1992 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)	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)
Keywords	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
Research Abstract	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)

Research Products

(26 results)

All Other

All Publications (26 results)

[Publications] 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)
[Publications] 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)
[Publications] Akemi Toyota: "The alkylation of 6-chloropurine by alcohols by Mitsunobu reaction" Chem.Pharm.Bull.40. 1039-1041 (1992)
[Publications] 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)
[Publications] 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)
[Publications] 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)
[Publications] M.Sekine: "Regioselective O-methylation of hydroxyl groups via 1,3-benzothiazol-2-yl ether intermediates" Natural Product Letters. 1. 25-28 (1992)
[Publications] M.Sekine: "Synthesis and properties of N,N-dibenzoylated deoxy-cytidine derivatives" Natural Product Letters. 1. 135-140 (1992)
[Publications] 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)
[Publications] M.Sekine: "Syntheses and properties of dansylated deoxycytidine 3',5'-bisphosphate derivatives useful for 3'-labeling of oligorilbonucleotides" Nucleosides & Nucleotides. 11. 1713-1730 (1992)
[Publications] 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)
[Publications] 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)
[Publications] 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)
[Publications] 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)
[Publications] 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.
[Publications] Akemi Toyota: "Mitsunobu reactions for the synthesis of carbocyclic analogues of nucleosides:examination for the regio-selectivity" Synthetic Commun.
[Publications] Akemi Toyota: "The alkylation of 2-amino-6-chloropurine with alcohols by Mitsunobu reaction for the synthesis of carbocyclic guanosine analogs" Heterocycles.
[Publications] 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)
[Publications] 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.
[Publications] 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)
[Publications] 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.
[Publications] S.Kobayashi: "Synthesis of thiazole-based DNA-targeting molecules aiming at guanin specificity" Synlett.59 (1992)
[Publications] R.Iwase: "Molecular design of a eukaryotic messenger RNA and Its chemical synthesis" Nucleic Acids Res.20. 1643-1648 (1992)
[Publications] 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)
[Publications] T.Kimachi: "New synthesis of 5-amno-5-deazaflavin derivatives by direct coupling of 5-deazalfavins and amines" J.Heterocyclic.Chem.29. 763 (1992)
[Publications] T.Sasaki: "Depvelopment of antitumor liposoluble platinum complex in lipiodol for intrahepatic arterial admistration" Oncologia. 26. 127 (1993)

1992 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: "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)

[Publications] 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)

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

[Publications] 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)

[Publications] 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)

[Publications] 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)

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

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

[Publications] 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)

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

[Publications] 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)

[Publications] 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)

[Publications] 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)

[Publications] 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)

[Publications] 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.

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

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

[Publications] 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)

[Publications] 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.

[Publications] 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)

[Publications] 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.

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

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

[Publications] 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)

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

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

金子主税東北大学, 薬学部, 教授 (40013833)