WO2005023829A1 - 金属錯体型核酸 - Google Patents
金属錯体型核酸 Download PDFInfo
- Publication number
- WO2005023829A1 WO2005023829A1 PCT/JP2004/002529 JP2004002529W WO2005023829A1 WO 2005023829 A1 WO2005023829 A1 WO 2005023829A1 JP 2004002529 W JP2004002529 W JP 2004002529W WO 2005023829 A1 WO2005023829 A1 WO 2005023829A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- metal
- group
- derivative
- double
- nucleotide
- Prior art date
Links
- 108020004707 nucleic acids Proteins 0.000 title description 15
- 150000007523 nucleic acids Chemical class 0.000 title description 15
- 102000039446 nucleic acids Human genes 0.000 title description 15
- 150000004696 coordination complex Chemical class 0.000 title description 12
- 229910052751 metal Inorganic materials 0.000 claims abstract description 289
- 239000002184 metal Substances 0.000 claims abstract description 289
- 108091034117 Oligonucleotide Proteins 0.000 claims abstract description 144
- 125000003729 nucleotide group Chemical group 0.000 claims abstract description 67
- 239000002773 nucleotide Substances 0.000 claims abstract description 23
- 125000004429 atom Chemical group 0.000 claims description 133
- 150000003833 nucleoside derivatives Chemical class 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 18
- 230000002194 synthesizing effect Effects 0.000 claims description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 8
- 125000000962 organic group Chemical group 0.000 claims description 6
- 125000005842 heteroatom Chemical group 0.000 claims description 5
- 150000008300 phosphoramidites Chemical class 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000003277 amino group Chemical group 0.000 claims description 4
- 125000004043 oxo group Chemical group O=* 0.000 claims description 4
- XYFCBTPGUUZFHI-UHFFFAOYSA-N phosphine group Chemical group P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 4
- 238000001308 synthesis method Methods 0.000 claims description 4
- 125000000101 thioether group Chemical group 0.000 claims description 4
- 125000000464 thioxo group Chemical group S=* 0.000 claims description 4
- 230000000536 complexating effect Effects 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- 125000004122 cyclic group Chemical group 0.000 claims description 2
- 239000002585 base Substances 0.000 description 29
- 150000001875 compounds Chemical class 0.000 description 26
- 239000010949 copper Substances 0.000 description 24
- 239000000243 solution Substances 0.000 description 24
- 150000002500 ions Chemical class 0.000 description 21
- 108020004414 DNA Proteins 0.000 description 19
- 239000003446 ligand Substances 0.000 description 18
- 239000002904 solvent Substances 0.000 description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 17
- 238000006243 chemical reaction Methods 0.000 description 16
- 230000006870 function Effects 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 125000004432 carbon atom Chemical group C* 0.000 description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 238000010898 silica gel chromatography Methods 0.000 description 8
- 230000000295 complement effect Effects 0.000 description 7
- 239000010931 gold Substances 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 238000010521 absorption reaction Methods 0.000 description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 description 6
- 239000002777 nucleoside Substances 0.000 description 6
- 125000003835 nucleoside group Chemical group 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- -1 Metal complex nucleic acid Chemical class 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- GGOZGYRTNQBSSA-UHFFFAOYSA-N pyridine-2,3-diol Chemical compound OC1=CC=CN=C1O GGOZGYRTNQBSSA-UHFFFAOYSA-N 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- 101100274581 Caenorhabditis elegans chc-1 gene Proteins 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- 238000000862 absorption spectrum Methods 0.000 description 4
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- 230000008859 change Effects 0.000 description 4
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 3
- 125000002103 4,4'-dimethoxytriphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)(C1=C([H])C([H])=C(OC([H])([H])[H])C([H])=C1[H])C1=C([H])C([H])=C(OC([H])([H])[H])C([H])=C1[H] 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
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- 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 description 3
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- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 125000004076 pyridyl group Chemical group 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- LWAVGNJLLQSNNN-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 4-azidobenzoate Chemical compound C1=CC(N=[N+]=[N-])=CC=C1C(=O)ON1C(=O)CCC1=O LWAVGNJLLQSNNN-UHFFFAOYSA-N 0.000 description 2
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- 108020004635 Complementary DNA Proteins 0.000 description 2
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical compound [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 description 2
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical group OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 239000002841 Lewis acid Substances 0.000 description 2
- 239000002879 Lewis base Substances 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- PHENPABYBHPABM-UHFFFAOYSA-N acetic acid;octane Chemical compound CC(O)=O.CCCCCCCC PHENPABYBHPABM-UHFFFAOYSA-N 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- IVRMZWNICZWHMI-UHFFFAOYSA-N azide group Chemical group [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 description 2
- 229920001222 biopolymer Polymers 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
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- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
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- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 2
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
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- 239000002244 precipitate Substances 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
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- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 description 2
- PGZVFRAEAAXREB-UHFFFAOYSA-N 2,2-dimethylpropanoyl 2,2-dimethylpropanoate Chemical compound CC(C)(C)C(=O)OC(=O)C(C)(C)C PGZVFRAEAAXREB-UHFFFAOYSA-N 0.000 description 1
- YIXDEYPPAGPYDP-IUYQGCFVSA-N 2-deoxy-D-ribono-1,4-lactone Chemical class OC[C@H]1OC(=O)C[C@@H]1O YIXDEYPPAGPYDP-IUYQGCFVSA-N 0.000 description 1
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- CIYMSCIMEZGJEA-UHFFFAOYSA-N 2-methyl-3-phenylmethoxy-3h-pyridin-4-one Chemical compound CC1=NC=CC(=O)C1OCC1=CC=CC=C1 CIYMSCIMEZGJEA-UHFFFAOYSA-N 0.000 description 1
- NYPYPOZNGOXYSU-UHFFFAOYSA-N 3-bromopyridine Chemical compound BrC1=CC=CN=C1 NYPYPOZNGOXYSU-UHFFFAOYSA-N 0.000 description 1
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- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 1
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- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000027756 respiratory electron transport chain Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 125000005031 thiocyano group Chemical group S(C#N)* 0.000 description 1
- 229940113082 thymine Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
- C07H21/02—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids with ribosyl as saccharide radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
- C07H21/04—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids with deoxyribosyl as saccharide radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H23/00—Compounds containing boron, silicon, or a metal, e.g. chelates, vitamin B12
Definitions
- the present invention provides a metal complex-type nucleic acid comprising an oligonucleotide derivative having a metal coordination group and a metal atom, a method for producing the metal complex-type nucleic acid, and selective one-dimensional heterogeneous metal atom in the metal complex-type nucleic acid. Regarding arraying.
- DNA molecules have various structures (single- or double-stranded helix, triplex, hairpin structure, ring structure, etc.) and have highly regulated functions. Therefore, it was attractive to many researchers.
- DNA is a biopolymer composed of four types of nucleoside units having different nucleobases, and these components are linked via phosphodiester bonds in a specific order that reflects genetic information.
- the process of base pairing between complementary DNA or RNA strands is simple. Hydrogen bonding and stacking interactions between nucleobases are important factors for stabilizing complementary DNA strands. In particular, hydrogen bonds play an important role in specific recognition between DNA strands. Under such circumstances, many studies have been conducted to modify the surface of DNA with metal complexes (Hurley, DJ et al., J. Am. Chem. So 1998, 120, 2194 and Rack, JJ et al., J. Am. Am. Chem.
- the metal complex type DNA produced here was extremely unstable against air oxidation and the like, and was not practical for arranging and integrating metal atoms.
- the types of metal atoms that can be incorporated are limited, and it is difficult to control and arrange a desired number of metal atoms.
- An object of the present invention is to provide a novel structure in which metal atoms can be arranged one-dimensionally and which can exist stably.
- the present inventors have conducted intensive studies to solve the above object, and as a result, are formed from a metal atom and an oligonucleotide derivative including a nucleotide derivative in which the base portion of the nucleotide is substituted with a metal coordination group that is hardly oxidized.
- the present inventors have found that the above problems can be solved by a double-stranded oligonucleotide derivative (also referred to as a metal complex-type nucleic acid in this specification), and have completed the present invention.
- the present invention includes the following inventions.
- a double-stranded oligonucleotide derivative comprising two oligonucleotide derivatives containing at least one nucleotide derivative substituted with a metal coordination group in which the base portion of the nucleotide is hardly oxidized, and a metal atom, Induction of each oligonucleotide
- the stability constant for the metal atom of a metal coordinating group is the 1 ⁇ 2 M one 1 or more, (1) or (2) a double-stranded O Rigo nucleotide derivative according.
- metal atoms the same or different, Cu 2 +, Cu +, A l 3 +, G a 3 +, L a 3+, F e 3 +, C o 3 +, A s 3 +, S i 4 +, T i 4 +, P d 2 +, P t 2 +, + P t 4 + N i 2, A g +, H g +, H g 2+, C d 2 +, Au +, Au 3 + , R h +, Ir + force selected from (1) to (5).
- each of the oligonucleotide derivatives includes a plurality of nucleotide derivatives, and includes the same number of metal atoms as the smaller of the number of nucleotide derivatives in each oligonucleotide derivative. Double-stranded oligonucleotide derivative.
- a double-stranded structure containing two or more metal coordination groups and two or more metal atoms, and various metal coordination groups are selectively coordinated with specific types of metal atoms to form a complex.
- the metal coordination group contains a metal coordination group that is easily coordinated with a specific coordination structure, and the metal coordination group is coordinated to a metal atom that easily has the same coordination structure as the coordination structure.
- the oligonucleotide derivative contains a coordinating metal coordinating group in a planar tetracoordinate structure, and the metal coordinating group is coordinated to a metal atom that easily has a planar tetracoordinate structure.
- the oligonucleotide derivative contains a metal coordination group that is easily coordinated in a linear two-coordinate structure, and the metal coordination group is coordinated to a metal atom that easily has a linear two-coordinate structure.
- a metal coordination group that can function as a harder base coordinates to a harder metal atom and a metal coordination group that can function as a softer base coordinates to a softer metal atom.
- each metal contained in each oligonucleotide derivative comprising two oligonucleotide derivatives containing at least one nucleotide derivative in which the base portion of the nucleotide is substituted with a metal coordination group that is not easily oxidized, and a metal atom
- V wherein the base moiety is not easily oxidized, a nucleotide derivative substituted with a metal coordinating group, and optionally a step of synthesizing the oligonucleotide derivative by binding the nucleotide by a phosphoramidite method; and a metal coordination of the oligonucleotide derivative.
- the step of synthesizing the oligonucleotide derivative is performed so that a plurality of nucleotide derivatives are incorporated, and the two oligonucleotides are coordinated by coordinating a metal atom to a metal coordination group of the oligonucleotide derivative.
- the synthesis method according to (13), wherein the step of binding the derivative comprises coordinating selectable metal atoms to various metal coordinating groups of the nucleotide derivative.
- the double-stranded oligonucleotide derivative of the present invention (hereinafter, also sometimes referred to as a metal complex-type nucleic acid) contains at least one nucleotide derivative in which a base portion of the nucleotide is substituted with a metal coordination group that is hardly oxidized. It has a double-stranded structure in which two lignonucleotide derivatives are bound.
- Each of the metal coordinating groups contained in each oligonucleotide derivative is coordinated to a metal atom to form a complex, whereby the oligonucleotide derivatives are bonded to each other to form a double strand.
- a nucleotide derivative means a compound having a structure in which a base portion of a nucleotide is substituted with a metal coordination group.
- the oligonucleotide derivative is defined as at least one of the nucleotides in the oligonucleotide. One has a structure substituted with one of the above nucleotide derivatives.
- the oligonucleotide derivative of the present invention contains at least one nucleotide derivative, but may contain a nucleotide that is not substituted with a metal coordination group, or may be composed of only the nucleotide derivative.
- the metal coordinating group means a group having a metal coordinating moiety capable of forming a complex by coordinating to a metal atom. In other words, it is a group having a function as a ligand.
- the double-stranded oligonucleotide derivative of the present invention is obtained by replacing a base portion of at least one nucleotide in each oligonucleotide chain with a metal coordination group in a natural double helix structure composed of two oligonucleotides. It has the following structure. Then, when the two complementary oligonucleotide derivatives form a double helix, the nucleotide on the phase capture side corresponding to the position where the nucleotide derivative is present in one of the oligonucleotide derivatives also becomes a nucleotide derivative. Is preferred.
- metal coordinating groups bonded to the sugar moiety of the nucleotide derivative face each other, and each metal present at the corresponding position of each oligonucleotide derivative is present.
- the coordinating groups together form a metal complex structure by coordinating to the metal atom.
- the complex structure connects the two oligonucleotide derivatives. Therefore, the number of metal coordination groups contained in the complementary strand of the oligonucleotide derivative is usually the same.
- the metal complex-type nucleic acid of the present invention introduces a group having a metal coordination site into an oligonucleotide in order to apply the structure of the nucleic acid, which originally controls genetic information, to a functional material.
- a double helical structure is formed by using a metal complex structure.
- the double-stranded oligonucleotide derivative of the present invention has a structure in which the nucleotide moiety of the nucleotide is substituted with a metal coordination group that is hardly oxidized. Is a metal coordination group that is not oxidized by oxygen in air or in a solvent at normal temperature and normal pressure.
- the metal coordinating groups of the present invention preferably has stability constant for the metal atom is 1 0 2 M- 1 or more, 1 0 6 ⁇ 1 0 3 ° is intended more preferably M- 1.
- Stability Constant has the usual meaning in the art and is a measure of the stability of the complex. It is shown as an equilibrium constant when a complex is formed from a hydrated metal atom and a ligand.
- Examples of the metal coordination group of the present invention include an optionally substituted 2-, 3- or 4-pyridyl group.
- substituent include, but are not particularly limited to, a hydroxyl group, an alkyl group having 1 to 10 carbon atoms (eg, a methyl group, an ethyl group, and a propyl group).
- the pyridyl group serving as the skeleton is preferably a 3-pyridyl group among 2-, 3- or 4-pyridyl groups.
- Such a metal coordination group has a coordination structure in a linear two-coordinate structure.
- the carbon atom adjacent to the nitrogen atom of the pyridyl group serving as the skeleton is a carboxyl group, 2-imidazolyl group, 4-imidazolyl group, 2-pyridyl group, or the like. It may be substituted, and such a metal coordination group functions as a bidentate coordination group. If the molecule is designed so that the donor atom comes third from the carbon next to the nitrogen atom of pyridine, it will function as a bidentate ligand.
- Such a metal coordinating group include the following.
- vicinal, hydroxyl, mercapto, A ring group containing a conjugated unsaturated bond having a group selected from a mino group, an alkoxy group, a thioether group and a phosphine group and an oxo group or a thioxo group is exemplified.
- Vicinal means that two substituents are attached to adjacent carbon atoms, one each.
- the ring group may further have a substituent, for example, an alkyl group having 1 to 10 carbon atoms (eg, a methyl group, an ethyl group, a propyl group), an alkoxy group, a halogen group, a nitro group, a cyano group, an azide group. Or a phenyl group.
- the ring group is preferably a 3- to 8-membered ring, more preferably a 5- or 6-membered ring, wherein all ring members are carbon atoms or some of them are nitrogen atoms. In the case of a 6-membered ring in which all ring members are carbon atoms, a ring group containing a conjugated unsaturated bond means an aromatic ring.
- the ring is a 6-membered ring having one nitrogen atom and two double bonds, and is a group bonded to a sugar via the nitrogen atom.
- the ring group is a 6-membered ring, the above two substituents are preferably present at the 3- and 4-positions.
- Such a metal coordination group is coordinated with a planar tetracoordinate structure.
- Such a metal coordinating group include the following.
- Still another example of the metal coordinating group of the present invention is a saturated organic group having a vicinal amino or mercapto group and optionally having a hetero atom.
- the saturated organic group include a linear or branched chain hydrocarbon group having 3 to 10 carbon atoms, preferably 4 to 5 carbon atoms, a cyclic hydrocarbon group having 5 to 8 carbon atoms, and preferably 6 carbon atoms;
- the hydrogen group include a saturated organic group in which one to three, preferably one, carbon atom constituting the hydrocarbon group is substituted with a heteroatom (an oxygen atom, a nitrogen atom, a sulfur atom, etc.). Preference is given to groups having a heteroatom, preferably an oxygen atom.
- the saturated organic group has two vicinal substituents selected from an amino group and a mercapto group. Such a metal coordination group is easy to coordinate in a planar tetracoordinate structure.
- Such a metal coordinating group include the following.
- the double-stranded oligonucleotide derivative of the present invention may have a plurality of metal coordination groups of the same type, or may have different metal coordination groups.
- the double-stranded oligonucleotide derivative having a metal coordination group as described above is hard to be oxidized and can be stably present, it is practical as a material for one-dimensionally arranging metal atoms.
- the double-stranded oligonucleotide derivative is stably present has the following two meanings.
- the stability can be measured by NMR spectrum, mass spectrum, elemental analysis, absorption spectrum, electron spin resonance spectrum, and the like.
- the metal atom includes both a metal atom having no charge and a metal atom having a charge, that is, a so-called metal ion.
- the central metal atom that forms a complex with a metal coordinating group is not particularly limited as long as it forms a complex.
- d 8 metal atoms and d 1 ° metal atom is not more preferable.
- the d 8 metal atom means a metal atom and metal ion has eight d electrons.
- the metal coordination group to be introduced into the oligonucleotide is preferably selected according to the central metal atom and the metal complex structure to be formed.
- the central metal atom and the metal coordination group can be selected based on the coordination number, charge, coordination structure and HSAB theory.
- the oligonucleotide derivative By adjusting the number of nucleotide derivatives included, a desired number of metal atoms can be introduced. Further, in each oligonucleotide, by continuously arranging nucleotide derivatives having a metal coordination group, metal atoms can be continuously arranged inside the double-stranded oligonucleotide derivative. Usually, the number of metal coordination groups contained in each oligonucleotide derivative is the same, and the same number of metal atoms will be introduced.
- each oligonucleotide derivative When the number of metal coordinating groups contained in each oligonucleotide derivative is different, the smaller number of metal atoms will be introduced into the double strand.
- a very thin wire of metal atoms By continuously arranging metal atoms, a very thin wire of metal atoms can be created, and electron transfer between metal atoms becomes easy, exhibiting an excellent mechanism as a molecular beam.
- the double-stranded oligonucleotide derivative of the present invention can be used as a solution in the state of molecules in which metal atoms are arranged, it has the advantages of high moldability and easy device fabrication.
- A is the same or different and represents a metal coordinating group
- M is the same or different and represents a metal atom
- R represents H or OH
- m represents an integer of 0 to 498, preferably an integer of 0 to 98
- a and M form a metal complex.
- R when R is H, it becomes a metal complex type DNA, and when R is OH, it becomes a metal complex type RNA.
- the metal complex formed in the double-stranded oligonucleotide preferably has a planar four-coordinate structure and a linear two-coordinate structure. This is because the metal complex can be arranged most regularly by stacking in the oligonucleotide duplex.
- the present invention also includes two or more metal coordinating groups and two or more metal atoms, and various metal coordinating groups are selectively coordinated to a specific type of metal atom to form a complex.
- the present invention relates to a double-stranded oligonucleotide derivative that forms a chain.
- metal coordinating groups selectively coordinate with a specific type of metal atom means that the type of metal coordinating group and the type of metal atom have selectivity.
- the metal coordination group and the metal atom that are easily complexed with each other Is preferentially complexed. More specifically, when an oligonucleotide derivative having a certain type of metal coordination group and a plurality of types of metal atoms coexist, the metal coordination group preferentially coordinates to a specific type of metal atom.
- the metal atom takes precedence over the position where the specific metal coordination group is present It means that it is coordinated.
- oligonucleotide derivative having various metal coordination groups at arbitrary positions in the oligonucleotide derivative, desired types of metal atom species are arranged at desired positions in a desired order. Double-stranded oligonucleotide derivatives can be produced.
- a metal atom has selectivity for a metal coordination group which is easily coordinated with the same coordination structure as its coordination structure.
- a metal atom that tends to have a planar tetracoordinate structure has selectivity for a metal coordination group that is easily coordinated in a planar tetracoordinate structure.
- the easy to take metal atom planar tetracoordinate structure include d 8 metal atom, for example, R h +, I r + , N i 2 +, P d 2 +, Pt 2 + , Au 3 + ions and the like.
- Cu 2 + ions having a large Jahn-Teller effect are also likely to have a planar four-coordinate structure.
- a metal atom that easily forms a linear two-coordinate structure has selectivity for a metal coordinating group that is easily coordinated in a linear two-coordinate structure.
- the metal atom that easily has a linear two-coordinate structure include d 1 (5 metal atoms, and examples thereof include Cu + , Ag + , Au + , and Hg2 + .
- the metal coordination group and the metal atom have selectivity based on the HSAB theory.
- the HS AB theory classifies metal atoms by treating the central metal atom and ligand as Lewis acids and bases, respectively.
- a harder metal atom has an affinity for a metal coordination group that can function as a harder base.
- a metal coordinating group include one or more groups selected from an oxo group, a hydroxyl group, a carboxyl group, a phosphoric acid group, and an ether group, and form a complex with a metal via the group.
- Metal coordinating groups include S i 4 +, T i 4+, etc. .
- softer metal atoms have an affinity for metal coordination groups that can function as softer bases.
- a metal coordinating group may have, for example, at least one group selected from a thioxo group, a mercapto group, a thioether group, a thiocyano group and a phosphine group, and form a complex with the metal via the group.
- Metal coordination groups may have, for example, at least one group selected from a thioxo group, a mercapto group, a thioether group, a thiocyano group and a phosphine group.
- the soft metal atom + P d 2+, P t 2, Ag +, Au +, Hg +, H g 2 +, Cu +, C d 2 +, P t 4 +, Rh + , and the like.
- examples of the metal coordination group that can function as an intermediate ligand include, for example, one or more groups selected from an amino group, a pyridyl group, an azide group, and a nitro group.
- a metal coordination group that forms a complex with a metal may be used.
- the intermediate metal atoms e.g., F e 2 +, C o 2 +, N i 2 +, Cu 2 +, Z n 2 +, P b 2 +, S n 2 +, S b 3 +, B i 3 +, Rh 3 +, Ru 2 +, O s 2+ , and the like.
- Cu 2 + ion has selectivity for the following metal coordinating groups
- P d P t 2 + , Ni 2 + ion has selectivity for the following metal coordinating groups
- two oligonucleotide derivatives containing a metal coordinating group that is easily coordinated in a planar four-coordinated structure and a metal coordinating group that is easily co-ordinated in a linear two-coordinated structure When coexisting with a metal atom that is easy to form and a metal atom that can easily form a linear two-coordinate structure, a metal atom that easily forms a planar four-coordinate structure at the position of a metal coordination group that is easy to coordinate in a planar four-coordinate structure Are incorporated to form a complex, and a metal atom that is likely to take a linear two-coordinate structure is incorporated at the position of the metal coordinating group coordinating with a linear two-coordinate structure to form a complex.
- a strand oligonucleotide derivative is formed. That is, each metal coordination group having selectivity for the metal atom to be arranged is selected.
- a desired metal atom can be arranged at a desired position.
- designing an oligonucleotide derivative when the two metal-coordinate groups face each other when forming a double-strand so that the two oligonucleotide-derivatives forming a double-chain are complementary, and It is preferable to design the complementary nucleotides to face each other.
- a method of regioselectively and one-dimensionally arranging various metal atoms has not been known at all.
- metal atoms By selectively arranging metal atoms at arbitrary positions, it becomes possible to arbitrarily control electronic, optical and magnetic interactions between metal atoms. Then, conductivity and magnetism can be controlled by external factors such as redox, light, and magnetic field. Furthermore, it can also be used to construct a reaction field using a composite metal catalyst.
- the double-stranded oligonucleotide derivative of the present invention can be synthesized, for example, by the following method.
- a single-stranded oligonucleotide derivative for forming a double strand can be synthesized as follows. First, a nucleoside derivative in which the base portion of the nucleoside is substituted with a metal coordination group is prepared. The method for synthesizing this nucleoside derivative will be described later.
- the hydroxyl group at the 5′-position of the ribofuranose ring of the nucleoside derivative is dimethoxytrimethylated, and then the hydroxyl group at the 3′-position is phosphoramidated, whereby the nucleoside derivative is phosphoramidated to produce a nucleotide derivative.
- An oligonucleotide derivative is synthesized from this nucleotide derivative using a DNA synthesizer using a phosphoramidite method known as a usual method for synthesizing nucleic acids, and finally, a protecting group such as a dimethoxytrityl group is removed. As a result, a single-stranded oligonucleotide derivative for forming the double-stranded oligonucleotide derivative of the present invention is obtained.
- the oligonucleotide derivative of the present invention may be formed only from nucleotide derivatives, but may contain natural nucleotides.
- the DNA synthesizer is used in accordance with the above synthesis method.
- the nucleotide derivative and the natural nucleotide are linked appropriately.
- nucleobases in an arbitrary sequence. Is established in A deoxynucleoside derivative in which the 5'-hydroxyl group of the deoxynucleoside having each of the nucleobases (adenine, guanine, cytosine, and thymine) is dimethoxytritylized and then the 3'-hydroxyl group is phosphoramidated, that is, a nucleotide, A DNA having a length of, for example, 2 to 100 bases can be easily synthesized by setting a predetermined base sequence in a commercially available automatic DNA synthesizer.
- the double-stranded oligonucleotide derivative of the present invention also utilizes such a DNA synthesizer to prepare a nucleoside derivative in which the above-mentioned base moiety is substituted with a metal coordination group and, if necessary, various natural nucleosides.
- a DNA synthesizer to prepare a nucleoside derivative in which the above-mentioned base moiety is substituted with a metal coordination group and, if necessary, various natural nucleosides.
- an oligonucleotide derivative having a metal coordination site introduced therein can be obtained.
- various nucleoside derivatives and nucleosides can be arranged in an arbitrary order, so that a metal coordinating group can be arranged at an arbitrary position of the oligonucleotide derivative.
- a double-stranded oligonucleotide derivative having a desired length can be produced by preparing an oligonucleotide derivative having a desired length.
- the length of the double-stranded oligonucleotide derivative of the present invention is, for example, 1 to 500 bases, preferably 1 to 100 bases, and more preferably 2 to 30 bases.
- the two complementary oligonucleotide derivatives thus obtained form a double-stranded structure by coordinating the metal coordination group of each oligonucleotide derivative to a metal atom. It becomes a double-stranded oligonucleotide derivative.
- Formation of a metal complex that is, incorporation of a metal atom into the double strand, can be carried out by coexisting two mutually complementary oligonucleotide derivatives having a metal coordination group at the corresponding position and a metal atom in a solvent.
- the metal atom can be provided by adding a salt that provides the desired metal atom to the solvent.
- the solvent to be used is not particularly limited, but for example, an aqueous solution can be used.
- the ligand has higher bond affinity with the target metal atom than the proton as a Lewis acid, and the metal atom has a higher affinity than the hydroxy ion as a Lewis base.
- the pH region has a high binding affinity with the ligand. Further, it is desirable that the temperature be low as long as the solvent does not freeze and solutes do not precipitate.
- Oligonucleotides having nucleotide derivatives in which the base is replaced by a metal coordination group Derivatives are unlikely to associate with each other in the absence of metal atoms, and the stability of the double strand is low, but a stable double strand is formed by the coexistence of metal atoms. Therefore, it is possible to control the formation of the double-stranded oligonucleotide derivative by the presence or absence and the concentration of the metal atom.
- the present invention also relates to a nucleoside derivative in which a base moiety of the nucleoside is substituted with a metal coordination group.
- nucleoside derivative of the present invention examples include the following.
- the nucleoside derivative of the present invention generally comprises condensation of a deoxyribose derivative and a metal ligand site by a F 1 iede 1-Crafts reaction, condensation of a deoxyribonolactone derivative with a lithoide of a metal ligand site, Alternatively, a nucleoside skeletal structure is obtained by an addition reaction between a glycal and an organometallic compound of a metal ligand, and is obtained by a subsequent deprotection reaction.
- an oligonucleotide derivative having a metal coordination group at an arbitrary position can be obtained using a DNA automatic synthesizer. That is, by designing an artificial nucleic acid based on the function to be imparted and selecting a coordination site and a metal atom, a compound having a structure in which an arbitrary metal atom is arranged at an arbitrary position can be easily synthesized.
- Figure 1 shows oligonucleotide derivatives with hydroxypyridone and pyridine groups. It illustrates a structure of a metal complex type DNA placing the Cu 2 + ions and Hg 2+ ions regioselectively into duplexes conductor as one aspect of the present invention.
- FIG. 2 shows the results of measurement of the UV absorption spectrum in Example 5 in which the molar ratio of Cu 2+ ion to the oligonucleotide derivative double-stranded was changed in the presence of the oligonucleotide derivative.
- FIG. 3 shows the change in absorption at 277 nm of the UV absorption spectrum measured in Example 5 by changing the molar ratio of the Cu 2+ ion and the oligonucleotide derivative duplex in the presence of the oligonucleotide derivative. Represent.
- FIG. 4 shows the results of Example 6 in which the circular dichroism spectrum was measured by changing the molar ratio of Hg 2 + ions to 2 Cu 2+ 'd (5, 1 GHPHC-3,) 2 .
- nucleoside derivatives and nucleotide derivatives having a hydroxypyridone group were synthesized.
- Bn benzyl
- Piv bivaloyl
- DMTr 4,4'dimethoxytrityl
- nucleoside derivative and a nucleoside derivative having a pyridine group were synthesized.
- DMTr represents 4,4, dimethoxytrityl.
- Dissolved compound P-3 (2.7 g, 6.2 mmo1) was dissolved in tetrahydrofuran (100 mL), and tetrabutylammonium fluoride solution in tetrahydrofuran (1.0 M, 18 6 mL, 186 mm o 1) was added at room temperature. After stirring the resulting reaction solution for 70 minutes, the reaction was stopped by adding a saturated aqueous solution of ammonium chloride (10 OmL) to the reaction solution, and the solution was concentrated. The residue was dispersed in ethyl acetate, insoluble salts were removed by filtration, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (ethyl acetate) to obtain Compound P as a colorless oil (1.1 g, 89%).
- a nucleoside derivative and a nucleotide derivative having a hydroxypyridinethione group were synthesized according to the following scheme.
- H means the nucleotide derivative having a hydroxypyridone group prepared above
- P means the nucleotide derivative having a pyridine group prepared above. Since the oligonucleotide derivative represented by SEQ ID NO: 1 is a self-complementary strand, the same sequence can form a double-stranded oligonucleotide derivative.
- the reagents and concentrations used were the same as those used for the synthesis of natural DNA oligomers.
- the synthesis was performed on a 1 ⁇ 1 scale according to the manufacturer's protocol. The only change to the normal synthesis cycle was the extension of the coupling time to 15 minutes. After the oligomer was removed from the support and deprotected by treatment with 25% 3 (55. C, 12 hours), the crude oligonucleotide derivative was purified and detritylated.
- the molar ratio of the Cu 2+ ion to the oligonucleotide derivative duplex (the duplex of the oligonucleotide derivative containing no metal atom) was changed.
- the UV absorption spectrum was measured (Hitachi U-3500 spectrometer). The result is shown in figure 2.
- “double-stranded” means the concentration of the oligonucleotide derivative double-stranded, that is, 1 of the total concentration of the oligonucleotide derivative single-stranded.
- the gradual addition of Cu 2+ ions reduced the absorption at 277 nm, with a new absorption at 306 nm.
- the absorption at 306 nm indicates that the hydroxyl group of the hydroxypyridone group was deprotonated and formed a complex with Cu 2 + ions.
- the absorption at 306 nm changed systematically while passing the iso-absorption point until two equivalents of Cu 2 + ions were added to the duplex.
- Cu 2+ ions bind to each of the two hydroxypyridone sites in the oligonucleotide to form base pairs, and a double-stranded oligonucleotide containing two copper ions, 2C It was shown that u 2+ ⁇ d (5, one GHPHC—3 ′) 2 was formed.
- a metal complex-type nucleic acid that can exist stably can be constructed, and various metal atoms can be arranged one-dimensionally.
- the metal complex-type nucleic acid of the present invention can be used for electronic devices and memory materials using molecular wires and polymer magnetic materials.
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JPH05507619A (ja) * | 1990-06-04 | 1993-11-04 | モンサント カンパニー | Rna加水分解/開裂 |
AU739391B2 (en) * | 1996-07-03 | 2001-10-11 | President And Fellows Of Harvard College | Oligonucleotide linker and techniques involving immobilized and linked oligonucleotides |
-
2004
- 2004-03-02 WO PCT/JP2004/002529 patent/WO2005023829A1/ja active Application Filing
- 2004-03-02 US US10/570,172 patent/US20070105116A1/en not_active Abandoned
- 2004-03-02 JP JP2005513584A patent/JP4783149B2/ja not_active Expired - Fee Related
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6011143A (en) * | 1997-09-12 | 2000-01-04 | Canon Kabushiki Kaisha | Artificial nucleic acids and a method of making |
Non-Patent Citations (3)
Title |
---|
TAKEZAWA H. ET AL.: "Nishurui no kinzoku haiigata nucleotide o fukumu jinko DNA o mochiita kinzoku ion no hetero shusekika", THE CHEMICAL SOCIETY OF JAPAN, DAI 38 KAI SHUKI NENKAI (2003 NEN) KOEN YOKOSHU II, 2003, pages 1101, XP002985709 * |
TANAKA K. ET AL.: "A discrete self-assembled metal array in artificial DNA", SCIENCE, vol. 299, no. 5610, 2003, pages 1212 - 1213, XP002985711 * |
TANAKA K. ET AL.: "Kinzoki sakutai-gata jinko DNA o mochiita kinzoku ion no nano shusekika", DAI 17 KAI ABSTRACTS, SYMPOSIUM ON BIOFUNCTIONAL CHEMISTRY, 2002, pages 4 - 5, XP002985710 * |
Also Published As
Publication number | Publication date |
---|---|
US20070105116A1 (en) | 2007-05-10 |
JP4783149B2 (ja) | 2011-09-28 |
JPWO2005023829A1 (ja) | 2006-11-02 |
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