1993 Fiscal Year Annual Research Report

特異な構造をもつヌクレオシドの化学合成と反応

Research Project

Project/Area Number	04226103
Research Institution	Tohoku University
Principal Investigator	金子主税東北大学, 薬学部, 教授 (40013833)
Co-Investigator(Kenkyū-buntansha)	小林進相模中央研究所, 主席研究員 (70101102) 佐々木琢磨金沢大学, がん研究所, 教授 (90109976) 関根光雄東京工業大学, 生命理工学部, 助教授 (40111679) 西村善文横浜市立大学, 大学院総合理学部, 教授 (70107390) 向山光昭東京理科大学, 理学部, 教授 (60016003)
Keywords	炭素環ヌクレオシド / アデノシンデアミナーゼ / 核酸塩基 / β-ヌクレオシド / C-myb protooncogene / 投げ縄構造 / RNAの化学合成 / CNDAC
Research Abstract	1)生物機能を有するヌクレオシドの光学活性体を効率よく得るため,生物学的手法による光学分割を試みた.その結果,adenosine deaminaseが高圧によって活性化されることを見出し,抗HIV活性を有する炭素環ヌクレオシドの高エナンチオ選択的光学分割に成功した. 2)2,3,5-トリ-O-ベンジル-1-O-ヨードアセチル-D-リボフラノースに対して求核剤を作用させる反応で,添加物あるいは触媒を適当に選ぶことにより,対応するα-またはβ-リボシドが高収率かつ高選択的に得られることを見出した.また,2,3,5-トリ-O-ベンゾイル-D-リボフラノシルメチルカーボネイトに対してトリメチルシリル化した核酸塩基を作用させることにより,対応するβ-ヌクレオシドが高収率かつ完全な選択性をもって得られる反応を明らかにした. 3)DNAの塩基配列の識別機構を解析した.特に核内がん原遺伝子産物のMybが認識するDNAの配列を調べた.系統的に配列を変異させ,AACxGx(C/T/A)配列がMybの認識に必須であることがわかった.蛋白側とDNA結合ドメインの3個のリピート(各52アミノ酸残基)の内3番目のリピートがAACを,2番目のリピートがGx(C/T/A)を認識していることがわかった.また複合体中のDNAをNMRにより解析することによりそれを認識した. 4)投げ縄構造をもつRNAの化学合成にはヌクレオシドの2'および3'水酸基に異なるリン酸基の導入が必要である.そこで,まず基本骨格である2'-リン酸基をもつRNAの化学合成法の確立を目指し,2'-リン酸基の保護基として2-シアノ-1,1-ジメチルエチル基を用い,さらにリン酸基をチオリン酸基に置き換えたアミダイト合成ユニットを構築し,2'-リン酸基をもつオリゴウリジル酸10量体を合成することができた. 5)新規抗腫瘍ヌクレオシドCNDACの作用機序を耐熱性菌由来のDNAポリメラーゼによる特異的DNA増幅反応系を用いて検討した.CNDACの5'-トリリン酸体(CNDA CTP)は反応産物である増幅DNAを顕著に減少せしめ,DNA伸長反応を阻害することが明らかとなった.さらに,その阻害作用はDNA塩基配列中のCに対する特異的なターミネーション活性によることが明らかとなり,抗腫瘍性発現において細胞内でのCNDACTPによるDNA合成阻害の重要性が示唆された.

Research Products
(26 results)

All Other

All Publications (26 results)

[Publications] Nobuya Katagiri: "Remarkable accerelation for the deamination of BCA by adenosine deaminase under high pressure" Chem.Pharm.Bull.41. 1027-1029 (1993)
[Publications] Akemi Toyota: "Mitsunobu reactions for the synthesis of carbocyclic analogues of nucleosides" Synthetic Commun.23. 1295-1305 (1993)
[Publications] Akemi Toyota: "The alkylation of 2-amino-6-chloropurine with alcohols by Mitsunobu reaction for the synthesis of carbocyclic guanosine analogs" Heterocycles. 36. 1625-1630 (1993)
[Publications] Nobuya Katagiri: "Remarkable acceleration for the deamination of carbocyclic purine nucleosides by adenosine deaminase under high pressure" Nucleic Acids Symp.Ser.29. 95-96 (1993)
[Publications] Nobuya Katagiri: "Synthetic Studies on High Modified Nucleosides Directed towards Creation of Anti-HIV Agents" Yakugaku Zasshi. 113. 285-306 (1993)
[Publications] Chikara Kaneko: "Design of New Reactions and its Application to Creative Drug Research" Yakugaku Zasshi. 113. 627-646 (1993)
[Publications] Teruaki Mukaiyama: "Catalytic Stereoselective Synthesis of α-or-β-Ribofuranosides by combined Use of Silver Salts and Lithium Perchlorate or Diphenyltin Sulfide" Chemistry Lett.781-784 (1993)
[Publications] Naoyuki Shimomura: "Catalytic Stereoselective Synthesis of β-Ribofuranosides from Methyl Ribofuranosyl Carbonate and Trimethylsilylated Nucleoside Bases by Combined Use of Silver Salts and Diphenyltin Sulfide" Chemistry Lett.1627-1630 (1993)
[Publications] Naoyuki Shimomura: "Catalytic Stereoselective Synthesis of β-Ribofuranosides from D-Ribofuranose and Alcohols" Chemistry Lett.1941-1944 (1993)
[Publications] Naoyuki Shimomura: "Tin(II)Chloride Catalyzed Synthesis of Ribofuranosides" Chemistry Lett.433-436 (1994)
[Publications] Jun Tamikawa: "Recognition of specific DNA sequences by the C-myb protooncogene product:Role of three repeat units in the DNA-binding domain" Proc.Natl.Acad.Sci.USA. 90. 9320-9324 (1993)
[Publications] A.Sarai: "Thermal Stability of the DNA-Binding Domain of the Myb Oncoprotein" Biochemistry. 32. 7759-7764 (1993)
[Publications] M.Sekine: "Nucleo-cytoplasmic Transport of UsnRNPs: Definition of a Nucleo Location Signal in the Sm Core Domain that Binds a Transport" EMBO Journal. 12. 573-583 (1993)
[Publications] M.Sekine: "New 5'-Hydroxyl Protecting Groups for Rapid Internucleotidic Bond Formation" Tetrahedron Letters. 34. 8289-8292 (1993)
[Publications] M.Sekine: "Synthesis of a New Class of 2'-Phosphorylated Oligoribonucleotides Capable of Conversion to Oligoribonucleotides" Journal of Organic Chemistry. 58. 3204-3208 (1993)
[Publications] K.Nishikawa: "Sequence Analysis of Low Molecular-Weight RNAs by the Use of Non-Radioactive Labeling" Nucleic Acids Symposium Series. 29. 75-76 (1993)
[Publications] M.Sekine: "Chemical Synthesis of Branched Oligoribonucleotides and Their Related Compounds" Studies in Natural Products Chemistry. 14. 283 (1994)
[Publications] Kakefuda,A.,et al.: "Stereoselective radical deoxyganation of tert-alcohols in the sugar moiety of nucleosides" Tetrahedron. 49. 8513-8528 (1993)
[Publications] Yoshimura,Y.,et al.: "Synthesis and biological activity of 1-(2-deoxy-2-C-fluoromethyl-and 2-C-hydromethylarabinofuranosyl)-cytosines" Nucleic Acids Symposium Series. 29. 33-34 (1993)
[Publications] Minakawa,N.,et al.: "A transition-state analogue in purine nucleoside biosynthesis:The design and synthesis an imidazo 4,5-c azepine nucleoside" Bioorganic & Medicinal Chemistry Letters. 3. 183-186 (1993)
[Publications] Azuma,A.,et al.: "2'-C-Cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine and its derivatives.A new class of Nucleoside with a broad antitumor spectrum" J.Med.Chem.36. 4183-4189 (1993)
[Publications] Matsuda,A.,et al.: "Synthesis of 1-(2-deoxy-2-isocyano-β-D-arabinofuranosyl)cytosine and related nucleosides as potent antitumor agents" J.Med.Chem.36. 4190-4194 (1993)
[Publications] Tsuchiya,Y.,et al.: "Expression of type IV collagenases in human tumor cell lines that can form liver colonies in chick embryo" Int.J.Cancer. 56. 46-51 (1994)
[Publications] Chikara Kaneko: "Organic Synthesis under High-Pressure" Sanei Pub.Co.,Kyoto, 8 (1993)
[Publications] 佐々木琢磨: "日本生化学編新生化学実験講座13 バイオテクノロジー" (株)東京化学同人, 462 (1993)
[Publications] 遠藤良夫・佐々木琢磨: "癌の悪性化と転移" (株)中外医学社, 212 (1993)

1993 Fiscal Year Annual Research Report

特異な構造をもつヌクレオシドの化学合成と反応

Principal Investigator

金子 主税 東北大学, 薬学部, 教授 (40013833)

Research Products

[Publications] Nobuya Katagiri: "Remarkable accerelation for the deamination of BCA by adenosine deaminase under high pressure" Chem.Pharm.Bull.41. 1027-1029 (1993)

[Publications] Akemi Toyota: "Mitsunobu reactions for the synthesis of carbocyclic analogues of nucleosides" Synthetic Commun.23. 1295-1305 (1993)

[Publications] Akemi Toyota: "The alkylation of 2-amino-6-chloropurine with alcohols by Mitsunobu reaction for the synthesis of carbocyclic guanosine analogs" Heterocycles. 36. 1625-1630 (1993)

[Publications] Nobuya Katagiri: "Remarkable acceleration for the deamination of carbocyclic purine nucleosides by adenosine deaminase under high pressure" Nucleic Acids Symp.Ser.29. 95-96 (1993)

[Publications] Nobuya Katagiri: "Synthetic Studies on High Modified Nucleosides Directed towards Creation of Anti-HIV Agents" Yakugaku Zasshi. 113. 285-306 (1993)

[Publications] Chikara Kaneko: "Design of New Reactions and its Application to Creative Drug Research" Yakugaku Zasshi. 113. 627-646 (1993)

[Publications] Teruaki Mukaiyama: "Catalytic Stereoselective Synthesis of α-or-β-Ribofuranosides by combined Use of Silver Salts and Lithium Perchlorate or Diphenyltin Sulfide" Chemistry Lett.781-784 (1993)

[Publications] Naoyuki Shimomura: "Catalytic Stereoselective Synthesis of β-Ribofuranosides from Methyl Ribofuranosyl Carbonate and Trimethylsilylated Nucleoside Bases by Combined Use of Silver Salts and Diphenyltin Sulfide" Chemistry Lett.1627-1630 (1993)

[Publications] Naoyuki Shimomura: "Catalytic Stereoselective Synthesis of β-Ribofuranosides from D-Ribofuranose and Alcohols" Chemistry Lett.1941-1944 (1993)

[Publications] Naoyuki Shimomura: "Tin(II)Chloride Catalyzed Synthesis of Ribofuranosides" Chemistry Lett.433-436 (1994)

[Publications] Jun Tamikawa: "Recognition of specific DNA sequences by the C-myb protooncogene product:Role of three repeat units in the DNA-binding domain" Proc.Natl.Acad.Sci.USA. 90. 9320-9324 (1993)

[Publications] A.Sarai: "Thermal Stability of the DNA-Binding Domain of the Myb Oncoprotein" Biochemistry. 32. 7759-7764 (1993)

[Publications] M.Sekine: "Nucleo-cytoplasmic Transport of UsnRNPs: Definition of a Nucleo Location Signal in the Sm Core Domain that Binds a Transport" EMBO Journal. 12. 573-583 (1993)

[Publications] M.Sekine: "New 5'-Hydroxyl Protecting Groups for Rapid Internucleotidic Bond Formation" Tetrahedron Letters. 34. 8289-8292 (1993)

[Publications] M.Sekine: "Synthesis of a New Class of 2'-Phosphorylated Oligoribonucleotides Capable of Conversion to Oligoribonucleotides" Journal of Organic Chemistry. 58. 3204-3208 (1993)

[Publications] K.Nishikawa: "Sequence Analysis of Low Molecular-Weight RNAs by the Use of Non-Radioactive Labeling" Nucleic Acids Symposium Series. 29. 75-76 (1993)

[Publications] M.Sekine: "Chemical Synthesis of Branched Oligoribonucleotides and Their Related Compounds" Studies in Natural Products Chemistry. 14. 283 (1994)

[Publications] Kakefuda,A.,et al.: "Stereoselective radical deoxyganation of tert-alcohols in the sugar moiety of nucleosides" Tetrahedron. 49. 8513-8528 (1993)

[Publications] Yoshimura,Y.,et al.: "Synthesis and biological activity of 1-(2-deoxy-2-C-fluoromethyl-and 2-C-hydromethylarabinofuranosyl)-cytosines" Nucleic Acids Symposium Series. 29. 33-34 (1993)

[Publications] Minakawa,N.,et al.: "A transition-state analogue in purine nucleoside biosynthesis:The design and synthesis an imidazo 4,5-c azepine nucleoside" Bioorganic & Medicinal Chemistry Letters. 3. 183-186 (1993)

[Publications] Azuma,A.,et al.: "2'-C-Cyano-2'-deoxy-1-β-D-arabinofuranosylcytosine and its derivatives.A new class of Nucleoside with a broad antitumor spectrum" J.Med.Chem.36. 4183-4189 (1993)

[Publications] Matsuda,A.,et al.: "Synthesis of 1-(2-deoxy-2-isocyano-β-D-arabinofuranosyl)cytosine and related nucleosides as potent antitumor agents" J.Med.Chem.36. 4190-4194 (1993)

[Publications] Tsuchiya,Y.,et al.: "Expression of type IV collagenases in human tumor cell lines that can form liver colonies in chick embryo" Int.J.Cancer. 56. 46-51 (1994)

[Publications] Chikara Kaneko: "Organic Synthesis under High-Pressure" Sanei Pub.Co.,Kyoto, 8 (1993)

[Publications] 佐々木琢磨: "日本生化学編新生化学実験講座13 バイオテクノロジー" (株)東京化学同人, 462 (1993)

[Publications] 遠藤良夫・佐々木琢磨: "癌の悪性化と転移" (株)中外医学社, 212 (1993)

金子主税東北大学, 薬学部, 教授 (40013833)