Development of artificial nucleic acid conjugates as base materials for genome-based drug discovery and DNA-based diagnostics

• Project/Area Number: 19390030
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Drug development chemistry
• Research Institution: Osaka University
• Principal Investigator: IMANISHI Takeshi Osaka University, 名誉教授 (40028866)
• Co-Investigator(Kenkyū-buntansha): DOI Takefumi 大阪大学, 大学院・薬学研究科, 教授 (00211409) ; KODAMA Tetsuya 大阪大学, 大学院・薬学研究科, 助教 (00432443)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥18,590,000 (Direct Cost: ¥14,300,000、Indirect Cost: ¥4,290,000); Fiscal Year 2008: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000); Fiscal Year 2007: ¥12,610,000 (Direct Cost: ¥9,700,000、Indirect Cost: ¥2,910,000)
• Keywords: ゲノム創薬 / 人工核酸 / 遺伝子検出 / 遺伝子診断 / DNA

Research Abstract

ライフサイエンス領域での基盤材料となる人工核酸として、これまでにない新しい架橋構造を持つ架橋型人工核酸(BNA)を種々設計し、その合成法を確立した。また、新しい蛍光分子やDNAアルキル化分子を創製するとともに更なる誘導体化を実施し、核酸との複合体化を可能とした。さらに、核酸イメージング技術や送達法等への応用が期待できる核酸の別機能性分子との効率的複合体化法の開発に成功した。複合体化BNAの遺伝子発現抑制活性を評価し、血清中での高い安定性や、培養細胞内での高い遺伝子発現抑制能を見いだした。

Research Products

• [Journal Article] A Bridged Nucleic Acid, 2',4'-BNA^<COC> : Synthesis of Fully Modified Oligonucleotides Bearing Thymine, 5-Methylcytosine, Adenine and Guanine 2',4'-BNA^<COC> Monomers, and RNA-selective Nucleic Acid Recognition (2009)
  • Author(s): Yasunori Mitsuoka, Tetsuya Kodama, Ryo Ohnishi, Yoshiyuki Hari, Takeshi Imanishi and Satoshi Obika
  • Journal Title: Nucleic Acids Res 37 Pages: 1225-1238
  • Peer Reviewed
• [Journal Article] Design, Synthesis, and Evaluation of a Novel Bridged Nucleic Acid, 2',5'-BNA ^<ON> with S-type Sugar Conformation Fixed by N-O Linkage (2009)
  • Author(s): Tetsuya Kodama, Chieko Matsuo, Hidetsugu Ori, Tetsuya Miyoshi, Satoshi Obika, Kazuyuki Miyashita, Takeshi Imanishi
  • Journal Title: Tetrahedron 65 Pages: 2116-2123
  • Peer Reviewed
• [Journal Article] Synthesis of a Novel trans-3',4'-BNA Monomer Bearing a 4,8-Dioxa-5-azabicyclo-[5.3.0]decane Skeleton (2009)
  • Author(s): Tetsuya Kodama, Kensaku Sugaya, Takeshi Baba, Takeshi Imanishi, Satoshi Obika
  • Journal Title: Heterocycles 79 Pages: 873-882
  • NAID: 40016543114
  • Peer Reviewed
• [Journal Article] Synthesis of a novel trans-3', 4' -BNA monomer bearinga 4, 8-dioxa-5-azabicyclo[5. 3. 0]decane skeleton. (2009)
  • Author(s): Tetsuya Kodama
  • Journal Title: Heterocycles 79(印刷中)
  • Peer Reviewed
• [Journal Article] Synthesis and properties of 2 ' -deoxy-trans-3', 4' -BNA with S-type sugar puckering. (2009)
  • Author(s): Tetsuya Kodama
  • Journal Title: Heterocycles 77 Pages: 1209-1217
  • NAID: 40016454354
  • Peer Reviewed
• [Journal Article] Synergistic stabilization of nucleic acid assembly by 2' - 0, 4' -C-methylene bridged nucleic acid modification and additions of Comb-type cat ionic copolymers. (2009)
  • Author(s): Hidetaka Torigoe
  • Journal Title: Biochemistry 48(印刷中)
  • Peer Reviewed
• [Journal Article] A bridged nucleic acid, 2', 4'-BNACOC : Synthesis of fullymodified oligonucleotides bearing thymine, 5-methylcyto-sine, adenine and guanine 2', 4'-BNAC0C monomers, andRNA-selective nucleic acid recognition. (2009)
  • Author(s): Yasunori Mitsuoka
  • Journal Title: Nucleic Acids Res. 37 Pages: 1225-1238
  • Peer Reviewed
• [Journal Article] Design, synthesis, and evaluation of a novel bridgednucleic acid, 2′, 5′ -BNA^ON, with S-type sugarconformation fixed by N-O linkage. (2009)
  • Author(s): Te tsuya Kodama
  • Journal Title: Tetrahedron 65 Pages: 2116-2123
  • Peer Reviewed
• [Journal Article] Synthesis and properties of 3'-amino-2',4'-BNA, a bridged nucleic acid with a N3'-P5' phosphoramidate linkage. Bioorg (2008)
  • Author(s): Satoshi Obika, S.M.Abdur Rahman, Bingbing Song, Mayumi Onoda, Makoto Koizumi, Koji Morita, Takeshi Imanishi
  • Journal Title: Med. Chem 16 Pages: 9230-9237
  • Peer Reviewed
• [Journal Article] Design, synthesis and properties of 2',4'-BNA ^<NC> : A bridged nucleic acid analogue (2008)
  • Author(s): S. M. Abdur. Rahman, Sayori. Seki, Satoshi. Obika, Haruhisa Yoshikawa, Kazuyuki Miyashita, Takeshi Imanishi
  • Journal Title: J. Am. Chem. Soc. 130 Pages: 4886-4896
  • Peer Reviewed
• [Journal Article] Systematic analysis of enzymatic DNA polymferizationusing oligo-DNA templates and triphosphate analogsinvolving 2', 4'-bridged nucleosides. (2008)
  • Author(s): Masayasu Kuwahara
  • Journal Title: Nucleic Acids Res. 36 Pages: 4257-4265
  • Peer Reviewed
• [Journal Article] Biologically active 2-5A analogs containing 3' -0, 4' -C-propylene adenosine as potent RNase L agonists. (2008)
  • Author(s): Koji Morita
  • Journal Title: Nucleic Acids Symp. Ser. 52 Pages: 637-638
• [Journal Article] Promotion of triplex formation by 2' -0, 4' -C-aminome-thylene bridged nucleic acid (2', 4' -BNA^NC)modification. (2008)
  • Author(s): Kiyomi Sasaki
  • Journal Title: Nucleic Acids Symp. Ser. 52 Pages: 419-420
• [Journal Article] Synthesis and properties of 3′-amino-2′, 4′-BNA, a bridgednucleic acid with a N3'→P5' phosphoramidate linkage. (2008)
  • Author(s): Satoshi Obika
  • Journal Title: Bioorg. Med. Chem. 16 Pages: 9230-9237
  • Peer Reviewed
• [Journal Article] Total Synthesis of Leustroducsin B. (2008)
  • Author(s): Kazuyuki Miyashita
  • Journal Title: J. Org. Chem. 73 Pages: 5360-5370
  • Peer Reviewed
• [Journal Article] Development of anovel nucleoside analogue with S-type sugar conformation: 2'deoxy-trans-3', 4'-bridged nucleic acids (2007)
  • Author(s): 尾崎朋久
  • Journal Title: Tetrahedron 63 Pages: 8977-8986
  • Peer Reviewed
• [Presentation] カルバマート骨格を有する新規架橋型人工核酸の合成とその評価 (2008)
  • Author(s): 西田勝、見玉」互也、馬場武、小比賀聡、今西武
  • Organizer: 第34回反応と合成の進歩シンポジウム
  • Place of Presentation: 京都
• [Presentation] 架橋型人工核酸BNA修飾によるsiRNAの高機能化 (2008)
  • Author(s): 佐藤寛之、津田直人、生川径祐、今西武、小比賀聡
  • Organizer: 第81回日本生化学会大会・第31回日本分子生物学会年会合同大会
  • Place of Presentation: 兵庫
• [Presentation] 2,2'一ビスベンズイミダゾール骨格を有した新規蛍光分子の開発とオリゴヌクレオチドラベル化に関する研究 (2008)
  • Author(s): 松山憲司、渡部徹也、兒玉哲也、小比賀聡、宮下和之、今西武
  • Organizer: 第三回バイオ関連化学合同シンポジウム2008
  • Place of Presentation: 神奈川
• [Presentation] 3,4一エポキシピペリジン構造を有する新規DNAアルキル分子の合成と活性評価 (2008)
  • Author(s): 河田裕治、山口卓男、宮下和之、小比賀聡、今西武
  • Organizer: 第27回メディシナルケミストリーシンポジウム
  • Place of Presentation: 大阪
• [Presentation] ウレア骨格を有する新規架橋型人工核酸の合成とその評価 (2008)
  • Author(s): 西田 勝
  • Organizer: 第18回アンチセンスシンポジウム
  • Place of Presentation: 岐阜
• [Presentation] 架橋型人工核酸BNAのsiRNAへの応用 (2008)
  • Author(s): 佐藤 寛之
  • Organizer: 第18回アンチセンスシンポジウム
  • Place of Presentation: 岐阜
• [Presentation] 架橋型人工核酸BNAのsiRNAへの展開 (2008)
  • Author(s): 佐藤寛之
  • Organizer: 第8回遺伝子デリバリー研究会
  • Place of Presentation: 兵庫
• [Presentation] 架橋型人工核酸BNAを用いたsiRNAによる遺伝子発現抑制 (2008)
  • Author(s): 佐藤寛之
  • Organizer: 第三回バイオ関連化学合同シンポジウム2008
  • Place of Presentation: 神奈川
• [Presentation] 2, 2'-ビスベンズイミダゾール骨格を有した新規蛍光分子の開発とオリゴヌクレオチドラベル化に関する研究 (2008)
  • Author(s): 松山 憲司
  • Organizer: 第三回バイオ関連化学合同シンポジウム2008
  • Place of Presentation: 神奈川
• [Presentation] クリックケミストリーを利用したオリゴヌクレオチド上での新規機能性核酸塩基の構築 (2008)
  • Author(s): 中原 基
  • Organizer: 第三回バイオ関連化学合同シンポジウム2008
  • Place of Presentation: 神奈川
• [Presentation] 3, 4-エポキシピペリジン構造を有するazinomycin類縁体の合成研究 (2008)
  • Author(s): 河田裕治
  • Organizer: 第38回複素環化学討論会
  • Place of Presentation: 広島
• [Presentation] 3, 4-エポキシピペリジン構造を有する新規DNAアルキル分子の合成と活性評価 (2008)
  • Author(s): 河田 裕治
  • Organizer: 第27回メディシナルケミストリーシンポジウム
  • Place of Presentation: 大阪
• [Presentation] 3, 4-エポキシピベリジン構造を有するazinomycin誘導体の合成研究 (2008)
  • Author(s): 河田 裕治
  • Organizer: 第94回有機合成シンポジウム
  • Place of Presentation: 東京
• [Presentation] 糖部をS型に束縛した架橋型人工核酸2'-deoxy型trans3', 4'-BNAの合成とその機能性評価 (2007)
  • Author(s): 菅谷建作
  • Organizer: 第27回有機合成若手セミナー
  • Place of Presentation: 京都大学薬学記念講堂
  • Year and Date: 2007-11-15
• [Presentation] 新規DNAアルキル化分子としての3, 4-エポキシピペリジン誘導体の合成 (2007)
  • Author(s): 河田裕治
  • Organizer: 第27回有機合成若手セミナー
  • Place of Presentation: 京都大学薬学記念講堂
  • Year and Date: 2007-11-15
• [Presentation] 糖部立体配座をS型に固定化した新規核酸類縁体(trans-3', 4'-BNA)の合成(3) (2007)
  • Author(s): 菅谷建作
  • Organizer: 第57回日本薬学会近畿支部大会
  • Place of Presentation: 大阪薬科大学
  • Year and Date: 2007-10-27
• [Presentation] Synthesis andproperties of a 2'-deoxy analogue of trans-3',4'-BNA having an S-type sugar conformation (2007)
  • Author(s): 兒玉哲也、松尾智恵子、小里英嗣、小比賀聡、宮下和之、今西武
  • Organizer: 5th International Symposium on Nucleic Acids Chemistry
  • Place of Presentation: Tokyo
• [Presentation] Studies toward the total synthesis of azinomycin A, a potent antitumor antibiotic (2007)
  • Author(s): 山口卓男、河田裕治、宮下和之、今西武
  • Organizer: The 21st International Congress for Heterocyclic Chemistry
  • Place of Presentation: Sydney
• [Presentation] Synthesis and properities of a 2'-deoxy analogue of trans-3', 4'-BNA having S-type sugar conformation (2007)
  • Author(s): 菅谷建作
  • Organizer: 第5回国際核酸化学シンポジウム
  • Place of Presentation: 東京大学安田講堂
• [Presentation] Synthesis and chemical properties of a novel 2', 4'-bridged nucleic acid analogue bearing a seven-membered cyclic carbamate structure (2007)
  • Author(s): 西田勝
  • Organizer: 第5回国際核酸化学シンポジウム
  • Place of Presentation: 東京大学安田講堂