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Development of highly functional medicines targeting genomic DNA/RNA

Research Project

Project/Area Number 09557201
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section展開研究
Research Field 医薬分子機能学
Research InstitutionOsaka University

Principal Investigator

IMANISHI Takeshi  Graduate School of Pharmaceutical Sciences, Osaka University, Professor, 薬学研究科, 教授 (40028866)

Co-Investigator(Kenkyū-buntansha) OBIKA Satoshi  Graduate School of Pharmaceutical Sciences, Osaka University, Research Associate, 薬学研究科, 助手 (80243252)
Project Period (FY) 1997 – 1999
Project Status Completed (Fiscal Year 1999)
Budget Amount *help
¥10,700,000 (Direct Cost: ¥10,700,000)
Fiscal Year 1999: ¥2,300,000 (Direct Cost: ¥2,300,000)
Fiscal Year 1998: ¥2,100,000 (Direct Cost: ¥2,100,000)
Fiscal Year 1997: ¥6,300,000 (Direct Cost: ¥6,300,000)
KeywordsNucleoside Analog / Oligonucleotide / Antisense / Conformation / Cationic Liposome / Gene Delivery / ヌクレオシド類縁体 / 遺伝子医薬品 / オリゴヌクレオチド誘導体 / アンチセンス核酸 / 化学合成 / カチオン性脂質 / リポソーム / カテオン性脂質
Research Abstract

In order to develop novel and highly functional medicines which can inhibit a target gene expression selectively, we designed and synthesized nucleoside analogues as a key synthon for an antisense or an antigene molecule. We accomplished the effective synthesis of the novel nucleoside analogues in which the sugar puckering was restricted in N-conformation. These nucleoside analogues were introduced into oligonucleotides by using a DNA synthesizer, giving conformationally locked oligonucleotides. The properties of these modified oligonucleotides as an antisense or an antigene molecule were studied by Tm measurements, gel retardation experiments, DNase I footprinting experiments. From these experiments, unprecedented thermal stabilities of duplex formation towards complementary DNA and RNA were observed. Furthermore, good triplex forming abilities of the modified oligonucleotides were also confirmed. In addition, the selective inhibition of the target gene expression in living cells was accomplished by addition of these modified oligonucleotides into cell culture medium. These results clearly indicate that the conformationally locked oligonucelotide was a promising candidate for an antisense and an antigene molecule.
On the other hands, development of an ideal gene delivery system is of great importance for antisense and antigene methodology and other gene therapies. Therefore, we designed and synthesized novel symmetrical cationic lipids which have biodegradable ester linkages. The cationic liposomes prepared from the cationic lipids and natural lipid DOPE show an efficient gene delivery into living cells and low cytotoxicity. It means that this cationic liposome is an effective gene delivery reagent.

Report

(4 results)
  • 1999 Annual Research Report   Final Research Report Summary
  • 1998 Annual Research Report
  • 1997 Annual Research Report
  • Research Products

    (40 results)

All Other

All Publications (40 results)

  • [Publications] S. Obika: "A Symmetrical and Biodegrable Catioic Lipid. Synthesis and Application for Efficient Gene Transfection"Bioorg. Med. Chem. Lett.. 7・14. 1817-1820 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] S. Obika: "Synthesis and Conformation of 3'-O, 4'-C- Methyreneribonucleosides, Novel Bicyclic Nucleoside Analogs for 2', 5'-Linked Oligonucleotide Modification"Chem. Commun.. ・17. 1643-1644 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] S. Obika: "Synthesis of 2'-O, 4'-C-Methyleneuridine and -cytidine. Novel Bicyclic Nucleosides Having a Fixed C3' -endo Sugar Puckering"Tetrahedron Lett.. 38・50. 8735-8738 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] S. Obika: "Stability and Structural Features of the Duplexes Containing Nucleoside Analogues with a Fixed N-Type Conformation, 2'-O, 4'-C- Methyreneribonucleosides"Tetrahedron Lett.. 39・30. 5401-5404 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] S. Obika: "Facile Synthesis and Conformation of 3''-O, 4'-C-Methyreneribonucleosides"Chem. Commun.. ・.23. 2423-2424 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] S. Obika: "Synthesis of a Conformationally Locked AZT Analogue, 3'-Azido-3'-deoxy-2'-O, 4'-C-methylene-5-methyluridine"Tetrahedron Lett.. 40・35. 6465-6468 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] W. Yu: "Gene Transfer Mediated by YKS-220 Cationic Particles : Convenient and Efficient Gene Delivery Reagent"J. Biochem.. 125・6. 1034-1038 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] T. Imanishi: "Syntheses and Properties of Novel Conformationally Restrained Nucleoside Analogues"J. Syn. Org. Chem., Jpn.. 57・11. 969-980 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] S. Obika: "Properties of Cationic Liposomes Composed of Cationic Lipid YKS-220 Having an Ester Linkage : Adequate Stability, High Transfection Efficiency, and Low Cytotoxicity"Biol. Pharm. Bull.. 22・2. 187-190 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] S. Obika: "Preparation and Properties of 2', 5'-Linked Oligonucleotide Analogues Containing 3'-O, 4'-C-Methyreneribonucleosides"Bioorg. Med. Chem. Lett.. 9・4. 515-518 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] S. Obika: "Synthesis of Conformationally Locked C-Nucleosides Having a 2, 5-Dioxabicyclo[2.2.1]heptane Ring System"Tetrahedron Lett.. 41・2. 215-219 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] S. Obika: "Triplex Formation by an Oligonucleotide Containing Conformationally Locked C-Nucleside, 5-(2-O, 4-C,-Methylene-β-D-ribofuranosyl)oxazole"Tetrahedron Lett.. 41・2. 221-224 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] S. Obika: "A. Symmetrical and Biodegradable Cationic Lipid. Synthesis and Application for Efficient Gene Transfection"Bioorg. Med. Chem. Lett.. 7. 1817-1820 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] S. Obika: "Synthesis and Conformation of 3'-O, 4'-C-Methyreneribonucleosides, Novel Bicyclic Nucleoside Analogs for 2', 5'-Linked Oligonucleotide Modification"Chem. Commun.. 1643-1644 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] S. Obika: "Synthesis of 2'-O, 4'-C-Methyleneuridine and -cytidine. Novel Bicyclic Nucleosides Having a Fixed C3'-endo Sugar Puckering"Tetrahedron Lett.. 38. 8735-8738 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] S. Obika: "Stability and Structural Features of the Duplexes Containing Nucleoside Analogues with a Fixed N-Type Conformation, 2'-O, 4'-C-Methyleneribonucleosides"Tetrahedron Lett.. 39. 5401-5404 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] S. Obika: "Properties of Cationic Liposomes Composed of Cationic Lipid YKS-220 Having an Ester Linkage : Adequate Stability, High Transfection Efficiency, and Low Cytotoxicity"Biol. Pharm. Bull.. 22. 187-190 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] W. Yu: "Gene Transfer Mediated by YKS-220 Cationic Particles : Covenient and Efficient Gene Delivery Reagent"J. Biochem.. 125. 1034-1038 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] S. Obika: "Preparation and Properties of 2', 5'-Linked Oligonucleotide Analogues Containing 3'-O, 4'-C-Methyleneribonucleosides"Bioorg. Med. Chem. Lett.. 9. 515-518 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] S. Obika: "Synthesis of a Conformationally Locked AZT Analogue, 3'-Azido-3'-deoxy-2'-O, 4'-C-methylene-5-methyluridine"Tetrahedron Lett.. 40. 6465-6468 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] T. Imanishi: "Syntheses and Properties of Novel Conformationally Restrained Nucleoside Analogues"J. Syn. Org. Chem., Jpn.. 57. 969-980 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] S. Obika: "Facile Synthesis and Conformation of 3'-O, 4'-C-Methyleneribonucleoosides"Chem. Commun.. 2423-2424 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] S. Obika: "Synthesis of Conformationally Locked C-Nucleosides Having a 2, 5-Dioxabicyclo[2. 2. 1]heptane Ring System"Tetrahedron Lett.. 41. 215-219 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] S. Obika: "Triplex Formation by an Oligonucleotide Containing Conformationally Locked C-Nucleoside, 5-(2-O, 4-C-Methylene-β-D-ribofuranosyl) oxazole"Tetrahedron Lett.. 41. 221-224 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] S . Obika: "Facile Synthesis and Conformation of 3'-0,4'-C-Methyleneribonucleoosides"Chem. Commun.. ・23. 2423-2424 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] S . Obika: "Synthesis of a Conformationally Locked AZT Analogue. 3'-Azick3'-deoxy-2'-0,4'-C-methylene-5-methyluridine"Tetrahedron Lett.. 40・35. 6465-6468 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] W. Yu: "Gene Transfer Mediated by YKS-220 Cationic Particles : Covenient and Efficient Gene Delivery Reagent"J. Biochem.. 125・6. 1034-1038 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] T. Imanishi: "Syntheses and Properties of Novel Conformationally Restrained Nucleoside Analogues"J. Syn. Org. Chem., Jpn.. 57・11. 969-680 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] S. Obika: "Properties of Cationic Liposomes Composed of Cationic Lipid YKS-220 Having an Ester Linkage : Adequate Stability; High Transfection Efficiency, and Low Cytotoxicity"Biol. Pharm. Bull.. 22・2. 187-190 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] S . Obika: "Preparation and Properties of 2',5'-Linked Oligonucleotide Analogues Containing 3'-0,4'-C-Methyleneribonucleosides"Bioorg. Med. Chem. Lett.. 9・4. 515-518 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] S. Obika: "Synthesis of Conformationally Locked C-Nucleosides Having a 2,5- Dioxabicyclor[2.2.1]heptane Ring System"Tetrahedron Lett.. 4 1 ・2. 215-219 (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] S. Obika: "Triplex Formation by an Oligonucleotide Containing Conformationally Locked C-Nucleoside, 5-(2- 0,4-C-Methylene- β-D-ribofuranosyl)oxazole"Tetrahedron Lett.. 4 1 ・2. 221-224 (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] T.Imanishi et al.: "Preparation and Properties of 2′,5′-Linked Oligonucleotide Analogues Containing 3′-O,4′-C-Methyleneribonucleosides" Bioorg.Med.Chem.Lett.9・4. 515-518 (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] T.Imanishi et al.: "Properties of Cationic Liposomes Composed of Cationic Lipid YKS-220 Having an Ester Linkage:Adequate Stability,High Transfection Efficiency,and Low Cytotoxicity" Biol.Pharm.Bull.22・2. 187-190 (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] T.Imanishi et al.: "Stability and Structural Features of the Duplexes Containing Nucleoside Analogues with a Fixed N-Type Conformation,2′-O,4′-C-Methyleneribonucleosides" Tetrahedron Lett.39・30. 5401-5404 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Takeshi Imanishi et al.: "Synthesis of 2′-O,4′-C-Methyleneuridine and-cytidine.Novel Bicyclic Nucleosides Having a Fixed C3′-endo Sugar Puckering" Tetrahedron Lett.38・50. 8735-8738 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Takeshi Imanishi et al.: "Synthesis and Conformation of 3′-O,4′-Methanoribonucleosides,Novel Bicyclic Nucleoside Analogs for 2′,5′-Linked Oligonucleotide Modification" Chem.Commun.1643-1644 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Takeshi Imanishi et al.: "A Symmetrical and Biodegradable Catioic Lipid.Synthesis and Application for Efficient Gene Transfection" Bioorg.Med.Chem.Lett.7・14. 1817-1820 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Takeshi Imanishi et al.: "Properties of Novel Oligonucleotide Analogues Containing an Acyclic Nucleoside and a Carbamate Linkage" Bioorg.Med.Chem.Lett.6・12. 1357-1360 (1996)

    • Related Report
      1997 Annual Research Report
  • [Publications] Takeshi Imanishi et al.: "Syntheses of Novel Nucleoside Dimer Analogues Containing an Acyclic Nucleoside and a Carbamate Linkage" Tetrahedron Lett.36・47. 8617-8620 (1995)

    • Related Report
      1997 Annual Research Report

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Published: 1997-04-01   Modified: 2016-04-21  

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