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Studies on the synthesis, conformational analysis, and biological activity of active vitamin D analogs in the purpose of developing therapeutic agent with selective activity

Research Project

Project/Area Number 04671289
Research Category

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

Allocation TypeSingle-year Grants
Research Field Chemical pharmacy
Research InstitutionTokyo Medical and Dental University

Principal Investigator

YMADA Sachiko  Tokyo Med. Dental Univ. Inst. Med. Dental Eng. Professor, 医用器材研究所, 教授 (10014078)

Co-Investigator(Kenkyū-buntansha) YAMAMOTO Keiko  Tokyo Med. Dental Univ. Inst. Med. Dental Eng. Research Associate, 医用研, 助手 (90147017)
SHIMIZU Masato  Tokyo Med. Dental Univ. Inst. Med. Dental Eng. Associate Professor, 医用研, 助教授 (50126231)
Project Period (FY) 1992 – 1993
Project Status Completed (Fiscal Year 1993)
Budget Amount *help
¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 1993: ¥600,000 (Direct Cost: ¥600,000)
Fiscal Year 1992: ¥800,000 (Direct Cost: ¥800,000)
Keywordsvitamin D / analog / synthesis / conformational analysis / structure activity relationship / conjugate addition / receptor / vitamin D binding protein / 活性型ビタミンD / 合成アナローグ / 化学合成 / 生理活性 / 側鎖修飾体 / 有機銅試薬
Research Abstract

(1) Syntheses and biological activity of active vitamin D_3 side chain analogs :
Active vitamin D_3 analogs alkylated at the 22-position were designed and synthesized to study the stereochemical structures required to bind to the receptor (VDR) for the active vitamin D_3 and to serum vitamin D binding protein (DBP). (22R)-and(22S)-Methylated analogs were synthesized via kinetically controlled conjugate addition of Me_2CuLi to (22E)-and (22Z)-22-en-24-one as the key step. Only the 22S-methyl analog mimicked the activities of the active vitamin D_3. The results suggest that the side chain conformation of the active viramin D_3 best fitted to VDR and DBP is the same 17-20-22-23 anti form. Additional eight 22-substituted active vitamin D analogs who are diastereomers at C(20) and C(22) were synthesized by using the same synthetic strategy. Conformational analysis and biological activity of these analogs provided an insight into the spatial arrangement of vitamin D side chain esponsible for the activities.
(2) Syntheses and biological activity of 1-substituted active vitamin D_3 analogs :
To study the A-ring conformation responsible for the activity of the active vitamin D_3, various 1beta-substituted 1alpha, 25-dihydroxyvitamin D_3 derivatives were synthesized via two routes. In the method 1, synthesis was started with readily available C(22)-steroid. The method 2 used 1-oxoprevitamin D as the starting material which gave predominantly (64%) 1beta-R-1alpha-hydroxy previtamin D on treatment with RLi. Interestignly the introduction of a methyl group at the 1beta-position masked almost completely the action of 1-alpha hydroxyl group.

Report

(3 results)
  • 1993 Annual Research Report   Final Research Report Summary
  • 1992 Annual Research Report
  • Research Products

    (37 results)

All Other

All Publications (37 results)

  • [Publications] Yamada,S.;Morizono,D.;Yamamoto,K.: "Mild Oxidation of Aldehydes to the Corresponding Carboxylic Acids and Esters:Alkaline Iodine Oxidation revisited" Tetrahedron Lett. 33. 4329-4332 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Imae,Y.;Yamamoto,K.;Shimizu,M.;Ishimi,Y.;Suda,T.;Yamada,S.: "Human Promyelocytic Leukemia Cells (HL-60) Produce 1α,25-Dihydroxyvitamin D_326,23-Lactone from 1α,25-Dihydroxyvitamin D_3." Iyo Kizai Kenkyusho Hokoku. 26. 29-34 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Yamamoto,K.;Yamada,S.;Yamaguchi,K.: "Highly Diastereoselective Conjugate Addition of Organocuprate to Acyclic E-ad Z-Enones:Reversal Stereoselectivity under Kinetic and Thermodynamic Conditions" Tetrahedron Lett.33. 7521-7524 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Shimizu,M.;Gao,Y.;Aso,T.;Nakatsu,K.;Yamada,S.: "Fluorometric Assay of 25-Hydroxyvitamin D_3 and 24R,25-Dihydroxyvitamin D_3 in Plasma" Anal.Biochem.204. 258-264 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Hayashi,T.;Ojima,K.;Konno,K.;Manaka,K.;Yamaguchi,K.;Yamada,S.;Takayama,H.: "A New Synthesis of 24-Fluoro-1,25-Dihydroxyvitamin D2 and Its 24-Epimer,and Determination of the C-24 Configuration" Chem.Pharm.Bull.40. 2932-2936 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Yamamoto,K.;Takahashi,J.;Hamano,K.;Yamada,S.;Yamaguchi,K.;DeLuca,H.F.: "Stereoselective Syntheses of (22R)- and (22S)-22-Methyl-1α,25-Dihydroxyvitamin D_3:Active Vitamin D_3 Analogs with Restricted Side Chain Conformation." J.Org.Chem.58. 2530-2537 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Shimizu,M.;Yamazaki,T.;Yamada,S.: "Fluorescence-Labeling Reaction of Vitamin D Metabolites and Analogs with Fluorescent 1,2,4-Triazoline-3,5-dione(DMEQ-TAD)" BioMed.Chem.Lett.3. 1809-1814 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Gao,Y.;Shimizu,M.;Yamada,S.;Ozaki,Y.;Aso,T.: "The Effects of Chemotherapy Including Cisplatin on Vitamin D Metabolism" Endocrine J.40. 737-742 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 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しい蛍光標識試薬の開発並びにそのビタミンD及びビタミンA代謝物の定量への応用" ビタミン. 68. 15-30 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] 山田幸子、高山浩明: "ビタミンDと亜硫酸ガス(SO_2)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
      1993 Final Research Report Summary
  • [Publications] 山本恵子、山田幸子: "活性型ビタミンDの立体配座を固定したアナログの設計、合成及び生理活性" 医用器材研究所報告. 27. 21-32 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Shimizu,M.;Yaguchi,K.;Iwasaki,Y.;Yamada,S.: "Reaction of Geometrical Isomers of Retinoic Acid with 1,2,4-Triazoline-3,5-dione and Photochemical Reaction of the Adducts with Fluorescent Chromophore" Tetrahedron Lett.(in press.).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Yamamoto, K. ; Shimizu, M. ; Yamada, S. ; Iwata, S. ; Hoshino, O.: "Facile Stereoselective Synthesis of (23S,25R)-1alpha, 25-Dihydroxyvitamin D_3 26,23-Lactone, A Major Metabolite of 1alpha, 25-Disydroxyvitamin D_3." J.Org.Chem.57. 33-39 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Yamada, S. ; Morizono, D, ; Yamamoto, K.: "Mild Oxidation of Aldehydes to the corresponding Carboxylic Acids and Esters : Alkaline Iodine Oxidation Revisited" Tetrahedron Lett.33. 4329-4332 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Imae, Y. ; Yamamoto, K. ; Shimizu, M. ; Ishimi, Y. ; Suda, T. ; Yamada, S.: "Human Promyelocytic Leukemia Cells (HL-60) Produce 1alpha, 25-Dihydroxyvitamin D_3 26,23-Lactone from 1alpha, 25-Dihydroxyvitamin D_3" Iyo Kizai Kenkyusho Hokoku. 26. 29-34 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Yamamoto, K. ; Yamada, S. ; Yamaguchi, K.: "Highly Diastereoselective Conjugate Addition of Organocuprate to Acyclic E- ad Z-Enones : Reversal Stereoselectivity under Kinetic and Thermodynamic Conditions" Tetrahedron Lett.33. 7521-7524 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Shimizu, M. ; Gao, Y. ; Aso, T. ; Nakatsu, K. ; Yamada, S.: "Fluorometric Assay of 25-Hydroxyvitamin D_3 and 24R,25-Dihydroxyvitamin D_3 in Plasma" Anal.Biochem. 204. 258-264 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Hayashi, T. ; Ojima, K. ; Konno, K. ; Manaka, K. ; Yamaguchi.K. ; Yamada, S. ; Takayama, H.: "A New Synthesis of 24-Fluoro-1,25-Dihydroxyvitamin D_2 and Its 24-Epimer, and Determination of the C-24 Configuration" Chem.Pharm.Bull.40. 2932-2936 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Yamamoto, K. ; Takahashi, J. ; Hamano, K. ; Yamada, S. ; Yamaguchi, K. ; DeLuca, H.F.: "Stereoselective Syntheses of (22R)-and (22S)-22=Methyl-1alpha, 25-Dihydroxyvitamin D_3 : Active Vitamin D_3 Analogs with Restricted Side chain Conformation." J.Org.Chem. 58. 2530-2537 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Shimizu, M. ; Yamazaki, T. ; Yamada, S.: "Fluorescence-Labeling Reaction of Vitamin D Metabolites and Analogs with Fluorescent 1,2,4-Triazoline-3,5-dione (DMEQ-TAD)" BioMed.Chem. Lett.3. 1809-1814 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Gao, Y. ; Shimizu, M. ; Yamada, S. ; Ozaki, Y. ; Aso, T.: "The Effects of Chemotherapy Including Cisplatin on Vitamin D Metabolism" Endocrine J.40. 737-742 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Yamamoto, K. ; Yamada, S.: "Design, Synthesis and Biological Activities of Active Vitamin D_3 Analogs with a Restricted Side Chain Conformation" Iyo Kizai Kenkyusho Hokoku. 27. 21-32 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Shimizu, M, ; Yamada, S.: "New Fluorescence-Labeling Reagent Targeting Conjugated Dienes : Application to the Fluorometric Analysis of Vitamin D and A Metabolites" Bitamin. 68. 15-30 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Yamada, S. ; Takayama, H.: "Reaction of Vitamin D with Sulfur Dioxide, and Its Application to the Structural Modification of Vitamin D" Bitamin. 68. 135-144 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Shimizu, M. ; Yaguchi, K. ; Iwasaki, Y, ; Yamada, S.: "Reaction of Geometrical Isomers of Retinoic Acid with 1,2,4-Triazoline-3,5-dione and Photochemical Reaction of the Adducts with Fluorescent Chromophore" Tetrahedron Lett.(in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Shimizu,M.;Yamazaki,T.;Yamada,S.: "Fluorescence-Labeling Reaction of Vitamin D Metabolites and Analogs with Fluorescent 1,2,4-Triazoline-3,5-dione(DMEQ-TAD)" BioMed.Chem.Lett.3. 1809-1814 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Gao,Y.;Shimizu,M.;Yamada,S.;Ozaki,Y.;Aso,T.: "The Effects of Chemotherapy Including Cisplatin on Vitamin D Metabolism" Endocrine J.40. 737-742 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] 清水正人、山田幸子: "共役ジエンを標的とする新しい蛍光標識試薬の開発並びにそのビタミンD及びビタミンA代謝物の定量への応用" ビタミン. 68. 15-30 (1994)

    • Related Report
      1993 Annual Research Report
  • [Publications] 山田幸子、高山浩明: "ビタミンDと亜硫酸ガス(SO_2)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)

    • Related Report
      1993 Annual Research Report
  • [Publications] 山本恵子、山田幸子: "活性型ビタミンDの立体配座を固定したアナログの設計、合成及び生理活性" 医用器材研究所報告. 27. 21-32 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Shimizu,M.;Yaguchi,K.;Iwasaki,Y.;Yamada,S.: "Reaction of Geometrical Isomers of Retinoic Acid with 1,2,4-Triazoline-3,5-dione and Photochemical Reaction of the Adducts with Fluorescent Chromophore" Tetrahedron Lett.(in press.).

    • Related Report
      1993 Annual Research Report
  • [Publications] S.Yamada: "Mild Oxidation of Aldehydes to the Corresponding Car-boxylic Acids and Esters:Alkaline Iodine Oxidation Revisited." Tetrahedron Lett.33. 4329-4332 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] M.Shimizu: "Fluorometric assay of 25-hydroxyvitamin D_3 and 24R,25-dihydroxyvitamin D_3 in plasma." Anal.Biochem.204. 258-264 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] T.Hayashi: "A New Synthesis of 24-Fluoro-1α,25-dihydroxyvitamin D_2 and Its 24-Epimer,and Determination of the C-24 Con-figuration." Chem.Pharm.Bull.40. 2932-2936 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] K.Yamamoto: "Highly Diastereoselective Conjugate Addition of Orga-nocuprate to Acyclic E- and Z-Enones:Reversal Stere-oselectivity under Kinetic and Thermodynamic Condi-tions." Tetrahedron Lett.33. 7521-7524 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] K.Yamamoto: "Facile stereoselective synthesis of (23S,25R)-1α,25-dihydroxyvitamin D_3 26,23-lactone,a major metabolite of 1α,25-dihydroxyvitamin D_3." J.Org.Chem.57. 33-39 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Y.Imae: "Human Promyelocytic Leukemia Cells (HL-60) Produce 1α,25-Dihydroxyvitamin D3 26,23-Lactone from 1α,25-Dihydroxyvitamin D_3" Iyo Kizai Kenkyusho Hokoku. 26. 29-34 (1992)

    • Related Report
      1992 Annual Research Report

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Published: 1992-04-01   Modified: 2016-04-21  

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