2001 Fiscal Year Annual Research Report

生命の分子メカニズムに基づく生体高機能性化合物の設計と合成

Research Project

Project/Area Number	11470469
Research Institution	Osaka University
Principal Investigator	今西武大阪大学, 薬学研究科, 教授 (40028866)
Co-Investigator(Kenkyū-buntansha)	小比賀聡大阪大学, 薬学研究科, 助手 (80243252) 宮下和之大阪大学, 薬学研究科, 助教授 (10166168) 土井健史大阪大学, 薬学研究科, 教授 (00211409)
Keywords	オリゴヌクレオチド類縁体 / オリゴヌクレオシド / アンチセンス / ピリドキサールモデル化合物 / 非天然型アミノ酸 / 化学発光 / カチオン性リポソーム / 遺伝子導入
Research Abstract	申請者らは、生命の分子メカニズムに基づく生体高機能性化合物の設計と合成を目指し、以下の4項目について検討を加えた。(1)新規架橋型ヌクレオシド類縁体(BNA)を組み込んだ様々なオリゴヌクレオチド(ODN)を合成した。天然型ODNやホスホロチオエート型ODNとの物性、アンチセンス分子としての機能性などについて評価を行ない、これらBNA型ODN類の優れたアンチセンス機能を見い出した。さらに、新たな核酸切断分子の開発にも成功した。(2)金属イオン捕捉能を有するピリドキサールモデル化合物の不斉反応への応用として、光学活性ベンゼノファン構造を有するモデル化合物をセリン誘導体のメルカプタン類によるβ置換反応に適応し、側鎖金属イオン捕捉側鎖の最適化を行った。その結果、本反応を立体選択的に行うことに成功した。(3)ホタルルシフェリンのベンゾチアゾール環部分を各種ヘテロ環で置き換えたヘテロ環置換ルシフェリン誘導体の合成を行い、その化学発光能について評価を行った。その結果、ベンズオキサゾール体が天然ルシフェリンと同程度の化学発光能を有することを明らかにした。(4)面対称構造を有する新規カチオン性脂質をリポソーム化し、その優れた遺伝子導入ベクターとしての機能を明らかにした。さらに、ODN類の細胞内への効率的導入を目的とした細胞膜透過性ペプチド-ODNコンジュゲート体の合成にも成功した。

Research Products

(15 results)

All Other

All Publications (15 results)

[Publications] K.Miyashita, T.Imanishi et al.: "Oxiranes having an acridane structure as a novel chemiluminescent precursor: synthesis and chemiluminescent studies"Tetrahedron. 57・16. 3361-3367 (2001)
[Publications] K.Miyashita, T.Imanishi et al.: "Regio-and stereoselective α-alkylation of N-terminal amino acid residue of peptides using a pyridoxal model compound with a chiral ansa-structure"Tetrahedron. 57・27. 5773-5780 (2001)
[Publications] S.Obika, T.Doi, T.Imanishi et al.: "2'-0, 4'-C-Methylene bridged nucleic acid (2', 4'-BNA): Synthesis and triplex-forming properties"Bioorg. Med. Chem.. 9・4. 1001-1011 (2001)
[Publications] S.Obika, T.Imanishi et al.: "A 2', 4'-bridged nucleic acid containing 2-pyridone as a nuclease: Efficient recognition of a C・G interruption by triplex formation with a obpyrimidine motif"Angew. Chem., Int. Ed. Engl.. 40・11. 2079-2081 (2001)
[Publications] S.Obika, T.Imanishi et al.: "Promotion of triplex formation by 2'-O, 4'-C-methylene bridged nucleic acid (BNA) modification: Thermodynamic and kinetic studies"Nucleosides, Nucleotides and Nucleic Acids. 20・4-7. 1235-1238 (2001)
[Publications] S.Obika, T.Imanishi et al.: "3'-Amino-2', 4'-BNA: Novel bridged nucleic acids having an N3'->P5'phosphoramidate linkage"Chem. Commun.. 2001・19. 1992-1993 (2001)
[Publications] S.Obika, T.Imanishi et al.: "Inhibition of ICAM-I gene expression by antisense 2', 4'-BNA oligonucleotides"Nucleic Acids Res. Suppl.. 2001・1. 145-146 (2001)
[Publications] S.Obika, T.Imanishi et al.: "2, 4'-BNA bearing unnatural nucleobases: Toward the expansion of the target sequence of double-stranded DNA in triplex formation"Nucleic Acids Res. Suppl.. 2001・1. 171-172 (2001)
[Publications] T.Imanishi et al.: "2'-0, 4'-C-Ethylene-bridged nucleic acids (ENA) with nuclease-resistance and high affinity for RNA"Nucleic Acids Res. Suppl.. 2001・1. 241-242 (2001)
[Publications] S.Obika, T.Imanishi et al.: "Triplex formation involving 2', 4'-BNA with 2-pyridone base analogue : Efficient and selective recognition of C:G interruption"Nucleic Acids Res. Suppl.. 2001・1. 281-282 (2001)
[Publications] T.Imanishi et al.: "2'-0, 4'-C-ethylene-bridged nucleic acids (ENA): highly nuclease-resistarlt and thermodynamically stable oligonucleotides for antisense drug"Bioorg. Med. Chem. Lett.. 12・1. 73-76 (2002)
[Publications] S.Obika, T.Imanishi et al.: "Synthesis and conformation of 3', 4'-BNA monomers, 3'-0, 4'-C-methyleneribonucleosides"Tetrahedron. (印刷中). (2002)
[Publications] S.Obika, T.Imanishi et al.: "Effective synthesis of C-nucleosides with 2', 4'-BNA modification"Tetrahedron. (印刷中). (2002)
[Publications] K.Miyashita, S.Obika, T imanishi et al.: "A 3, 4-Epoxypiperidine structure as a novel and simple DNA-cleavage unit"Bioorg. Med. Chem. Lett.. (印刷中). (2002)
[Publications] T.Imanishi, S.Obika: "BNAs: Novel nucleic acid analogs with a bridged sugar moiety"Chem. Commun.. (印刷中). (2002)

2001 Fiscal Year Annual Research Report

生命の分子メカニズムに基づく生体高機能性化合物の設計と合成

Principal Investigator

今西 武 大阪大学, 薬学研究科, 教授 (40028866)

Research Products

[Publications] K.Miyashita, T.Imanishi et al.: "Oxiranes having an acridane structure as a novel chemiluminescent precursor: synthesis and chemiluminescent studies"Tetrahedron. 57・16. 3361-3367 (2001)

[Publications] K.Miyashita, T.Imanishi et al.: "Regio-and stereoselective α-alkylation of N-terminal amino acid residue of peptides using a pyridoxal model compound with a chiral ansa-structure"Tetrahedron. 57・27. 5773-5780 (2001)

[Publications] S.Obika, T.Doi, T.Imanishi et al.: "2'-0, 4'-C-Methylene bridged nucleic acid (2', 4'-BNA): Synthesis and triplex-forming properties"Bioorg. Med. Chem.. 9・4. 1001-1011 (2001)

[Publications] S.Obika, T.Imanishi et al.: "A 2', 4'-bridged nucleic acid containing 2-pyridone as a nuclease: Efficient recognition of a C・G interruption by triplex formation with a obpyrimidine motif"Angew. Chem., Int. Ed. Engl.. 40・11. 2079-2081 (2001)

[Publications] S.Obika, T.Imanishi et al.: "Promotion of triplex formation by 2'-O, 4'-C-methylene bridged nucleic acid (BNA) modification: Thermodynamic and kinetic studies"Nucleosides, Nucleotides and Nucleic Acids. 20・4-7. 1235-1238 (2001)

[Publications] S.Obika, T.Imanishi et al.: "3'-Amino-2', 4'-BNA: Novel bridged nucleic acids having an N3'->P5'phosphoramidate linkage"Chem. Commun.. 2001・19. 1992-1993 (2001)

[Publications] S.Obika, T.Imanishi et al.: "Inhibition of ICAM-I gene expression by antisense 2', 4'-BNA oligonucleotides"Nucleic Acids Res. Suppl.. 2001・1. 145-146 (2001)

[Publications] S.Obika, T.Imanishi et al.: "2, 4'-BNA bearing unnatural nucleobases: Toward the expansion of the target sequence of double-stranded DNA in triplex formation"Nucleic Acids Res. Suppl.. 2001・1. 171-172 (2001)

[Publications] T.Imanishi et al.: "2'-0, 4'-C-Ethylene-bridged nucleic acids (ENA) with nuclease-resistance and high affinity for RNA"Nucleic Acids Res. Suppl.. 2001・1. 241-242 (2001)

[Publications] S.Obika, T.Imanishi et al.: "Triplex formation involving 2', 4'-BNA with 2-pyridone base analogue : Efficient and selective recognition of C:G interruption"Nucleic Acids Res. Suppl.. 2001・1. 281-282 (2001)

[Publications] T.Imanishi et al.: "2'-0, 4'-C-ethylene-bridged nucleic acids (ENA): highly nuclease-resistarlt and thermodynamically stable oligonucleotides for antisense drug"Bioorg. Med. Chem. Lett.. 12・1. 73-76 (2002)

[Publications] S.Obika, T.Imanishi et al.: "Synthesis and conformation of 3', 4'-BNA monomers, 3'-0, 4'-C-methyleneribonucleosides"Tetrahedron. (印刷中). (2002)

[Publications] S.Obika, T.Imanishi et al.: "Effective synthesis of C-nucleosides with 2', 4'-BNA modification"Tetrahedron. (印刷中). (2002)

[Publications] K.Miyashita, S.Obika, T imanishi et al.: "A 3, 4-Epoxypiperidine structure as a novel and simple DNA-cleavage unit"Bioorg. Med. Chem. Lett.. (印刷中). (2002)

[Publications] T.Imanishi, S.Obika: "BNAs: Novel nucleic acid analogs with a bridged sugar moiety"Chem. Commun.. (印刷中). (2002)

今西武大阪大学, 薬学研究科, 教授 (40028866)