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Design of Novel Antisense Nucleic Acids with Resistance for Nuclease digestion

Research Project

Project/Area Number 07457551
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field 医薬分子機能学
Research InstitutionOsaka University of Pharmaceutical Sciences

Principal Investigator

URATA Hidehito  Osaka University of Pharmaceutical Sciences, Research associates, 薬学部, 助手 (80211085)

Project Period (FY) 1995 – 1997
Project Status Completed (Fiscal Year 1997)
Budget Amount *help
¥5,500,000 (Direct Cost: ¥5,500,000)
Fiscal Year 1997: ¥400,000 (Direct Cost: ¥400,000)
Fiscal Year 1996: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 1995: ¥4,400,000 (Direct Cost: ¥4,400,000)
KeywordsAntisense / Oligonucleotide / L-Nucleoside / Conformational fixation / Carbocyclic Nucleoside / オリゴヌクレチド
Research Abstract

1.Design and racemic synthesis of novel carbocyclic uridine, cytidine, adenosine and guanosine analogs (1-4), whose glycosidic torsion angle is fixed at around X=180゚ by means of the 5-membered O-cyclic structure between the base and sugar moiety, has been achieved.
2.The optically active cyclopentane unit (5) has been synthesized from cyclopentadiene via asymmetric hydroboration by using (+)-diisopinocampheylborane. Then, synthesis of optically active 1-4 was performed by using compound 5 as a starting material according to the synthetic protocol for synthesis of racemic 1-4. Synthesis of (-)-1 has been achieved, and synthesis of (-)-2 and (-)-3 will be achieved in near future. However, modification of the synthetic pathway of (-)-4 is now investigating, because low solubility of the synthetic intermediates causes difficulties for their purification.
3.After conversion of (-)-1 to its 3'-phosphoramidite derivative, oligodeoxynucleotides containing the (-)-1 residues (6-9) have been synt … More hesized by means of automated DNA synthesizer. Resistance to 3'-venome phosphodiesterase digestion and hybridization properties towards (dA)_<12> and (rA)_<12> of these oligodeoxynucleotides have been evaluated.
5'-TTTTTTTTTTTT-3' (6) 5'-TTTTTcUcUTTTTT-3' (8)
5'-TTTTTTcUTTTTT-3' (7) 5'-cUcUcUcUcUcUcUcUcUcUcUcU-3' (9) cU= (-)-1
(1) Resistance to venome phosphodiesterase digestion
Under the conditions 6 is hydrolyzed by the enzyme in a few minutes, 9 was not hydrolyzed at all. In the case of 7 and 8, the sequence between the cU residue and the 3'-end thymine residue was hydrolyzed repidly, but the hydrolyze rate was greatly decreased at the cU residue.
(2) Hybridization properties with the complementary sequences
Tm values of 7 and 8 were lowered by more than 10゚C per substitution compared to 6, independent of salt concentration. On the other hand, 9 was not be able to hybridize with (dA)_<12> and (rA)_<12> at low salt concentration, however, formed a stable duplex only with (rA)_<12> at high salt conditions. Less

Report

(4 results)
  • 1997 Annual Research Report   Final Research Report Summary
  • 1996 Annual Research Report
  • 1995 Annual Research Report
  • Research Products

    (10 results)

All Other

All Publications (10 results)

  • [Publications] Hidehito Urata et al.: "Sequence Dependence of Thermodynamic Stability of Heterochiral DNA" Tetrahedron Letters. 37. 5551-5554 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Hedehito Urata et al.: "Design and Racemic Synthesis of Conformationally Restricted Carbocyclic Pyrimidine Nucleoside Analogs Based on the Structure of the L-Nucleoside Residue in Heterochiral DNA" Chem.Pharm.Bull.(in press). (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Hirofumi Ohishi et al.: "The Crystal Structure of (±)-Cyclocytidine Analogue Having a Low Anti Conformation Around Glycosyl Bond" Acta Crystallographica Section C. (in press). (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Hidehito Urata et al.: "Sequence Dependence of Thermodynamic Stability of Heterochiral DNA" Tetrahedron Letters. 37. 5551-5554 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Hidehito Urata et al.: "Design and Racemic Synthesis of Conformationally Restricted CarbocyclicPyrimidine Nucleoside Analogs Based on the Structure of the L-Nucleoside Residue in Heterochiral DNA" Chem.Pharm.Bull.46 (in press). (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Hirofumi Ohishi et al.: "The Crystal Structure of ((]SY.+-。[)) -Cyclocytidine Analogue Having a Low Anti Conformation Around Glycosyl Bond" Acta Crystallographica Section C. (in press). (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Hidehito Urata, et al.: "Sequence Dependence of Thermodynamic Stability of Heterochirai DNA" Tetrahedron Letters. 37. 5551-5554 (1996)

    • Related Report
      1997 Annual Research Report
  • [Publications] Hidehito Urata, et al.: "Design and Racemic Synthesis of Conformationally Restricted Carbocylic Pyrimidine Nucleoside Analogs Based on the Structure of the L-Nucleoside Residue in Heterochirai DNA" Chem.Pharm.Bull.(in press). (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] Hirofumi Ohishi, et al.: "The Crystal Structure of(±)-Cyclocytidine Analogue Having a Low Anti Conformation Around Glycosyl Bond" Acta Crystallographica Section C. (in press). (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] Hidehito Urata el al.: "Sequence Dependence of Thermodynamic Stability of Heterochiral DNA" Tetrahedron Letters. 37(31). 5551-5554 (1996)

    • Related Report
      1996 Annual Research Report

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

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