CA2671873C - Oligonucleotides containing high concentrations of guanine monomers - Google Patents
Oligonucleotides containing high concentrations of guanine monomers Download PDFInfo
- Publication number
- CA2671873C CA2671873C CA2671873A CA2671873A CA2671873C CA 2671873 C CA2671873 C CA 2671873C CA 2671873 A CA2671873 A CA 2671873A CA 2671873 A CA2671873 A CA 2671873A CA 2671873 C CA2671873 C CA 2671873C
- Authority
- CA
- Canada
- Prior art keywords
- oligonucleotide
- solvent
- coupling
- seq
- nucleoside
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 108091034117 Oligonucleotide Proteins 0.000 title claims abstract description 146
- 239000000178 monomer Substances 0.000 title claims abstract description 75
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 title claims abstract description 66
- 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 title abstract description 18
- 238000005859 coupling reaction Methods 0.000 claims abstract description 107
- 230000008878 coupling Effects 0.000 claims abstract description 104
- 238000010168 coupling process Methods 0.000 claims abstract description 104
- 239000002777 nucleoside Substances 0.000 claims abstract description 84
- 238000000034 method Methods 0.000 claims abstract description 81
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 62
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 54
- -1 nucleoside phosphoramidite Chemical class 0.000 claims abstract description 50
- 150000003833 nucleoside derivatives Chemical class 0.000 claims abstract description 35
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 177
- 239000002904 solvent Substances 0.000 claims description 109
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 48
- 239000003153 chemical reaction reagent Substances 0.000 claims description 29
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 claims description 29
- 230000003213 activating effect Effects 0.000 claims description 25
- AVQQQNCBBIEMEU-UHFFFAOYSA-N 1,1,3,3-tetramethylurea Chemical compound CN(C)C(=O)N(C)C AVQQQNCBBIEMEU-UHFFFAOYSA-N 0.000 claims description 24
- 239000004793 Polystyrene Substances 0.000 claims description 23
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 22
- 239000003880 polar aprotic solvent Substances 0.000 claims description 22
- 229920002223 polystyrene Polymers 0.000 claims description 21
- 239000002773 nucleotide Substances 0.000 claims description 11
- 125000003729 nucleotide group Chemical group 0.000 claims description 11
- 238000005571 anion exchange chromatography Methods 0.000 claims description 10
- 108091081548 Palindromic sequence Proteins 0.000 claims description 9
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 claims description 8
- 239000012190 activator Substances 0.000 claims description 7
- 230000001590 oxidative effect Effects 0.000 claims description 7
- 238000000746 purification Methods 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 6
- XGDRLCRGKUCBQL-UHFFFAOYSA-N 1h-imidazole-4,5-dicarbonitrile Chemical compound N#CC=1N=CNC=1C#N XGDRLCRGKUCBQL-UHFFFAOYSA-N 0.000 claims description 5
- 238000010511 deprotection reaction Methods 0.000 claims description 5
- MYRTYDVEIRVNKP-UHFFFAOYSA-N 1,2-Divinylbenzene Chemical compound C=CC1=CC=CC=C1C=C MYRTYDVEIRVNKP-UHFFFAOYSA-N 0.000 claims description 4
- GONFBOIJNUKKST-UHFFFAOYSA-N 5-ethylsulfanyl-2h-tetrazole Chemical compound CCSC=1N=NNN=1 GONFBOIJNUKKST-UHFFFAOYSA-N 0.000 claims description 4
- MIKUYHXYGGJMLM-GIMIYPNGSA-N Crotonoside Natural products C1=NC2=C(N)NC(=O)N=C2N1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O MIKUYHXYGGJMLM-GIMIYPNGSA-N 0.000 claims description 4
- NYHBQMYGNKIUIF-UHFFFAOYSA-N D-guanosine Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(CO)C(O)C1O NYHBQMYGNKIUIF-UHFFFAOYSA-N 0.000 claims description 4
- 229940029575 guanosine Drugs 0.000 claims description 4
- GXGKKIPUFAHZIZ-UHFFFAOYSA-N 5-benzylsulfanyl-2h-tetrazole Chemical compound C=1C=CC=CC=1CSC=1N=NNN=1 GXGKKIPUFAHZIZ-UHFFFAOYSA-N 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 2
- KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Substances C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 claims 1
- 238000002515 oligonucleotide synthesis Methods 0.000 abstract description 5
- 239000000243 solution Substances 0.000 description 63
- 239000000047 product Substances 0.000 description 41
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 32
- 108020004414 DNA Proteins 0.000 description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 239000000463 material Substances 0.000 description 14
- 239000005289 controlled pore glass Substances 0.000 description 13
- 239000000872 buffer Substances 0.000 description 11
- SSJJWVREPZVNBF-DGXVIIAXSA-N dG10 Chemical compound C1=NC(C(NC(N)=N2)=O)=C2N1[C@H](O[C@@H]1COP(O)(=O)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=O)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=O)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=O)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=O)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=O)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=O)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=O)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)CO)C[C@@H]1OP(O)(=O)OC[C@@H](O1)[C@@H](O)C[C@@H]1N1C(N=C(NC2=O)N)=C2N=C1 SSJJWVREPZVNBF-DGXVIIAXSA-N 0.000 description 11
- 238000004128 high performance liquid chromatography Methods 0.000 description 11
- 239000000203 mixture Substances 0.000 description 11
- JXTHNDFMNIQAHM-UHFFFAOYSA-N dichloroacetic acid Chemical compound OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- 150000008300 phosphoramidites Chemical class 0.000 description 8
- 238000011049 filling Methods 0.000 description 7
- 239000012535 impurity Substances 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 230000002776 aggregation Effects 0.000 description 5
- 238000004220 aggregation Methods 0.000 description 5
- 229960005215 dichloroacetic acid Drugs 0.000 description 5
- 238000004090 dissolution Methods 0.000 description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 5
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 4
- 230000006820 DNA synthesis Effects 0.000 description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 229910052786 argon Inorganic materials 0.000 description 4
- 230000003647 oxidation Effects 0.000 description 4
- 238000007254 oxidation reaction Methods 0.000 description 4
- 239000011877 solvent mixture Substances 0.000 description 4
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 108091006629 SLC13A2 Proteins 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000005349 anion exchange Methods 0.000 description 3
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
- 238000009833 condensation Methods 0.000 description 3
- 230000005494 condensation Effects 0.000 description 3
- 238000006731 degradation reaction Methods 0.000 description 3
- 238000011068 loading method Methods 0.000 description 3
- 239000002808 molecular sieve Substances 0.000 description 3
- 150000007523 nucleic acids Chemical group 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- HNSDLXPSAYFUHK-UHFFFAOYSA-N 1,4-bis(2-ethylhexyl) sulfosuccinate Chemical compound CCCCC(CC)COC(=O)CC(S(O)(=O)=O)C(=O)OCC(CC)CCCC HNSDLXPSAYFUHK-UHFFFAOYSA-N 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- 239000012630 HPLC buffer Substances 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 230000006819 RNA synthesis Effects 0.000 description 2
- 239000007983 Tris buffer Substances 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- BTGRAWJCKBQKAO-UHFFFAOYSA-N adiponitrile Chemical group N#CCCCCC#N BTGRAWJCKBQKAO-UHFFFAOYSA-N 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000009295 crossflow filtration Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000006642 detritylation reaction Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 230000010354 integration Effects 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 108020004707 nucleic acids Proteins 0.000 description 2
- 102000039446 nucleic acids Human genes 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 229920000193 polymethacrylate Polymers 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 238000010532 solid phase synthesis reaction Methods 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 150000003536 tetrazoles Chemical class 0.000 description 2
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 description 2
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- 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 description 2
- 238000005406 washing Methods 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- 102000040650 (ribonucleotides)n+m Human genes 0.000 description 1
- BYEAHWXPCBROCE-UHFFFAOYSA-N 1,1,1,3,3,3-hexafluoropropan-2-ol Chemical compound FC(F)(F)C(O)C(F)(F)F BYEAHWXPCBROCE-UHFFFAOYSA-N 0.000 description 1
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 description 1
- 125000001731 2-cyanoethyl group Chemical group [H]C([H])(*)C([H])([H])C#N 0.000 description 1
- 108091023037 Aptamer Proteins 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- RFFFKMOABOFIDF-UHFFFAOYSA-N Pentanenitrile Chemical compound CCCCC#N RFFFKMOABOFIDF-UHFFFAOYSA-N 0.000 description 1
- 230000000397 acetylating effect Effects 0.000 description 1
- 239000004411 aluminium Substances 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000008033 biological extinction Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000011035 continuous diafiltration Methods 0.000 description 1
- 239000007822 coupling agent Substances 0.000 description 1
- 238000011033 desalting Methods 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000003269 fluorescent indicator Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- ZTOMUSMDRMJOTH-UHFFFAOYSA-N glutaronitrile Chemical compound N#CCCCC#N ZTOMUSMDRMJOTH-UHFFFAOYSA-N 0.000 description 1
- AILKHAQXUAOOFU-UHFFFAOYSA-N hexanenitrile Chemical compound CCCCCC#N AILKHAQXUAOOFU-UHFFFAOYSA-N 0.000 description 1
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 150000002972 pentoses Chemical class 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- DDBREPKUVSBGFI-UHFFFAOYSA-N phenobarbital Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NC(=O)NC1=O DDBREPKUVSBGFI-UHFFFAOYSA-N 0.000 description 1
- 150000004713 phosphodiesters Chemical class 0.000 description 1
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920005553 polystyrene-acrylate Polymers 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000012465 retentate Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000005987 sulfurization reaction Methods 0.000 description 1
- GOMLCFUVZKLQCO-HTLAMOOLSA-N thrombin aptamer Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](COP(O)(=O)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=O)O[C@H]2[C@H]([C@@H](O[C@@H]2COP(O)(=O)O[C@H]2[C@H]([C@@H](O[C@@H]2COP(O)(=O)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=O)O[C@H]2[C@H]([C@@H](O[C@@H]2COP(O)(=O)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=O)O[C@H]2[C@H]([C@@H](O[C@@H]2COP(O)(=O)O[C@H]2[C@H]([C@@H](O[C@@H]2COP(O)(=O)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=O)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=O)O[C@H]2[C@H]([C@@H](O[C@@H]2COP(O)(=O)O[C@H]2[C@H]([C@@H](O[C@@H]2CO)N2C3=C(C(NC(N)=N3)=O)N=C2)O)N2C3=C(C(NC(N)=N3)=O)N=C2)O)N2C3=C(C(NC(N)=N3)=O)N=C2)O)N2C3=C(C(NC(N)=N3)=O)N=C2)O)N2C3=C(C(NC(N)=N3)=O)N=C2)O)N2C3=C(C(NC(N)=N3)=O)N=C2)O)N2C3=C(C(NC(N)=N3)=O)N=C2)O)[C@@H](OP(O)(=O)OC[C@@H]2[C@H]([C@@H](O)[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP(O)(=O)OC[C@@H]2[C@H]([C@@H](O)[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)O)C1 GOMLCFUVZKLQCO-HTLAMOOLSA-N 0.000 description 1
- 229940113082 thymine Drugs 0.000 description 1
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 1
- WVLBCYQITXONBZ-UHFFFAOYSA-N trimethyl phosphate Chemical class COP(=O)(OC)OC WVLBCYQITXONBZ-UHFFFAOYSA-N 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 239000003643 water by type Substances 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/06—Separation; Purification
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Immunology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Saccharide Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US86958806P | 2006-12-12 | 2006-12-12 | |
| US60/869,588 | 2006-12-12 | ||
| PCT/US2007/087183 WO2008073960A2 (en) | 2006-12-12 | 2007-12-12 | Oligonucleotides containing high concentrations of guanine monomers |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2671873A1 CA2671873A1 (en) | 2008-06-19 |
| CA2671873C true CA2671873C (en) | 2018-10-09 |
Family
ID=39456527
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2671873A Active CA2671873C (en) | 2006-12-12 | 2007-12-12 | Oligonucleotides containing high concentrations of guanine monomers |
Country Status (7)
| Country | Link |
|---|---|
| US (3) | US8586728B2 (enExample) |
| EP (1) | EP2125854B1 (enExample) |
| JP (1) | JP5389662B2 (enExample) |
| CN (1) | CN101611048B (enExample) |
| AU (1) | AU2007333147B2 (enExample) |
| CA (1) | CA2671873C (enExample) |
| WO (1) | WO2008073960A2 (enExample) |
Families Citing this family (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE102008063490B4 (de) * | 2008-12-17 | 2023-06-15 | Merck Patent Gmbh | Organische Elektrolumineszenzvorrichtung und Verfahren zum Einstellen des Farbortes einer weiß emittierenden Elektrolumineszenzvorrichtung |
| WO2012059510A1 (en) | 2010-11-02 | 2012-05-10 | Girindus America, Inc. | Back pressure control during solid-phase synthesis on polymeric supports |
| US10040048B1 (en) | 2014-09-25 | 2018-08-07 | Synthego Corporation | Automated modular system and method for production of biopolymers |
| CA2972757A1 (en) | 2014-12-31 | 2016-07-07 | Arthur M. Krieg | Combination tumor immunotherapy |
| WO2017005818A1 (en) * | 2015-07-08 | 2017-01-12 | Kuros Biosciences Ag | Guanine-rich oligonucleotides |
| EP3436066A1 (en) | 2016-04-01 | 2019-02-06 | Checkmate Pharmaceuticals, Inc. | Fc receptor-mediated drug delivery |
| US20190076814A1 (en) | 2017-09-11 | 2019-03-14 | Synthego Corporation | Biopolymer synthesis system and method |
| WO2019080704A1 (zh) * | 2017-10-25 | 2019-05-02 | 深圳华大生命科学研究院 | 用于核酸合成的微流控芯片 |
| EP3752194A4 (en) | 2018-02-13 | 2022-03-16 | Checkmate Pharmaceuticals, Inc. | COMPOSITIONS AND METHODS FOR TUMOR IMMUNOTHERAPY |
| EP3775218A1 (en) | 2018-04-09 | 2021-02-17 | Checkmate Pharmaceuticals | Packaging oligonucleotides into virus-like particles |
| MX2021002745A (es) * | 2018-09-11 | 2021-05-12 | Amgen Inc | Metodos de purificacion de oligonucleotidos ricos en guanina. |
| BR112021007527A2 (pt) * | 2018-10-30 | 2021-08-03 | Toray Industries, Inc. | inibidor de ligação não específica para ácido nucleico, reagente de hibridização para ácido nucleico, métodos de hibridização de ácido nucleico e de detecção de um ácido nucleico e uso de um ácido nucleico |
| WO2020093322A1 (zh) * | 2018-11-08 | 2020-05-14 | 深圳华大生命科学研究院 | 一种微流控芯片及其制备方法和dna合成方法 |
| US12202848B2 (en) * | 2019-10-18 | 2025-01-21 | Fujifilm Wako Pure Chemical Corporation | Phosphoramidite activator |
| US20230322842A1 (en) * | 2020-04-14 | 2023-10-12 | Sumitomo Chemical Company, Limited | Composition containing nucleic acid oligomer |
| CN114425443B (zh) * | 2020-10-29 | 2025-10-31 | 江苏金斯瑞生物科技有限公司 | 一种寡核苷酸合成催化剂 |
| GB202114688D0 (en) | 2021-10-14 | 2021-12-01 | Exactmer Ltd | Solution phase polymer synthesis |
Family Cites Families (33)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS60500817A (ja) * | 1983-06-01 | 1985-05-30 | ベツクマン・インストルメンツ・インコ−ポレ−テツド | ヌクレオシド・ホスホルアミダイト中間体の製造方法 |
| US20030050263A1 (en) | 1994-07-15 | 2003-03-13 | The University Of Iowa Research Foundation | Methods and products for treating HIV infection |
| ATE292980T1 (de) | 1996-10-11 | 2005-04-15 | Univ California | Immunostimulierende oligonucleotidekonjugate |
| AU7350798A (en) | 1997-04-29 | 1998-11-24 | Universiteit Utrecht | Corona virus-like particles as tools for vaccination and therapy |
| AU750702B2 (en) | 1997-05-01 | 2002-07-25 | Chiron Corporation | Use of virus-like particles as adjuvants |
| US6171591B1 (en) | 1997-12-08 | 2001-01-09 | Pentamer Pharmaceuticals, Inc. | Recombinant nodavirus compositions and methods |
| US6541438B1 (en) | 1998-05-01 | 2003-04-01 | The Procter & Gamble Company | Laundry detergent and/or fabric care compositions comprising a modified cellulase |
| AU770802B2 (en) | 1998-10-21 | 2004-03-04 | Government Of The United States Of America, As Represented By The Secretary Of The Department Of Health And Human Services, The | Virus-like particles for the induction of autoantibodies |
| ES2317711T3 (es) | 1998-11-30 | 2009-04-16 | Cytos Biotechnology Ag | Presentacion molecular de alergenos, metodos de preparacion y uso. |
| JP2003520568A (ja) | 1999-02-02 | 2003-07-08 | バイオカシェ ファーマシューティカルズ， インコーポレイテッド | 高度な抗原提示プラットフォーム |
| JP2002537102A (ja) | 1999-02-26 | 2002-11-05 | カイロン コーポレイション | 吸着された高分子および微粒子を有するミクロエマルジョン |
| UA77152C2 (en) | 1999-09-25 | 2006-11-15 | Method for stimulation of immune response using nucleic acid-containing immunostimulating compositions, method for treatment of cancer and method for treatment or prophylaxis of allergy or asthma | |
| JP2003510290A (ja) | 1999-09-27 | 2003-03-18 | コーリー ファーマシューティカル グループ，インコーポレイテッド | 免疫刺激核酸誘導インターフェロンに関する方法 |
| US6949520B1 (en) | 1999-09-27 | 2005-09-27 | Coley Pharmaceutical Group, Inc. | Methods related to immunostimulatory nucleic acid-induced interferon |
| JP2003511420A (ja) | 1999-10-13 | 2003-03-25 | カイロン コーポレイション | タンパク質から細胞性免疫応答を得る方法 |
| AU1928201A (en) | 1999-11-24 | 2001-06-04 | Chiron Corporation | Hbv/hcv virus-like particle |
| AT409085B (de) | 2000-01-28 | 2002-05-27 | Cistem Biotechnologies Gmbh | Pharmazeutische zusammensetzung zur immunmodulation und herstellung von vakzinen |
| WO2001062275A1 (en) | 2000-02-24 | 2001-08-30 | The Board Of Trustees Of The Leland Stanford Junior University | Adjuvant treatment by in vivo activation of dendritic cells |
| AU2002248185A1 (en) | 2000-12-14 | 2002-07-16 | Coley Pharmaceutical Group, Inc. | Inhibition of angiogenesis by nucleic acids |
| US20030050268A1 (en) | 2001-03-29 | 2003-03-13 | Krieg Arthur M. | Immunostimulatory nucleic acid for treatment of non-allergic inflammatory diseases |
| EP1425040A2 (en) | 2001-09-14 | 2004-06-09 | Cytos Biotechnology AG | In vivo activation of antigen presenting cells for enhancement of immune responses induced by virus like particles |
| ATE447967T1 (de) | 2001-09-14 | 2009-11-15 | Cytos Biotechnology Ag | Verpackung von immunstimulierendem cpg in virusähnlichen partikeln: herstellungsverfahren und verwendung |
| US7524950B2 (en) | 2001-10-31 | 2009-04-28 | Agilent Technologies, Inc. | Uses of cationic salts for polynucleotide synthesis |
| ATE489969T1 (de) | 2002-06-20 | 2010-12-15 | Cytos Biotechnology Ag | Verpackte virusartige partikel in kombination mit cpg zur verwendung als adjuvantien mit allergenen. herstellungsverfahren und verwendung |
| JP5022028B2 (ja) | 2003-03-26 | 2012-09-12 | サイトス・バイオテクノロジー・アクチェンゲゼルシャフト | メラン−ａペプチドアナログ−ウイルス様粒子コンジュゲート |
| US7537767B2 (en) | 2003-03-26 | 2009-05-26 | Cytis Biotechnology Ag | Melan-A- carrier conjugates |
| US20060210588A1 (en) | 2003-03-26 | 2006-09-21 | Cytos Biotechnology Ag | Hiv-peptide-carrier-conjugates |
| CA2527102A1 (en) | 2003-07-10 | 2005-01-20 | Cytos Biotechnology Ag | Packaged virus-like particles |
| EP1646427A1 (en) * | 2003-07-22 | 2006-04-19 | Cytos Biotechnology AG | Cpg-packaged liposomes |
| JP4628686B2 (ja) * | 2004-02-25 | 2011-02-09 | 独立行政法人科学技術振興機構 | ホスホロアミダイトを含む３’末端ヌクレオシドユニット |
| EP1789460B1 (en) * | 2004-09-02 | 2013-01-09 | Isis Pharmaceuticals, Inc. | Polymeric beads for oligonucleotide synthesis |
| BRPI0516953A (pt) | 2004-09-21 | 2008-09-30 | Cytos Biotechnology Ag | partìculas do tipo vìrus compreendendo uma proteìna de fusão da proteìna de revestimento de ap205 e um polipeptìdeo antigênico |
| EP1973608A1 (en) | 2005-12-14 | 2008-10-01 | Cytos Biotechnology AG | Immunostimulatory nucleic acid packaged particles for the treatment of hypersensitivity |
-
2007
- 2007-12-12 CA CA2671873A patent/CA2671873C/en active Active
- 2007-12-12 JP JP2009541546A patent/JP5389662B2/ja active Active
- 2007-12-12 AU AU2007333147A patent/AU2007333147B2/en active Active
- 2007-12-12 WO PCT/US2007/087183 patent/WO2008073960A2/en not_active Ceased
- 2007-12-12 US US11/954,511 patent/US8586728B2/en active Active
- 2007-12-12 CN CN2007800498509A patent/CN101611048B/zh active Active
- 2007-12-12 EP EP07865549.5A patent/EP2125854B1/en active Active
-
2013
- 2013-10-15 US US14/054,068 patent/US20140200338A1/en not_active Abandoned
-
2015
- 2015-06-23 US US14/748,045 patent/US9914746B2/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| WO2008073960A2 (en) | 2008-06-19 |
| CA2671873A1 (en) | 2008-06-19 |
| US20080139797A1 (en) | 2008-06-12 |
| CN101611048A (zh) | 2009-12-23 |
| US8586728B2 (en) | 2013-11-19 |
| AU2007333147B2 (en) | 2013-12-19 |
| US9914746B2 (en) | 2018-03-13 |
| WO2008073960A3 (en) | 2008-08-07 |
| JP2010512169A (ja) | 2010-04-22 |
| AU2007333147A1 (en) | 2008-06-19 |
| US20160145293A1 (en) | 2016-05-26 |
| US20140200338A1 (en) | 2014-07-17 |
| EP2125854B1 (en) | 2016-10-26 |
| JP5389662B2 (ja) | 2014-01-15 |
| EP2125854A2 (en) | 2009-12-02 |
| CN101611048B (zh) | 2012-11-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2671873C (en) | Oligonucleotides containing high concentrations of guanine monomers | |
| Bonora et al. | Large scale, liquid phase synthesis of oligonucleotides by the phosphoramidite approach | |
| JP7377228B2 (ja) | グアニンリッチオリゴヌクレオチド | |
| EP2332954A2 (en) | Process for the preparation of phosphorothionate oligonucleotides | |
| Wengel et al. | Chemistry of locked nucleic acids (LNA): Design, synthesis, and bio-physical properties | |
| KR20160150051A (ko) | Rna 올리고뉴클레오티드 절단 방법 | |
| EP3870594B1 (en) | Process for the purification of oligonucleotides | |
| AU2022224306A1 (en) | Process for the de-tritylation of oligonucleotides | |
| CA3141195C (en) | Process for the preparation of oligonucleotides using modified oxidation protocol. | |
| AU2013204442A1 (en) | Oligonucleotides Containing High Concentrations of Guanine Monomers | |
| KR20200035267A (ko) | 이메텔스타트를 제조하기 위한 향상된 공정 | |
| Kumar et al. | Novel conditions for rapid and clean deprotection of oligodeoxyribonucleotides from universal polymer supports | |
| ES2741025T3 (es) | Oligonucleótidos ricos en guanina | |
| EP4041741A1 (en) | Method for the production of a catalytically active dna molecule having improved activity and its use in a method of treating asthma | |
| CN118546193A (zh) | 用于氧化亚磷酸三酯的氧化剂及其应用 | |
| HK40048836A (en) | Method for the production of a catalytically active dna molecule having improved activity and its use in a method of treating asthma | |
| CN101273050A (zh) | 缚酸剂在蔗糖-6-乙酸酯的氯化过程中去除反应物料的质子（酸性）中的应用 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| EEER | Examination request |
Effective date: 20121210 |