JPWO2005021570A1 - N−o結合性架橋構造型新規人工核酸 - Google Patents
N−o結合性架橋構造型新規人工核酸 Download PDFInfo
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- JPWO2005021570A1 JPWO2005021570A1 JP2005513440A JP2005513440A JPWO2005021570A1 JP WO2005021570 A1 JPWO2005021570 A1 JP WO2005021570A1 JP 2005513440 A JP2005513440 A JP 2005513440A JP 2005513440 A JP2005513440 A JP 2005513440A JP WO2005021570 A1 JPWO2005021570 A1 JP WO2005021570A1
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- amino
- nucleic acid
- oxo
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- 108020004707 nucleic acids Proteins 0.000 title claims description 22
- 102000039446 nucleic acids Human genes 0.000 title claims description 22
- 150000007523 nucleic acids Chemical class 0.000 title claims description 22
- 108091034117 Oligonucleotide Proteins 0.000 claims abstract description 106
- 125000006239 protecting group Chemical group 0.000 claims abstract description 86
- 150000003839 salts Chemical class 0.000 claims abstract description 51
- 150000001875 compounds Chemical class 0.000 claims abstract description 38
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 25
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 24
- 239000002777 nucleoside Substances 0.000 claims abstract description 22
- 150000003833 nucleoside derivatives Chemical class 0.000 claims abstract description 21
- 125000003396 thiol group Chemical group [H]S* 0.000 claims abstract description 13
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 claims abstract description 10
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims abstract description 6
- -1 p-toluenesulfonyl group Chemical group 0.000 claims description 502
- 125000003118 aryl group Chemical group 0.000 claims description 86
- 238000001668 nucleic acid synthesis Methods 0.000 claims description 76
- 125000003277 amino group Chemical group 0.000 claims description 65
- 125000000217 alkyl group Chemical group 0.000 claims description 53
- 125000004432 carbon atom Chemical group C* 0.000 claims description 51
- 125000002252 acyl group Chemical group 0.000 claims description 39
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 31
- 125000003545 alkoxy group Chemical group 0.000 claims description 27
- 125000001931 aliphatic group Chemical group 0.000 claims description 26
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 19
- 125000005843 halogen group Chemical group 0.000 claims description 19
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 18
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 claims description 17
- 125000003342 alkenyl group Chemical group 0.000 claims description 17
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 claims description 17
- 125000001424 substituent group Chemical group 0.000 claims description 16
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 15
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 14
- 229910052736 halogen Inorganic materials 0.000 claims description 13
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 13
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 12
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 12
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 11
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 11
- RYYIULNRIVUMTQ-UHFFFAOYSA-N 6-chloroguanine Chemical group NC1=NC(Cl)=C2N=CNC2=N1 RYYIULNRIVUMTQ-UHFFFAOYSA-N 0.000 claims description 10
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 claims description 10
- 150000002367 halogens Chemical class 0.000 claims description 10
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 8
- 125000004414 alkyl thio group Chemical group 0.000 claims description 7
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- 125000005499 phosphonyl group Chemical group 0.000 claims description 6
- 125000004545 purin-9-yl group Chemical group N1=CN=C2N(C=NC2=C1)* 0.000 claims description 6
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 6
- 108010076504 Protein Sorting Signals Proteins 0.000 claims description 5
- 125000005426 adeninyl group Chemical group N1=C(N=C2N=CNC2=C1N)* 0.000 claims description 5
- 238000003776 cleavage reaction Methods 0.000 claims description 5
- 230000003834 intracellular effect Effects 0.000 claims description 5
- 230000007017 scission Effects 0.000 claims description 5
- MSSXOMSJDRHRMC-UHFFFAOYSA-N 9H-purine-2,6-diamine Chemical group NC1=NC(N)=C2NC=NC2=N1 MSSXOMSJDRHRMC-UHFFFAOYSA-N 0.000 claims description 4
- 238000002372 labelling Methods 0.000 claims description 4
- 229940127073 nucleoside analogue Drugs 0.000 claims description 4
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
- BBAMTDMNXVSCRU-UHFFFAOYSA-N (4-chlorophenyl) dihydrogen phosphate Chemical group OP(O)(=O)OC1=CC=C(Cl)C=C1 BBAMTDMNXVSCRU-UHFFFAOYSA-N 0.000 claims description 3
- 125000005159 cyanoalkoxy group Chemical group 0.000 claims description 3
- 125000000524 functional group Chemical group 0.000 claims description 3
- 230000005937 nuclear translocation Effects 0.000 claims description 3
- SXADIBFZNXBEGI-UHFFFAOYSA-N phosphoramidous acid Chemical group NP(O)O SXADIBFZNXBEGI-UHFFFAOYSA-N 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 36
- 108020004414 DNA Proteins 0.000 abstract description 31
- 230000000692 anti-sense effect Effects 0.000 abstract description 16
- 102000053602 DNA Human genes 0.000 abstract description 6
- 108090000790 Enzymes Proteins 0.000 abstract description 4
- 102000004190 Enzymes Human genes 0.000 abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 105
- 239000000243 solution Substances 0.000 description 45
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 38
- 230000015572 biosynthetic process Effects 0.000 description 35
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 34
- 238000003786 synthesis reaction Methods 0.000 description 33
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 30
- 239000012043 crude product Substances 0.000 description 30
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 29
- 239000000203 mixture Substances 0.000 description 27
- 239000002904 solvent Substances 0.000 description 27
- 230000002829 reductive effect Effects 0.000 description 25
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 24
- 229910052757 nitrogen Chemical group 0.000 description 24
- 238000006243 chemical reaction Methods 0.000 description 23
- 239000012044 organic layer Substances 0.000 description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 22
- 125000005129 aryl carbonyl group Chemical group 0.000 description 21
- 239000007787 solid Substances 0.000 description 21
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 20
- 229920006395 saturated elastomer Polymers 0.000 description 20
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- 235000017557 sodium bicarbonate Nutrition 0.000 description 19
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 19
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
- 238000001816 cooling Methods 0.000 description 17
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 16
- 239000002585 base Substances 0.000 description 16
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
- 108090000623 proteins and genes Proteins 0.000 description 14
- 239000000463 material Substances 0.000 description 13
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 11
- 239000011541 reaction mixture Substances 0.000 description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- 238000005259 measurement Methods 0.000 description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 10
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 9
- 0 C*1OC(C)(N(C)*)OC2[C@@](C)(COC)O[C@](*)C12 Chemical compound C*1OC(C)(N(C)*)OC2[C@@](C)(COC)O[C@](*)C12 0.000 description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 8
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- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- KDCGOANMDULRCW-UHFFFAOYSA-N Purine Natural products N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 230000009368 gene silencing by RNA Effects 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 6
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- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 6
- 125000004219 purine nucleobase group Chemical group 0.000 description 6
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- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 6
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 description 6
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 5
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 5
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Classifications
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
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Abstract
Description
(1)相補なRNA鎖に対する二重鎖形成能が非常に高い。
(2)また、2’,4’−BNANC修飾DNAオリゴヌクレオチドは二本鎖DNA鎖に対する三重鎖形成能にも卓越している。
(3)ヌクレアーゼ耐性が抜群である。
(4)本発明の人工核酸2’,4’−BNANC分子中に含まれるN−O結合は還元試薬により緩和な条件下で選択的に開裂することができ、NH基とOH基が遊離する。このNH基やOH基を足掛かりに別機能性分子を結合させることで、オリゴヌクレオチド類縁体調製の前後を問わず、様々な複合体(コンジュゲート体)を得ることが容易である。別機能性分子としては、蛍光分子や化学発光分子や放射性同位原子を含む分子種などの標識用分子、様々なDNA(RNA)切断活性分子、細胞内や核内移行シグナルペプチド類等々、が可能である。
本発明のオリゴヌクレオチド類縁体は、下記一般式(II)で表されるヌクレオシド類縁体の単位構造のいずれか1種以上を1または2個以上含有するDNAオリゴヌクレオチド又はRNAオリゴヌクレオチド類縁体またはその薬理学上許容される塩である。但し、これら構造の1種以上を2個以上含有する場合は、当該構造間でBaseは同一または異なっていても良い。また、オリゴヌクレオチド類縁体中の各ヌクレオシド間の結合は、天然核酸と同じリン酸ジエステル結合[−OP(O2 −)O−]以外にホスホロチオアート結合[−OP(O)(S−)O−]を1又は2個以上含有していても良い。
一般式(I)及び(II)中、Baseの芳香族複素環基とは、炭化水素環の構成原子である炭素原子を、1個以上の窒素原子、硫黄原子もしくは酸素原子などのヘテロ原子に置き換えた構造を有し、芳香族性を示す5〜20員環のあらゆる基をいい、単環、縮合環を含む。具体的には、例えば、ピリミジンもしくはプリン核酸塩基、以下のα群から選択される置換基を1つ以上有していてもよいピリミジンもしくはプリン核酸塩基が挙げられる。ここで、ピリミジンもしくはプリン核酸塩基には、核酸の構成成分として一般に知られる塩基(例えば、グアニン、アデニン、シトシン、チミン、ウラシル)、及びその他これらに類する核酸成分の塩基として作用もしくは代用し得るあらゆる化学構造が含まれる。その他、チオフェン、チアントレン、フラン、ピラン、イソベンゾフラン、クロメン、キサンテン、フェノキサチイン、ピロール、イミダゾール、ピラゾール、イソチアゾール、イソキサゾール、ピリダジン、インドリジン、インドール、イソインドール、イソキノリン、キノリン、ナフチリジン、キノキサリン、キナゾリン、プテリジン、カルバゾール、フェナントリジン、アクリジン、ペリミジン、フェナジン、フェナルサジン、フェノチアジン、フラザン、フェノキサジン、ピロリジン、ピロリン、イミダゾリジン、イミダゾリン、ピラゾリジンなども含まれる。好適には、ピリミジンもしくはプリン核酸塩基、以下のα群から選択される置換基を1つ以上有していてもよいピリミジンもしくはプリン核酸塩基であり、具体的には、プリン−9−イル基、2−オキソ−ピリミジン−1−イル基、または下記α群から選択される置換基を有するプリン−9−イル基もしくは2−オキソ−ピリミジン−1−イル基が好適である。
(1)R1が、水素原子、脂肪族アシル基、芳香族アシル基、脂肪族あるいは芳香族スルホニル基、1〜3個のアリール基で置換されたメチル基、低級アルキル、低級アルコキシ、ハロゲンもしくはシアノ基でアリール環が置換された1〜3個のアリール基で置換されたメチル基、またはシリル基である化合物及びその塩、
(2)R1が、水素原子、アセチル基、ベンゾイル基、メタンスルホニル基、p−トルエンスルホニル基、ベンジル基、p−メトキシベンジル基、トリチル基、ジメトキシトリチル基、モノメトキシトリチル基又はtert−ブチルジフェニルシリル基である化合物及びその塩、
(3)R2が、水素原子、脂肪族アシル基、芳香族アシル基、脂肪族あるいは芳香族スルホニル基、1〜3個のアリール基で置換されたメチル基、低級アルキル、低級アルコキシ、ハロゲンもしくはシアノ基でアリール環が置換された1〜3個のアリール基で置換されたメチル基、シリル基、ホスホロアミダイト基、ホスホニル基、リン酸基または核酸合成の保護基で保護されたリン酸基である化合物及びその塩、
(4)R2が、水素原子、アセチル基、ベンゾイル基、メタンスルホニル基、p−トルエンスルホニル基、ベンジル基、p−メトキシベンジル基、tert−ブチルジフェニルシリル基、−P(OC2H4CN)(N(i−Pr)2)、−P(OCH3)(N(i−Pr)2)、ホスホニル基、又は、2−クロロフェニルもしくは4−クロロフェニルリン酸基である化合物およびその塩、
(5)R3が、水素原子、炭素数1〜5のアルキル基、炭素数1〜5のアルケニル基、炭素数6〜14のアリール基、1〜3個のアリール基で置換されたメチル基、メタンスルホニル基やp−トルエンスルホニル基などの低級脂肪族あるいは芳香族スルホニル基又はアセチル基などの炭素数1〜5の脂肪族アシル基やフェノキシアセチル基およびベンゾイル基などの芳香族アシル基である化合物およびその塩、また、R3の機能性分子ユニット置換基が、蛍光あるいは化学発光標識分子、核酸切断活性官能基、又は細胞内若しくは核内移行シグナルペプチドである請求項1〜6のいずれか1項に記載の化合物及びその塩、
(6)Baseが、6−アミノプリン−9−イル(即ち、アデニニル)、アミノ基が核酸合成の保護基で保護された6−アミノプリン−9−イル、2,6−ジアミノプリン−9−イル、2−アミノ−6−クロロプリン−9−イル、アミノ基が核酸合成の保護基で保護された2−アミノ−6−クロロプリン−9−イル、2−アミノ−6−フルオロプリン−9−イル、アミノ基が核酸合成の保護基で保護された2−アミノ−6−フルオロプリン−9−イル、2−アミノ−6−ブロモプリン−9−イル、アミノ基が核酸合成の保護基で保護された2−アミノ−6−ブロモプリン−9−イル、2−アミノ−6−ヒドロキシプリン−9−イル(即ち、グアニニル)、アミノ基が核酸合成の保護基で保護された2−アミノ−6−ヒドロキシプリン−9−イル、6−アミノ−2−メトキシプリン−9−イル、6−アミノ−2−クロロプリン−9−イル、6−アミノ−2−フルオロプリン−9−イル、2,6−ジメトキシプリン−9−イル、2,6−ジクロロプリン−9−イル、6−メルカプトプリン−9−イル、2−オキソ−4−アミノ−1,2−ジヒドロピリミジン−1−イル(即ち、シトシニル)、アミノ基が核酸合成の保護基で保護された2−オキソ−4−アミノ−1,2−ジヒドロピリミジン−1−イル、2−オキソ−4−アミノ−5−フルオロ−1,2−ジヒドロピリミジン−1−イル、アミノ基が核酸合成の保護基で保護された2−オキソ−4−アミノ−5−フルオロ−1,2−ジヒドロピリミジン−1−イル、4−アミノ−2−オキソ−5−クロロ−1,2−ジヒドロピリミジン−1−イル、2−オキソ−4−メトキシ−1,2−ジヒドロピリミジン−1−イル、2−オキソ−4−メルカプト−1,2−ジヒドロピリミジン−1−イル、2−オキソ−4−ヒドロキシ−1,2−ジヒドロピリミジン−1−イル(即ち、ウラシニル)、2−オキソ−4−ヒドロキシ−5−メチル−1,2−ジヒドロピリミジン−1−イル(即ち、チミニル)、4−アミノ−5−メチル−2−オキソ−1,2−ジヒドロピリミジン−1−イル(即ち、5−メチルシトシニル)基、または、アミノ基が核酸合成の保護基で保護された4−アミノ−5−メチル−2−オキソ−1,2−ジヒドロピリミジン−1−イルである化合物及びその塩、
(7)Baseが、ベンゾイルアミノプリン−9−イル、アデニル、2−イソブチリルアミノ−6−ヒドロキシプリン−9−イル、グアニニル、2−オキソ−4−ベンゾイルアミノ−1,2−ジヒドロピリミジン−1−イル、シトシニル、2−オキソ−5−メチル−4−ベンゾイルアミノ−1,2−ジヒドロピリミジン−1−イル、5−メチルシトシニル、ウラシニル又はチミニル基である化合物及びその塩を挙げることができる。
(8)R3が、水素原子、炭素数1〜5のアルキル基、ベンジル基などのアラルキル基、アセチル基やベンゾイル基などの低級脂肪族あるいは芳香族アシル基、メタンスルホニル基やp−トルエンスルホニル基などの脂肪族あるいは芳香族スルホニル基であるオリゴヌクレオチド類縁体及びその薬理学上許容される塩、
(9)Baseが、6−アミノプリン−9−イル(即ち、アデニニル)、アミノ基が核酸合成の保護基で保護された6−アミノプリン−9−イル、2,6−ジアミノプリン−9−イル、2−アミノ−6−クロロプリン−9−イル、アミノ基が核酸合成の保護基で保護された2−アミノ−6−クロロプリン−9−イル、2−アミノ−6−フルオロプリン−9−イル、アミノ基が核酸合成の保護基で保護された2−アミノ−6−フルオロプリン−9−イル、2−アミノ−6−ブロモプリン−9−イル、アミノ基が核酸合成の保護基で保護された2−アミノ−6−ブロモプリン−9−イル、2−アミノ−6−ヒドロキシプリン−9−イル(即ち、グアニニル)、アミノ基が核酸合成の保護基で保護された2−アミノ−6−ヒドロキシプリン−9−イル、6−アミノ−2−メトキシプリン−9−イル、6−アミノ−2−クロロプリン−9−イル、6−アミノ−2−フルオロプリン−9−イル、2,6−ジメトキシプリン−9−イル、2,6−ジクロロプリン−9−イル、6−メルカプトプリン−9−イル、2−オキソ−4−アミノ−1,2−ジヒドロピリミジン−1−イル(即ち、シトシニル)、アミノ基が核酸合成の保護基で保護された2−オキソ−4−アミノ−1,2−ジヒドロピリミジン−1−イル、2−オキソ−4−アミノ−5−フルオロ−1,2−ジヒドロピリミジン−1−イル、アミノ基が核酸合成の保護基で保護された2−オキソ−4−アミノ−5−フルオロ−1,2−ジヒドロピリミジン−1−イル、4−アミノ−2−オキソ−5−クロロ−1,2−ジヒドロピリミジン−1−イル、2−オキソ−4−メトキシ−1,2−ジヒドロピリミジン−1−イル、2−オキソ−4−メルカプト−1,2−ジヒドロピリミジン−1−イル、2−オキソ−4−ヒドロキシ−1,2−ジヒドロピリミジン−1−イル(即ち、ウラシニル)、2−オキソ−4−ヒドロキシ−5−メチル−1,2−ジヒドロピリミジン−1−イル(即ち、チミニル)、4−アミノ−5−メチル−2−オキソ−1,2−ジヒドロピリミジン−1−イル(即ち、5−メチルシトシニル)基、または、アミノ基が核酸合成の保護基で保護された4−アミノ−5−メチル−2−オキソ−1,2−ジヒドロピリミジン−1−イルであるオリゴヌクレオチド類縁体及びその薬理学上許容される塩、
(10)Baseが、ベンゾイルアミノプリン−9−イル、アデニル、2−イソブチリルアミノ−6−ヒドロキシプリン−9−イル、グアニニル、2−オキソ−4−ベンゾイルアミノ−1,2−ジヒドロピリミジン−1−イル、シトシニル、2−オキソ−5−メチル−4−ベンゾイルアミノ−1,2−ジヒドロピリミジン−1−イル、5−メチルシトシニル、ウラシニル又はチミニル基であるオリゴヌクレオチド類縁体及びその薬理学上許容される塩を挙げることができる。
(1)ヌクレオシド類縁体の合成
一般式(I)で表される化合物は、実施例に記載の方法および本分野の従来技術に基づいて合成できる。反応条件、保護基導入試薬、反応試薬は、具体的には実施例に記載の方法を参考にすることができるが、これに限定されず、本分野の技術常識に基づき使用可能な反応条件、試薬を適宜採用することができる。例えば、特開2000−297097号公報、特開平10−304889号公報に記載の方法を参考にすることができる。また、一般式(I)または(II)におけるBaseとして種々の天然、非天然の核酸塩基およびその他の芳香族複素環や芳香族炭化水素環を有する場合についても、特開平10−304889号公報に記載の方法を参考にして、本発明化合物の原料を合成することができる。
(2)オリゴヌクレオチド類縁体の合成
本発明のヌクレオシド類縁体を含むオリゴヌクレオチド類縁体は、公知のDNAシンセサイザーを用いて種々合成することができる。次いで、得られるオリゴヌクレオチド類縁体を逆相カラムを用いて精製し、生成物の純度を逆相HPLCやMALDI−TOF−MSで分析することにより、精製オリゴヌクレオチド類縁体の生成を確認できる。
本発明のヌクレオシド類縁体は、オリゴヌクレオチド類縁体の中に1個以上存在させることができる。また、オリゴヌクレオチド類縁体の2カ所以上の位置に、1又は2以上の天然ヌクレオチドを介して隔離された状態で存在させてもよい。本発明によれば、本発明のヌクレオシド類縁体を必要な位置に必要な数(長さ)で導入したオリゴヌクレオチド類縁体を合成することができる。オリゴヌクレオチド類縁体全体の長さとしてヌクレオチド単位が2〜50、好ましくは8〜30個である。
[実施例1]ヌクレオシド類縁体(2’,4’−BNANCアミダイト体)の合成
(1)化合物2の合成
前記の合成スキームに示す化合物1(49mg,0.073mmol)のテトラヒドロフラン溶液(3.5ml)に氷冷下、40%メチルアミン水溶液(0.11ml,1.50mmol)を加え、室温で3時間撹拌した。反応溶液の溶媒を留去した後、酢酸エチルで抽出し、有機層を水、飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥し、溶媒留去後、シリカゲルカラムクロマトグラフィー(n−ヘキサン:酢酸エチル=1:1)により精製し、化合物2(45mg,99%)を白色固体として得た。
窒素気流下、化合物2(146mg,0.23mmol)のピリジン溶液(1.5ml)に氷冷下、塩化メチルスルホニル(45(1,0.59mmol)を加え、室温で1時間撹拌した。反応溶液に水を加え、酢酸エチルで抽出し、有機層を飽和重曹水、飽和食塩水で洗浄後、無水硫酸ナトリウムにて乾燥した。溶媒を減圧留去し、得られた粗成績体3(170mg)は精製せず、次の反応に用いた。
前反応で得られた粗成績体3(170mg)の水−エタノール溶液(1:2,6ml)に、室温で1M水酸化ナトリウム水溶液(0.70ml,0.70mmol)を加え、1時間撹拌した。10%塩酸水溶液で中和後、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、得られた粗成績体をシリカゲルカラムクロマトグラフィー(クロロホルム:メタノール=15:1)により精製し、化合物4(139mg,95% from 2 in 2 steps)を白色固体として得た。
窒素気流下、化合物4(0.80g,1.28mmol)のエタノール溶液(10ml)に、20%水酸化パラジウム−炭素粉末(0.60g)、シクロヘキセン(5.2ml,51mmol)を加え、5時間加熱還流した。さらに水酸化パラジウム−炭素粉末(0.20g)を加え、17時間加熱還流した。反応溶液を濾過した後、溶媒を減圧留去した。得られた粗成績体5(0.46g)は、精製せず次の反応に用いた。
窒素気流下、化合物5(0.46g)のN,N−ジメチルホルムアミド溶液(10ml)に、1,3−ジクロロ−1,1,3,3−テトライソプロピルジシロキサン(0.45ml,1.41mmol)、イミダゾール(0.38g,5.63mmol)を加え、室温にて5時間撹拌した。反応液をエーテルで抽出し、有機層を水、飽和食塩水で洗浄した後、硫酸マグネシウムで乾燥した。溶媒を減圧留去し、得られた粗成績体をシリカゲルカラムクロマトグラフィー(n−ヘキサン:酢酸エチル=2:1→1:1)により精製し、化合物6(0.60g,68% from 4 in 2 steps)を白色固体として得た。
窒素気流下、化合物6(200mg,0.29mmol)のピリジン溶液(3ml)に氷冷下、無水トリフルオロメタンスルホン酸(0.15ml,0.88mmol)、4−(ジメチルアミノ)ピリジン(7mg,0.06mmol)を加え、室温で7.5時間撹拌した。反応溶液に水を加え、ジクロロメタンで抽出した。有機層を飽和重曹水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、得られた粗成績体7(0.29g)を精製せず、次の反応に用いた。
窒素気流下、前反応で得られた粗成績体7(0.29g)のアセトニトリル溶液(3ml)に、室温でN−ヒドロキシフタルイミド(67mg,0.41mmol)、1,8−ジアザビシクロ[5.4.0]−7−ウンデセン(61(1,0.41mmol)を加え、室温で12時間撹拌した。反応溶液をジクロロメタンで抽出し、有機層を水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、得られた粗成績体をシリカゲルカラムクロマトグラフィー(クロロホルム)により精製し、化合物8(0.15g,61% from 6 in 2 steps)を黄色固体として得た。
化合物8(1.16g,1.40mmol)のエタノール溶液(35ml)に、ヒドラジン−水和物(0.12ml,2.38mmol)を加え、室温で10分間撹拌した。反応溶液の溶媒を留去した後、濾過し、濾液を酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去し、得られた粗成績体9(0.93g)は精製せず、次の反応に用いた。
窒素気流下、前反応で得られた粗成績体9(0.93g)の塩化メチレン溶液(15ml)に氷冷下、飽和重曹水(4.0ml,4.2mmol)、クロロギ酸ベンジル(0.30ml,2.1mmol)を加え、1時間撹拌した。反応溶液に飽和重曹水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した。溶媒を減圧留去し、得られた粗成績体をシリカゲルカラムクロマトグラフィー(n−ヘキサン:酢酸エチル=4:1)により精製し、化合物10(0.92g,94% from 8 in 2 steps)を白色固体として得た。
窒素気流下、水素化ナトリウム(60% in oil,0.55g,13.7mmol)のテトラヒドロフラン懸濁液(25ml)に氷冷下、化合物10(3.81g,4.57mmol)のテトラヒドロフラン溶液(15ml)を滴下し、1時間撹拌した後、室温で5時間撹拌した。飽和シュウ酸水溶液で中和後、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、得られた粗成績体をシリカゲルカラムクロマトグラフィー(クロロホルム→クロロホルム:メタノール=100:1)により精製し、化合物11(2.87g,95%)を白色固体として得た。
窒素気流下、前反応で得られた粗成績体11(0.35mg,0.53mmol)の塩化メチレン溶液(10ml)に氷冷下、1M三塩化ホウ素ヘキサン溶液(5.29ml,5.29mmol)を加え、1時間撹拌した。反応溶液に飽和重曹水を加え、酢酸エチルで抽出し、有機層を水、飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、得られた粗成績体をシリカゲルカラムクロマトグラフィー(クロロホルム:メタノール=50:1)により精製し、化合物12(0.27g,96%)を白色固体として得た。
化合物12(0.19g,0.36mmol)の1M p−トルエンスルホン酸ピリジニウム−メタノール溶液(3.6ml)に、室温にて20%ホルムアルデヒド水溶液(0.06ml,0.40mmol)を加え、10分間撹拌した。さらに、氷冷下シアン化水素化ホウ素ナトリウム(45mg,0.72mmol)を加え、1時間撹拌した。反応溶液を酢酸エチルで抽出し、水、飽和重曹水、飽和食塩水で洗浄し、有機層を無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、得られた粗成績体をシリカゲルカラムクロマトグラフィー(n−ヘキサン:酢酸エチル=2:1)にて精製し、化合物13(0.19g,100%)を白色固体として得た。
化合物13(46mg,0.085mmol)のテトラヒドロフラン溶液(2ml)にフッ化テトラ−n−ブチルアンモニウム(1M inテトラヒドロフラン,0.17ml,0.17mmol)を加え、室温で5分間撹拌した。溶媒を減圧留去し、得られた粗成績体をシリカゲルカラムクロマトグラフィー(酢酸エチル:メタノール=15:1)により精製し、化合物14(25mg,100%)を白色固体として得た。
化合物14(0.16g,0.54mmol)のピリジン溶液(10ml)に塩化4,4’−ジメトキシトリチル(0.22g,0.64mmol)を加え、室温で12時間撹拌した。反応液に飽和重曹水を加え、酢酸エチルで抽出し、有機層を水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、得られた粗成績体をシリカゲルカラムクロマトグラフィー(1%トリエチルアミン含有n−ヘキサン:酢酸エチル=1:2→酢酸エチル:メタノール=30:1)にて精製し、化合物15(0.30g,93%)を白色固体として得た。
化合物15(0.17g,0.28mmol)及び4,5−ジシアノイミダゾール(40mg,0.34mmol)のアセトニトリル溶液(6ml)に、2−シアノエチル−N,N,N’,N’−テトライソプロピルホスホロアミダイト(0.13ml,0.42mmol)を加え、室温で4時間撹拌した。反応液に飽和重曹水を加え、酢酸エチルで抽出した。有機層を飽和重曹水、水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた粗成績体をシリカゲルカラムクロマトグラフィー(1%トリエチルアミン含有n−ヘキサン:酢酸エチル=1:1)、ついで再沈澱(酢酸エチル−ヘキサン)により精製し、化合物16(0.20g,88%)を白色固体として得た。
窒素気流下、1,2,4,−トリアゾール(278mg,4.03mmol)のアセトニトリル懸濁液(9ml)に、氷冷下、塩化ホスホリル(86ml,0.92mmol)を加え10分間激しく撹拌し、さらにトリエチルアミン(0.64ml,4.62mmol)を加え35分間撹拌した。氷冷下、化合物16(95mg,0.12mmol)のアセトニトリル溶液(3ml)を加え、5.5時間撹拌した後、室温でさらに2.5時間撹拌した。反応液に飽和重曹水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた粗成績体をシリカゲルカラムクロマトグラフィー(n−ヘキサン:酢酸エチル=1:2)、ついで再沈澱(酢酸エチル−ヘキサン)により精製し、化合物17(83mg,83%)を白色固体として得た。
化合物12(100mg,0.19mmol)およびトリエチルアミン(32ml,0.12mmol)の塩化メチレン溶液(3ml)に、氷冷下、塩化フェノキシアセチル(29ml,0.21mmol)を加え30分間撹拌した。反応液に飽和重曹水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた粗成績体をシリカゲルカラムクロマトグラフィー(n−ヘキサン:酢酸エチル=2:1)により精製し、化合物18(115mg,92%)を白色固体として得た。
窒素気流下、室温で化合物18(0.34g,0.51mmol)のテトラヒドロフラン溶液(10ml)にフッ化テトラn−ブチルアンモニウム(1Mテトラヒドロフラン溶液,1.0ml,1.0mmol)を加え、5分間撹拌した。溶媒を減圧留去し、得られた粗成績体をシリカゲルカラムクロマトグラフィー(酢酸エチル:メタノール=15:1)により精製し、化合物19(0.20g,95%)を白色固体として得た。
窒素気流下、室温で化合物19(0.17g,0.41mmol)のピリジン溶液(8ml)に塩化4,4’−ジメトキシトリチル(0.25g,0.73mmol)を加え、7時間撹拌した。反応液に飽和重曹水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた粗成績体をシリカゲルカラムクロマトグラフィー(1%トリエチルアミン含有n−ヘキサン:酢酸エチル=1:1→酢酸エチル:メタノール=50:1)により精製し、化合物20(0.25g,86%)を白色固体として得た。
化合物20(0.25g,0.35mmol)及び4,5−ジシアノイミダゾール(41mg,0.35mmol)のアセトニトリル溶液(7ml)に、2−シアノエチル−N,N,N’,N’−テトライソプロピルホスホロアミダイト(0.13ml,0.42mmol)を加え、室温で3時間撹拌した。反応液に飽和重曹水を加え、酢酸エチルで抽出した。有機層を飽和重曹水、水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた粗成績体をシリカゲルカラムクロマトグラフィー(1%トリエチルアミン含有n−ヘキサン:酢酸エチル=1:1)、ついで再沈澱(酢酸エチル−ヘキサン)により精製し、化合物21(0.27g,85%)を白色固体として得た。
窒素気流下、1,2,4,−トリアゾール(229mg,3.32mmol)のアセトニトリル懸濁液(10ml)に、氷冷下、塩化ホスホリル(71ml,0.76mmol)を加え10分間激しく撹拌し、さらにトリエチルアミン(0.53ml,3.81mmol)を加え35分間撹拌した。氷冷下、化合物21(90mg,0.10mmol)のアセトニトリル溶液(2ml)を加え、5時間撹拌した。反応液に飽和重曹水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた粗成績体を再沈澱(酢酸エチル−ヘキサン)により精製し、化合物22(90mg,95%)を白色固体として得た。
窒素気流下、1,2,4,−トリアゾール(1.41g,20.4mmol)のアセトニトリル懸濁液(61ml)に、氷冷下、塩化ホスホリル(0.44ml,4.67mmol)を加え10分間激しく撹拌し、さらにトリエチルアミン(3.27ml,23.4mmol)を加え35分間撹拌した。氷冷下、化合物11(409mg,0.62mmol)のアセトニトリル溶液(3ml)を加え、2時間撹拌した後、室温でさらに3時間撹拌した。反応液に飽和重曹水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた粗成績体23(497mg)は精製せず、次の反応に用いた。
化合物23(497mg)の1,4−ジオキサン溶液(10.6ml)に、室温で28%アンモニア水溶液(1.76ml)を加え、2時間撹拌した。溶媒を減圧流去し、得られた粗成績体をシリカゲルカラムクロマトグラフィー(クロロホルム:メタノール=30:1)により精製し、化合物24(343mg,84% from 11 in 2 steps)を白色固体として得た。
化合物24(175mg,0.26mmol)の塩化メチレン溶液(2.6ml)に、氷冷下、飽和重曹水(0.8ml,0.79mmol)と塩化ベンゾイル(92ml,0.79mmol)を加え、2時間撹拌した後、室温でさらに1.5時間撹拌した。反応液に飽和重曹水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた粗成績体をシリカゲルカラムクロマトグラフィー(クロロホルム)により精製し、化合物25(161mg,80%)を白色固体として得た。
窒素気流下、化合物25(115mg,0.15mmol)の塩化メチレン溶液(7.5ml)に、−78℃冷却下、1M三塩化ホウ素ヘキサン溶液(1.35ml,1.35mmol)を加え、1.5時間撹拌し、氷冷下でさらに2.5時間撹拌した。反応液に飽和重曹水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた粗成績体26(90mg)は精製せず、次の反応に用いた。
窒素気流下、化合物26(90mg)とトリエチルアミン(25ml,0.18mmol)の塩化メチレン溶液(1.5ml)に、氷冷下、塩化フェノキシアセチル(23ml,0.17mmol)を加え45分間撹拌した。反応液に飽和重曹水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた粗成績体をシリカゲルカラムクロマトグラフィー(n−ヘキサン:酢酸エチル=2:1)により精製し、化合物27(49mg,42% from 23 in 2 steps)を白色固体として得た。
窒素気流下、室温で化合物27(45mg,0.06mmol)のテトラヒドロフラン溶液(1.2ml)に、フッ化テトラn−ブチルアンモニウム(1Mテトラヒドロフラン溶液,0.12ml,0.12mmol)を加え、10分間撹拌した。溶媒を減圧留去し、得られた粗成績体をシリカゲルカラムクロマトグラフィー(n−ヘキサン:酢酸エチル=1:1)により精製し、化合物28(31mg,100%)を白色固体として得た。
(1)2’,4’−BNANC修飾オリゴヌクレオチドの合成
2’,4’−BNANCモノマーユニットを含有するオリゴヌクレオチド類縁体(1)〜(22)は、標準的なホスホロアミダイトプロトコールに従って、核酸自動合成機ExpediteTM 8909(ABI社製)により0.2mmolスケールで合成した。アミダイトと5’−末端の水酸基とのカップリング時間は、天然のヌクレオシドアミダイトでは94秒、2’,4’−BNANCアミダイト(16、17および21)では300秒に設定した。
実施例で合成したオリゴヌクレオチド類縁体(1)〜(5)および(13)〜(17)(アンチセンス鎖)と天然DNAあるいはRNAオリゴヌクレオチドのセンス鎖とをアニーリング処理したものの融解温度(Tm)を測定することにより、アンチセンス鎖の二重鎖形成能を調べた。
[実験例2]2’,4’−BNANC修飾オリゴヌクレオチドのTm測定(三重鎖形成能評価)
実施例で合成したオリゴヌクレオチド類縁体(6)〜(11)および(18)〜(21)について、実験例1と同様の方法により、下記の標的2本鎖DNAとの三重鎖形成能を調べた。測定の際の塩濃度やpHについては各表の下に記載してある条件を用いた。
実験例3:酵素耐性の測定
天然型(DNAオリゴヌクレオチド)及び非天然型の下記のオリゴヌクレオチドについて、オリゴヌクレオチドを3’側から分解するエキソヌクレアーゼに対する耐性を調べた。
HPLCによる各オリゴヌクレオチド類の残存率の経時変化を表6及び図1に示した。
Claims (20)
- 下記一般式(I)で表される化合物及びその塩。
R1、R2は、同一又は異なって、水素原子、核酸合成の水酸基の保護基、アルキル基、アルケニル基、シクロアルキル基、アリール基、アラルキル基、アシル基、スルホニル基、シリル基、リン酸基、核酸合成の保護基で保護されたリン酸基、または、−P(R4)R5[式中、R4及びR5は、同一または異なって、水酸基、核酸合成の保護基で保護された水酸基、メルカプト基、核酸合成の保護基で保護されたメルカプト基、アミノ基、炭素数1〜5のアルコキシ基、炭素数1〜5のアルキルチオ基、炭素数1〜6のシアノアルコキシ基、または、炭素数1〜5のアルキル基で置換されたアミノ基を示す。]を示す。
R3は、水素原子、アルキル基、アルケニル基、シクロアルキル基、アリール基、アラルキル基、アシル基、スルホニル基、及び機能性分子ユニット置換基を示す。
mは、0〜2の整数、及びnは、1〜3の整数である。) - R1が、水素原子、脂肪族アシル基、芳香族アシル基、脂肪族あるいは芳香族スルホニル基、1〜3個のアリール基で置換されたメチル基、低級アルキル、低級アルコキシ、ハロゲンもしくはシアノ基でアリール環が置換された1〜3個のアリール基で置換されたメチル基、または、シリル基である、請求項1に記載の化合物及びその塩。
- R1が、水素原子、アセチル基、ベンゾイル基、メタンスルホニル基、p−トルエンスルホニル基、ベンジル基、p−メトキシベンジル基、トリチル基、ジメトキシトリチル基、モノメトキシトリチル基、または、tert−ブチルジフェニルシリル基である、請求項1に記載の化合物及びその塩。
- R2が、水素原子、脂肪族アシル基、芳香族アシル基、脂肪族あるいは芳香族スルホニル基、1〜3個のアリール基で置換されたメチル基、低級アルキル、低級アルコキシ、ハロゲンもしくはシアノ基でアリール環が置換された1〜3個のアリール基で置換されたメチル基、シリル基、ホスホロアミダイト基、ホスホニル基、リン酸基、または、核酸合成の保護基で保護されたリン酸基である、請求項1〜3のいずれか1項に記載の化合物及びその塩。
- R2が、水素原子、アセチル基、ベンゾイル基、メタンスルホニル基、p−トルエンスルホニル基、ベンジル基、p−メトキシベンジル基、tert−ブチルジフェニルシリル基、−P(OC2H4CN)(N(i−Pr)2)、−P(OCH3)(N(i−Pr)2)、ホスホニル基、または、2−クロロフェニルもしくは4−クロロフェニルリン酸基である、請求項1〜3のいずれか1項に記載の化合物及びその塩。
- R3が、水素原子、フェノキシアセチル基、炭素数1〜5のアルキル基、炭素数1〜5のアルケニル基、炭素数6〜14のアリール基、1〜3個のアリール基で置換されたメチル基、メタンスルホニル基やp−トルエンスルホニル基などの低級脂肪族あるいは芳香族スルホニル基又はアセチル基などの炭素数1〜5の脂肪族アシル基やベンゾイル基などの芳香族アシル基である請求項1〜5のいずれか1項に記載の化合物及びその塩。
- R3の機能性分子ユニット置換基が、蛍光あるいは化学発光標識分子、核酸切断活性官能基、又は細胞内若しくは核内移行シグナルペプチドである請求項1〜6のいずれか1項に記載の化合物及びその塩。
- Baseが、プリン−9−イル基、2−オキソ−ピリミジン−1−イル基、または下記α群から選択される置換基を有するプリン−9−イル基もしくは2−オキソ−ピリミジン−1−イル基である、請求項1〜7のいずれか1項に記載の化合物及びその塩。
α群:水酸基、核酸合成の保護基で保護された水酸基、炭素数1〜5のアルコキシ基、メルカプト基、核酸合成の保護基で保護されたメルカプト基、炭素数1〜5のアルキルチオ基、アミノ基、核酸合成の保護基で保護されたアミノ基、炭素数1〜5のアルキル基で置換されたアミノ基、炭素数1〜5のアルキル基、および、ハロゲン原子。 - Baseが、6−アミノプリン−9−イル(即ち、アデニニル)、アミノ基が核酸合成の保護基で保護された6−アミノプリン−9−イル、2,6−ジアミノプリン−9−イル、2−アミノ−6−クロロプリン−9−イル、アミノ基が核酸合成の保護基で保護された2−アミノ−6−クロロプリン−9−イル、2−アミノ−6−フルオロプリン−9−イル、アミノ基が核酸合成の保護基で保護された2−アミノ−6−フルオロプリン−9−イル、2−アミノ−6−ブロモプリン−9−イル、アミノ基が核酸合成の保護基で保護された2−アミノ−6−ブロモプリン−9−イル、2−アミノ−6−ヒドロキシプリン−9−イル(即ち、グアニニル)、アミノ基が核酸合成の保護基で保護された2−アミノ−6−ヒドロキシプリン−9−イル、6−アミノ−2−メトキシプリン−9−イル、6−アミノ−2−クロロプリン−9−イル、6−アミノ−2−フルオロプリン−9−イル、2,6−ジメトキシプリン−9−イル、2,6−ジクロロプリン−9−イル、6−メルカプトプリン−9−イル、2−オキソ−4−アミノ−1,2−ジヒドロピリミジン−1−イル(即ち、シトシニル)、アミノ基が核酸合成の保護基で保護された2−オキソ−4−アミノ−1,2−ジヒドロピリミジン−1−イル、2−オキソ−4−アミノ−5−フルオロ−1,2−ジヒドロピリミジン−1−イル、アミノ基が核酸合成の保護基で保護された2−オキソ−4−アミノ−5−フルオロ−1,2−ジヒドロピリミジン−1−イル、4−アミノ−2−オキソ−5−クロロ−1,2−ジヒドロピリミジン−1−イル、2−オキソ−4−メトキシ−1,2−ジヒドロピリミジン−1−イル、2−オキソ−4−メルカプト−1,2−ジヒドロピリミジン−1−イル、2−オキソ−4−ヒドロキシ−1,2−ジヒドロピリミジン−1−イル(即ち、ウラシニル)、2−オキソ−4−ヒドロキシ−5−メチル−1,2−ジヒドロピリミジン−1−イル(即ち、チミニル)、4−アミノ−5−メチル−2−オキソ−1,2−ジヒドロピリミジン−1−イル(即ち、5−メチルシトシニル)、または、アミノ基が核酸合成の保護基で保護された4−アミノ−5−メチル−2−オキソ−1,2−ジヒドロピリミジン−1−イルである、請求項1〜8のいずれか1項に記載の化合物及びその塩。
- mが0であり、nが1である、請求項1〜9のいずれか1項に記載の化合物及びその塩。
- 下記一般式(II)で表されるヌクレオシド類縁体の単位構造の1種以上を1または2個以上含有するDNAオリゴヌクレオチド又はRNAオリゴヌクレオチド類縁体としてのオリゴヌクレオチド類縁体またはその薬理学上許容される塩。但し、オリゴヌクレオチド類縁体中の各ヌクレオシド間の結合形態は、天然核酸と同じリン酸ジエステル結合[−OP(O2 −)O−]以外にホスホロチオアート結合[−OP(O)(S−)O−]を1又は2個以上含有していてもよく、また、前記の構造の1種以上を2個以上含有する場合は、当該構造間でBaseは同一または異なることができる。
R3は、水素原子、アルキル基、アルケニル基、シクロアルキル基、アリール基、アラルキル基、アシル基、スルホニル基、シリル基、及び機能性分子ユニット置換基を示す。
mは、0〜2の整数、及びnは、1〜3の整数である。 - R1が、水素原子、脂肪族アシル基、芳香族アシル基、脂肪族あるいは芳香族スルホニル基、1〜3個のアリール基で置換されたメチル基、低級アルキル、低級アルコキシ、ハロゲンもしくはシアノ基でアリール環が置換された1〜3個のアリール基で置換されたメチル基、または、シリル基である、請求項11に記載のオリゴヌクレオチド類縁体またはその薬理学上許容される塩。
- R1が、水素原子、アセチル基、ベンゾイル基、メタンスルホニル基、p−トルエンスルホニル基、ベンジル基、p−メトキシベンジル基、トリチル基、ジメトキシトリチル基、モノメトキシトリチル基、または、tert−ブチルジフェニルシリル基である、請求項11に記載のオリゴヌクレオチド類縁体またはその薬理学上許容される塩。
- R2が、水素原子、脂肪族アシル基、芳香族アシル基、脂肪族あるいは芳香族スルホニル基、1〜3個のアリール基で置換されたメチル基、低級アルキル、低級アルコキシ、ハロゲンもしくはシアノ基でアリール環が置換された1〜3個のアリール基で置換されたメチル基、シリル基、ホスホロアミダイト基、ホスホニル基、リン酸基、または、核酸合成の保護基で保護されたリン酸基である、請求項11〜13のいずれか1項に記載のオリゴヌクレオチド類縁体またはその薬理学上許容される塩。
- R2が、水素原子、アセチル基、ベンゾイル基、ベンジル基、p−メトキシベンジル基、メタンスルホニル基、p−トルエンスルホニル基、tert−ブチルジフェニルシリル基、−P(OC2H4CN)(N(i−Pr)2)、−P(OCH3)(N(i−Pr)2)、ホスホニル基、または、2−クロロフェニルもしくは4−クロロフェニルリン酸基である、請求項11〜13のいずれか1項に記載のオリゴヌクレオチド類縁体またはその薬理学上許容される塩。
- R3が、水素原子、フェノキシアセチル基、炭素数1〜5のアルキル基、炭素数1〜5のアルケニル基、炭素数6〜14のアリール基、1〜3個のアリール基で置換されたメチル基、メタンスルホニル基やp−トルエンスルホニル基などの低級脂肪族あるいは芳香族スルホニル基又はアセチル基などの炭素数1〜5の脂肪族アシル基やベンゾイル基などの芳香族アシル基である、請求項11〜15のいずれか1項に記載のオリゴヌクレオチド類縁体またはその薬理学上許容される塩。
- R3の機能性分子ユニット置換基が、蛍光あるいは化学発光標識分子、核酸切断活性官能基、又は細胞内若しくは核内移行シグナルペプチドである請求項11〜16のいずれか1項に記載のオリゴヌクレオチド類縁体またはその薬理学上許容される塩。
- Baseが、プリン−9−イル基、2−オキソ−ピリミジン−1−イル基、または下記α群から選択される置換基を有するプリン−9−イル基もしくは2−オキソ−ピリミジン−1−イル基である、請求項11〜17のいずれか1項に記載のオリゴヌクレオチド類縁体またはその薬理学上許容される塩。
α群:水酸基、核酸合成の保護基で保護された水酸基、炭素数1〜5のアルコキシ基、メルカプト基、核酸合成の保護基で保護されたメルカプト基、炭素数1〜5のアルキルチオ基、アミノ基、核酸合成の保護基で保護されたアミノ基、炭素数1〜5のアルキル基で置換されたアミノ基、炭素数1〜5のアルキル基、および、ハロゲン原子。 - Baseが、6−アミノプリン−9−イル(即ち、アデニニル)、アミノ基が核酸合成の保護基で保護された6−アミノプリン−9−イル、2,6−ジアミノプリン−9−イル、2−アミノ−6−クロロプリン−9−イル、アミノ基が核酸合成の保護基で保護された2−アミノ−6−クロロプリン−9−イル、2−アミノ−6−フルオロプリン−9−イル、アミノ基が核酸合成の保護基で保護された2−アミノ−6−フルオロプリン−9−イル、2−アミノ−6−ブロモプリン−9−イル、アミノ基が核酸合成の保護基で保護された2−アミノ−6−ブロモプリン−9−イル、2−アミノ−6−ヒドロキシプリン−9−イル(即ち、グアニニル)、アミノ基が核酸合成の保護基で保護された2−アミノ−6−ヒドロキシプリン−9−イル、6−アミノ−2−メトキシプリン−9−イル、6−アミノ−2−クロロプリン−9−イル、6−アミノ−2−フルオロプリン−9−イル、2,6−ジメトキシプリン−9−イル、2,6−ジクロロプリン−9−イル、6−メルカプトプリン−9−イル、2−オキソ−4−アミノ−1,2−ジヒドロピリミジン−1−イル(即ち、シトシニル)、アミノ基が核酸合成の保護基で保護された2−オキソ−4−アミノ−1,2−ジヒドロピリミジン−1−イル、2−オキソ−4−アミノ−5−フルオロ−1,2−ジヒドロピリミジン−1−イル、アミノ基が核酸合成の保護基で保護された2−オキソ−4−アミノ−5−フルオロ−1,2−ジヒドロピリミジン−1−イル、4−アミノ−2−オキソ−5−クロロ−1,2−ジヒドロピリミジン−1−イル、2−オキソ−4−メトキシ−1,2−ジヒドロピリミジン−1−イル、2−オキソ−4−メルカプト−1,2−ジヒドロピリミジン−1−イル、2−オキソ−4−ヒドロキシ−1,2−ジヒドロピリミジン−1−イル(即ち、ウラシニル)、2−オキソ−4−ヒドロキシ−5−メチル−1,2−ジヒドロピリミジン−1−イル(即ち、チミニル)、4−アミノ−5−メチル−2−オキソ−1,2−ジヒドロピリミジン−1−イル(即ち、5−メチルシトシニル)、または、アミノ基が核酸合成の保護基で保護された4−アミノ−5−メチル−2−オキソ−1,2−ジヒドロピリミジン−1−イルである、請求項11〜18のいずれか1項に記載のオリゴヌクレオチド類縁体またはその薬理学上許容される塩。
- mが0であり、nが1である、請求項11〜19のいずれか1項に記載のオリゴヌクレオチド類縁体またはその薬理学上許容される塩。
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US6833361B2 (en) * | 1998-05-26 | 2004-12-21 | Ribapharm, Inc. | Nucleosides having bicyclic sugar moiety |
NZ513402A (en) * | 1999-02-12 | 2003-06-30 | Sankyo Co | Novel nucleosides and oligonucleotide analogues |
DK2354148T3 (da) * | 2002-02-13 | 2013-10-14 | Takeshi Imanishi | Nukleosidanaloger og oligonukleotiderivate omfattende nukleotidanalog deraf |
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US20070167387A1 (en) | 2007-07-19 |
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ATE555118T1 (de) | 2012-05-15 |
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US7427672B2 (en) | 2008-09-23 |
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