1992 年度実績報告書

特異な構造をもつヌクレオシドの化学合成と反応

研究課題

研究課題/領域番号	04226103
研究機関	東北大学
研究代表者	金子主税東北大学, 薬学部, 教授 (40013833)
研究分担者	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) 小林進東京大学, 薬学部, 助教授 (70101102) 向山光昭東京理科大学, 理学部, 教授 (60016003)
キーワード	炭素環ヌクレオシド / 抗HIV活性 / グリコシル化反応 / ルイス酸 / 塩基特異性 / 2'-リン酸化RNA / 転移反応 / フローサイトメトリー
研究概要	1.糖部環内酸素が炭素に置き変わった炭素環ヌクレオシドは酵素による加水分解を受けにくいためその生物機能がおおいに期待されている。しかし、天然より得ることが困難であるため純化学的合成に頼らざるを得ない。本研究において活性化されたイミンとシクロペンタジエンとの反応により2-アザビシクロ体を合成し、我々が既に見い出しているRRA反応(還元条件下での逆アルドール反応)条件下での選択的C-N結合の開裂を行い付加体より抗HIV活性を有するBCAアナローグに相当する炭素環ヌクレオシドの立体選択的合成に成功した。(金子) 2.立体選択的グリコシル反応の開発は糖質あるいはヌクレオシド合成の分野で最も重要な研究課題の一つである。今回、ルイス酸として二価スズ-トリフラートを用いアミノ糖のグリコシル化反応を行い高立体選択的にグリコシドを得ることに成功した。また、SnCl_3(ClO_4)を用いて各種アミノ酸と糖との反応より糖タンパクの構成成分となるα-ガラクトシドの高選択的合成にも成功した。更に、TMSOTf-Ph_2Sn=SあるいはAgClO_4を用いるリボフラノースの高立体選択的グリコシル化に成功し、このことはヌクレオシド類の効率的合成法の開発を示唆するものである。(向山) 3.特異的にDNAを認識するヘテロ環小分子として、今回新たにAC-2-BTならびにPN-4-BTを合成し塩基特異性を検討した。その結果、両者ともG-Cに高い親和性を示すことがわかり、当初仮定したようにチアゾール自体は、G-Cを認識することが確認できた。(小林) 4.2'-リン酸化されたRNAは生体内に存在するが、その生物機能は不明であり化学合成が望まれている。本研究において2'-リン酸化RNAの合成において問題となるリン酸基の2'-3'間の転移反応の抑制をめざし、2'-リン酸の保護基について検討した。その結果、リン酸基の保護基に2-シアノ-1,1-ジメチルエチル基を用いリン酸基のP=OをP=Sに置き換えることによって2'-3'間の転移反応を抑制することが出来た。(関根) 5.Ara-Cが効果を示さないヒト固形腫瘍に対して抗腫瘍効果を示す新規ヌクレオシドCNDACの作用機構を検討した。その結果、Ara-Cと同様5'-トリリン酸体となってDNAに取り込まれ効果を示することが明かとなった。また、フローサイメトリーでの測定によりCNDACは細胞をG2M期に蓄積させる作用を持つことが明かとなった。(佐々木)

研究成果
(26件)

すべてその他

すべて文献書誌 (26件)

[文献書誌] Nobuya Katagiri: "Synthesis and anti-HIV activity of 9-(c-4,t-5-dihydroxy-methylcyclopent-2-en-r-1-yl)-9H-adenine" J.Med.Chem.35. 1882-1886 (1992)
[文献書誌] Nobuya Katagiri: "Sysnthesis and biological evaluation of 9-(t-2,c-3-di-hydroxymethyl-r-1-cyclopropylmethyl)-9H-adenine(A lower methylene homolog of carbocyclic oxetanocim)and related compounds" Nucleosides & Nucleotides. 11. 707-718 (1992)
[文献書誌] Akemi Toyota: "The alkylation of 6-chloropurine by alcohols by Mitsunobu reaction" Chem.Pharm.Bull.40. 1039-1041 (1992)
[文献書誌] Nobuya Katagiri: "The difference in effects between high pressure and LiClO_4 for the Diels-Alder reaction of cyclopentadiene with methylenemalonates or O-acetylisonitrosomalonates" Chem.Pharm.Bull.40. 1737-1741 (1992)
[文献書誌] Nobuya Katagiri: "Resolution of 9-(c-4,t-5-bishydroxymethylcyclopent-2-en-r-1-yl)-9H-adenine(BCA)selective inhibition of human immunodeficiency virus by the (-) enantiomer" Biochem.Biophys.Res.Commun.184. 154-159 (1992)
[文献書誌] Nobuya Katagiri: "Synthesis of (1R,4S,5R)-(4,5-bishydroxymethylcyclopent-2-en-1-yl)-9H-adenine and selective inhivition of human immunodeficiency virus" Tetrahedron Lett.33. 3507-3510 (1992)
[文献書誌] M.Sekine: "Regioselective O-methylation of hydroxyl groups via 1,3-benzothiazol-2-yl ether intermediates" Natural Product Letters. 1. 25-28 (1992)
[文献書誌] M.Sekine: "Synthesis and properties of N,N-dibenzoylated deoxy-cytidine derivatives" Natural Product Letters. 1. 135-140 (1992)
[文献書誌] M.Sekine: "Synthesis of adenosine,guanosine and cytidine monomer building units bearing the ((2-(mehtylthio(phenyl)thio)-methyl(MPTM)group as the 2'-OH protecting group" Nucleosides & Nucleotides. 11. 679-691 (1991)
[文献書誌] M.Sekine: "Syntheses and properties of dansylated deoxycytidine 3',5'-bisphosphate derivatives useful for 3'-labeling of oligorilbonucleotides" Nucleosides & Nucleotides. 11. 1713-1730 (1992)
[文献書誌] A.Matsuda: "Synthesis and biological activity of 1-(2-deoxy-2-hydroxyimino-or methoxyiminotives useful for 3'-labeling of oligorilbonucleotides-β-D-erythropentofuranosyl)-thimine and-cytosine" Nucleosides & Nucleotides. 11. 237 (1992)
[文献書誌] M.Tanaka: "Antitumor activity of a novel nucleoside,2'-C-cyano-2'-deoxy-1-β-arbinofuranosylcytosine(CNDAC)against murrine and human tumors" Cancer Letters. 64. 67 (1992)
[文献書誌] Nobuya Katagiri: "A novel and efficient synthesis of 9-(c-4,t-5-bishydroxy-methylcyclopent-2-en-r-1-yl)-9H-adenine(BCA)having anti-HIV activity from norbornadiene" Heterocycles. 33. 1097-1100 (1992)
[文献書誌] Nobuya Katagiri: "High pressure mediated Diels Alder reaction using 2-iminomalonates as dienophiles:novel synthesis of carbo-cyclic nucleosides" Nucleic Acids Symp.Ser.27. 83-85 (1992)
[文献書誌] Nobuya Katagiri: "Remarkable accerelation for the deamination of BCA by adenosine deaminase under high pressure:enzymatic resolution of 9-(c-4,t-5-bishydroxymethylcyclopent-2-en-r-1-yl)-9H-adenine((+)-BCA)haveing anti-HIV activity." Chem.Parm.Bull.
[文献書誌] Akemi Toyota: "Mitsunobu reactions for the synthesis of carbocyclic analogues of nucleosides:examination for the regio-selectivity" Synthetic Commun.
[文献書誌] Akemi Toyota: "The alkylation of 2-amino-6-chloropurine with alcohols by Mitsunobu reaction for the synthesis of carbocyclic guanosine analogs" Heterocycles.
[文献書誌] Teruaki Mukaiyama: "Stereosective synthesis of 2-amino-2-deoxy-β-D-guluco-pyranosides and galactophyranosides by using a catalytic amount of Tin(II)trifluoromethanesulufonate" Chem.Lett.1755 (1992)
[文献書誌] K.Matsubara: "Stereosective synthesis of O-(2-azido-2-deoxy-α-D-gala-ctopyranosyl)-L-serine and L-threonine derivatives by using the catalytic amount of active acidic species" Chem.Lett.
[文献書誌] T.Mukaiyama: "Stereoselective glycosylation reaction starting form 1-O-trimethylsilyl sugars by using diphenyltin sulfide and a catalytic amount pfactive acidic species" Chem.Lett.1041 (1992)
[文献書誌] T.Mukaiyama: "Catalytic stereoselective synthesis of α-or β-ribofura-nosides by combined use of silver salts and lithium per-chlorate or diphenyltin sulfide" Chem.Lett.
[文献書誌] S.Kobayashi: "Synthesis of thiazole-based DNA-targeting molecules aiming at guanin specificity" Synlett.59 (1992)
[文献書誌] R.Iwase: "Molecular design of a eukaryotic messenger RNA and Its chemical synthesis" Nucleic Acids Res.20. 1643-1648 (1992)
[文献書誌] G.Kawai: "Conformationnal rigitity of specific pyrimidine residues in tRNA arises form posttranscriptional modifications that enhance steric interaction between the base and 2'OH" Biochemistry. 31. 1040-1046 (1992)
[文献書誌] T.Kimachi: "New synthesis of 5-amno-5-deazaflavin derivatives by direct coupling of 5-deazalfavins and amines" J.Heterocyclic.Chem.29. 763 (1992)
[文献書誌] T.Sasaki: "Depvelopment of antitumor liposoluble platinum complex in lipiodol for intrahepatic arterial admistration" Oncologia. 26. 127 (1993)

1992 年度 実績報告書

特異な構造をもつヌクレオシドの化学合成と反応

研究代表者

金子 主税 東北大学, 薬学部, 教授 (40013833)

研究成果

[文献書誌] Nobuya Katagiri: "Synthesis and anti-HIV activity of 9-(c-4,t-5-dihydroxy-methylcyclopent-2-en-r-1-yl)-9H-adenine" J.Med.Chem.35. 1882-1886 (1992)

[文献書誌] Nobuya Katagiri: "Sysnthesis and biological evaluation of 9-(t-2,c-3-di-hydroxymethyl-r-1-cyclopropylmethyl)-9H-adenine(A lower methylene homolog of carbocyclic oxetanocim)and related compounds" Nucleosides & Nucleotides. 11. 707-718 (1992)

[文献書誌] Akemi Toyota: "The alkylation of 6-chloropurine by alcohols by Mitsunobu reaction" Chem.Pharm.Bull.40. 1039-1041 (1992)

[文献書誌] Nobuya Katagiri: "The difference in effects between high pressure and LiClO_4 for the Diels-Alder reaction of cyclopentadiene with methylenemalonates or O-acetylisonitrosomalonates" Chem.Pharm.Bull.40. 1737-1741 (1992)

[文献書誌] Nobuya Katagiri: "Resolution of 9-(c-4,t-5-bishydroxymethylcyclopent-2-en-r-1-yl)-9H-adenine(BCA)selective inhibition of human immunodeficiency virus by the (-) enantiomer" Biochem.Biophys.Res.Commun.184. 154-159 (1992)

[文献書誌] Nobuya Katagiri: "Synthesis of (1R,4S,5R)-(4,5-bishydroxymethylcyclopent-2-en-1-yl)-9H-adenine and selective inhivition of human immunodeficiency virus" Tetrahedron Lett.33. 3507-3510 (1992)

[文献書誌] M.Sekine: "Regioselective O-methylation of hydroxyl groups via 1,3-benzothiazol-2-yl ether intermediates" Natural Product Letters. 1. 25-28 (1992)

[文献書誌] M.Sekine: "Synthesis and properties of N,N-dibenzoylated deoxy-cytidine derivatives" Natural Product Letters. 1. 135-140 (1992)

[文献書誌] M.Sekine: "Synthesis of adenosine,guanosine and cytidine monomer building units bearing the ((2-(mehtylthio(phenyl)thio)-methyl(MPTM)group as the 2'-OH protecting group" Nucleosides & Nucleotides. 11. 679-691 (1991)

[文献書誌] M.Sekine: "Syntheses and properties of dansylated deoxycytidine 3',5'-bisphosphate derivatives useful for 3'-labeling of oligorilbonucleotides" Nucleosides & Nucleotides. 11. 1713-1730 (1992)

[文献書誌] A.Matsuda: "Synthesis and biological activity of 1-(2-deoxy-2-hydroxyimino-or methoxyiminotives useful for 3'-labeling of oligorilbonucleotides-β-D-erythropentofuranosyl)-thimine and-cytosine" Nucleosides & Nucleotides. 11. 237 (1992)

[文献書誌] M.Tanaka: "Antitumor activity of a novel nucleoside,2'-C-cyano-2'-deoxy-1-β-arbinofuranosylcytosine(CNDAC)against murrine and human tumors" Cancer Letters. 64. 67 (1992)

[文献書誌] Nobuya Katagiri: "A novel and efficient synthesis of 9-(c-4,t-5-bishydroxy-methylcyclopent-2-en-r-1-yl)-9H-adenine(BCA)having anti-HIV activity from norbornadiene" Heterocycles. 33. 1097-1100 (1992)

[文献書誌] Nobuya Katagiri: "High pressure mediated Diels Alder reaction using 2-iminomalonates as dienophiles:novel synthesis of carbo-cyclic nucleosides" Nucleic Acids Symp.Ser.27. 83-85 (1992)

[文献書誌] Nobuya Katagiri: "Remarkable accerelation for the deamination of BCA by adenosine deaminase under high pressure:enzymatic resolution of 9-(c-4,t-5-bishydroxymethylcyclopent-2-en-r-1-yl)-9H-adenine((+)-BCA)haveing anti-HIV activity." Chem.Parm.Bull.

[文献書誌] Akemi Toyota: "Mitsunobu reactions for the synthesis of carbocyclic analogues of nucleosides:examination for the regio-selectivity" Synthetic Commun.

[文献書誌] Akemi Toyota: "The alkylation of 2-amino-6-chloropurine with alcohols by Mitsunobu reaction for the synthesis of carbocyclic guanosine analogs" Heterocycles.

[文献書誌] Teruaki Mukaiyama: "Stereosective synthesis of 2-amino-2-deoxy-β-D-guluco-pyranosides and galactophyranosides by using a catalytic amount of Tin(II)trifluoromethanesulufonate" Chem.Lett.1755 (1992)

[文献書誌] K.Matsubara: "Stereosective synthesis of O-(2-azido-2-deoxy-α-D-gala-ctopyranosyl)-L-serine and L-threonine derivatives by using the catalytic amount of active acidic species" Chem.Lett.

[文献書誌] T.Mukaiyama: "Stereoselective glycosylation reaction starting form 1-O-trimethylsilyl sugars by using diphenyltin sulfide and a catalytic amount pfactive acidic species" Chem.Lett.1041 (1992)

[文献書誌] T.Mukaiyama: "Catalytic stereoselective synthesis of α-or β-ribofura-nosides by combined use of silver salts and lithium per-chlorate or diphenyltin sulfide" Chem.Lett.

[文献書誌] S.Kobayashi: "Synthesis of thiazole-based DNA-targeting molecules aiming at guanin specificity" Synlett.59 (1992)

[文献書誌] R.Iwase: "Molecular design of a eukaryotic messenger RNA and Its chemical synthesis" Nucleic Acids Res.20. 1643-1648 (1992)

[文献書誌] G.Kawai: "Conformationnal rigitity of specific pyrimidine residues in tRNA arises form posttranscriptional modifications that enhance steric interaction between the base and 2'OH" Biochemistry. 31. 1040-1046 (1992)

[文献書誌] T.Kimachi: "New synthesis of 5-amno-5-deazaflavin derivatives by direct coupling of 5-deazalfavins and amines" J.Heterocyclic.Chem.29. 763 (1992)

[文献書誌] T.Sasaki: "Depvelopment of antitumor liposoluble platinum complex in lipiodol for intrahepatic arterial admistration" Oncologia. 26. 127 (1993)

1992 年度実績報告書

金子主税東北大学, 薬学部, 教授 (40013833)