] 8.Ishida H,Shimizu M,Yamamoto K,Iwasaki Y,Yamada S,Yamaguchi K: "Syntheses of 1-alkyl-1,25-dihydroxyvitamin D_3" J.Org.Chem. 60. 1828-1833 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] 9. Yamamoto K,Ohta M,DeLuca H F,Yamada S: "On the side chain conformation of 1^<alpha>,25-dihydroxyvitamin D_3 responsible for binding to the receptor" Bioorg.Med.Chem, Lett. 5. 979-984 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] 10.Horiuchi N,Saikatsu S,Akeno N,Abe M,Kimura S,Yamada S: "Synthesis of 25-hydroxyvitamin D_3 26,23-lactone but not 24,25-dihydroxyvitamin D_3 from 25-hydroxyvitamin D_3 in opossum kidney cells treated with 1^<alpha>,25-dihydroxyvitamin D_3." Horm.metab.Res. 27. 83-89 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] 11. Shimizu M,Iwasaki Y,Ishida H,Yamada S: "Determination of 25-hydroxyvitamin D_3 in human plasma using a nonradioactive tetranorvitamin D analogue as an internal standard." J.Chromatogr.B.672. 63-71 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] 12. Yamamoto, K,Sun, W-Y,Ohta, M,Hamada, K,DeLuca, HF,Yamada, S: "Conformationally Restricted Analogs of 1_<alpha>,25-Dihydroxyvitamin D_3 and Its 20-Epimer : Compounds for Study of the Three-Dimensional Structure of Vitamin D Responsible for Binding to the Receptor." J.Med.Chem. 39 (in press). (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] 山田幸子: "New photoisomerization of provitamin D caused by hydroxylation at C(1)" J.Chem.Soc.,Chem.Commun.423-424 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] 石田博基: "Syntheses of 1-alkyl-1,25-dihydroxyvitamin D_3" J.Org.Chem.60. 1828-1833 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] 山本恵子: "On the side chain conformation of 1α,25-dihydroxyvitamin D_3 responsible for binding to the receptor" Bioorg.Med.Chem.Lett.5. 979-984 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] 堀内登: "Synthesis of 25-hydroxyvitamin D_3 26,23-lactone but not 24,25-dihydroxyvitamin D_3 from 25-hydroxyvitamin D_3 in opossum kidney cells treated with 1α,25-dihydroxyvitamin D_3" Horm.metab.Res.27. 83-89 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] 清水正人: "Determination of 25-hydroxyvitamin D_3 in human plasma using a non-radioactive tetranorvitamin D analogue as an internal standard" J.Chromatogr.B.672. 63-71 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] 清水正人: "新蛍光性ジエノフィルの合成並びにビタミンD、ビタミンA及びマイクロシスチンとの反応と蛍光分析への応用" 薬学雑誌. 115. 584-602 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] 山田幸子: "ビタミンD代謝産物およびアナログの有機合成とその臨床応用" ビタミン. 70. 43-55 (1996)

    • Related Report
      1995 Annual Research Report
  • [Publications] 山本恵子: "Conformationally Restricted Analogs of la,25-Dihydroxyvitamin D3 and Its 20-Epimer:Compounds for Study of the Three-Dimensional Structure of Vitamin D Responsible for Binding to the Receptor" J.Med.Chem.39(in press). (1996)

    • Related Report
      1995 Annual Research Report
  • [Publications] 山田幸子,高山浩明: "ビタミンDと亜硫酸ガスの反応および同反応のビタミンDの化学修飾への・・・" ビタミン. 68. 135-144 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] 清水正人,山田幸子: "共役ジエンを標的とする新蛍光標識試薬の開発ならびに同試薬の・・・・" ビタミン. 68. 15-30 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Shimizu,M.,et al.,: "Reaction of Geometrical Isomers of Retinoic acid with------" Tetrahedron Lett.35. 1917-1920 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Tomiyama,S.,et al.,: "Gas chromatography/mass spectrometric analysis of ----" Steroids. 59. 559-563 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Imae,Y.,et al.,: "Biological activities of 24-fluoro-1,25-dihydroxyvitamin D2 ---" Biochim.Biophys.Acta. 1213. 303-308 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] 清水正人,他: "新しい蛍光標識求ジエン試薬合成ならびにビタミンD,A・・・・" 東京医歯大 医用器材研究所報告. 28. 11-27 (1994)

    • Related Report
      1994 Annual Research Report

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

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