CA1202254A - Oligonucleotide derivatives and production thereof - Google Patents

Info

Publication number

CA1202254A

CA1202254A CA000434126A CA434126A CA1202254A CA 1202254 A CA1202254 A CA 1202254A CA 000434126 A CA000434126 A CA 000434126A CA 434126 A CA434126 A CA 434126A CA 1202254 A CA1202254 A CA 1202254A

Authority

CA

Canada

Prior art keywords

group

oligonucleotide

phospho

shown below

compound

Prior art date

1982-08-09

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.)

Expired

Links

• Espacenet
• Global Dossier
• CIPO
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• 108091034117 Oligonucleotide Proteins 0.000 title claims abstract description 73
• 238000004519 manufacturing process Methods 0.000 title abstract description 7
• 238000000034 method Methods 0.000 claims abstract description 46
• 229920002684 Sepharose Polymers 0.000 claims abstract description 40
• 125000006239 protecting group Chemical group 0.000 claims abstract description 32
• 125000003277 amino group Chemical group 0.000 claims abstract description 31
• 239000002773 nucleotide Substances 0.000 claims abstract description 17
• 125000003729 nucleotide group Chemical group 0.000 claims abstract description 16
• 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 claims abstract description 10
• 125000006850 spacer group Chemical group 0.000 claims abstract description 9
• 150000001875 compounds Chemical class 0.000 claims description 121
• 230000015572 biosynthetic process Effects 0.000 claims description 22
• UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical group O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 claims description 22
• 238000003786 synthesis reaction Methods 0.000 claims description 21
• RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical group CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 claims description 20
• OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical group NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 claims description 18
• -1 o-nitrophenyl-sulphenyl group Chemical group 0.000 claims description 18
• GFFGJBXGBJISGV-UHFFFAOYSA-N adenyl group Chemical group N1=CN=C2N=CNC2=C1N GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 claims description 14
• 229930024421 Adenine Natural products 0.000 claims description 13
• 229960000643 adenine Drugs 0.000 claims description 13
• 239000002777 nucleoside Substances 0.000 claims description 13
• 150000003833 nucleoside derivatives Chemical class 0.000 claims description 12
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
• 125000001424 substituent group Chemical group 0.000 claims description 12
• 125000002252 acyl group Chemical group 0.000 claims description 11
• 150000008223 ribosides Chemical class 0.000 claims description 10
• 229940113082 thymine Drugs 0.000 claims description 10
• 239000003795 chemical substances by application Substances 0.000 claims description 9
• 229940104302 cytosine Drugs 0.000 claims description 9
• 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 7
• 239000000969 carrier Substances 0.000 claims description 7
• ATDGTVJJHBUTRL-UHFFFAOYSA-N cyanogen bromide Chemical compound BrC#N ATDGTVJJHBUTRL-UHFFFAOYSA-N 0.000 claims description 7
• 238000010532 solid phase synthesis reaction Methods 0.000 claims description 7
• 125000000217 alkyl group Chemical group 0.000 claims description 6
• 125000002947 alkylene group Chemical group 0.000 claims description 6
• 101100295741 Gallus gallus COR4 gene Proteins 0.000 claims description 5
• NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical group OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 5
• 230000008030 elimination Effects 0.000 claims description 5
• 238000003379 elimination reaction Methods 0.000 claims description 5
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
• YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical group CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 4
• 239000004793 Polystyrene Substances 0.000 claims description 4
• AUHZEENZYGFFBQ-UHFFFAOYSA-N mesitylene Substances CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 claims description 4
• 125000001827 mesitylenyl group Chemical group [H]C1=C(C(*)=C(C([H])=C1C([H])([H])[H])C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
• 230000000865 phosphorylative effect Effects 0.000 claims description 4
• 229920002401 polyacrylamide Chemical class 0.000 claims description 4
• 229920002223 polystyrene Polymers 0.000 claims description 4
• 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 4
• 125000001731 2-cyanoethyl group Chemical group [H]C([H])(*)C([H])([H])C#N 0.000 claims description 3
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical class O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 3
• 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 3
• 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 claims description 3
• PVJZBZSCGJAWNG-UHFFFAOYSA-N 2,4,6-trimethylbenzenesulfonyl chloride Chemical compound CC1=CC(C)=C(S(Cl)(=O)=O)C(C)=C1 PVJZBZSCGJAWNG-UHFFFAOYSA-N 0.000 claims description 2
• WPPONCHFOIIFIJ-UHFFFAOYSA-N N1N=NN=[C-]1 Chemical compound N1N=NN=[C-]1 WPPONCHFOIIFIJ-UHFFFAOYSA-N 0.000 claims description 2
• FTAJFJHHNHPSBP-UHFFFAOYSA-N [N+](=O)([O-])C1=[C-]N=NN1 Chemical compound [N+](=O)([O-])C1=[C-]N=NN1 FTAJFJHHNHPSBP-UHFFFAOYSA-N 0.000 claims description 2
• 125000003545 alkoxy group Chemical group 0.000 claims description 2
• 125000001183 hydrocarbyl group Chemical group 0.000 claims 8
• 125000004432 carbon atom Chemical group C* 0.000 claims 4
• 239000007787 solid Chemical class 0.000 claims 4
• GJBVFACNLHJXCO-UHFFFAOYSA-N 2,4-dihydrobenzotriazol-4-id-5-yl-oxido-oxophosphanium Chemical compound P(=O)(=O)C1=[C-]C2=C(NN=N2)C=C1 GJBVFACNLHJXCO-UHFFFAOYSA-N 0.000 claims 1
• AJZZHFTYVKGGRN-UHFFFAOYSA-N P(=O)(=O)C1=[C-]N=NN1 Chemical group P(=O)(=O)C1=[C-]N=NN1 AJZZHFTYVKGGRN-UHFFFAOYSA-N 0.000 claims 1
• 125000003835 nucleoside group Chemical group 0.000 claims 1
• 238000006243 chemical reaction Methods 0.000 description 37
• 238000001179 sorption measurement Methods 0.000 description 34
• 239000002585 base Substances 0.000 description 25
• 239000011347 resin Substances 0.000 description 20
• 229920005989 resin Polymers 0.000 description 20
• 239000000243 solution Substances 0.000 description 20
• 239000001913 cellulose Substances 0.000 description 15
• 229920002678 cellulose Polymers 0.000 description 15
• 108020004707 nucleic acids Proteins 0.000 description 15
• 150000007523 nucleic acids Chemical class 0.000 description 15
• 102000039446 nucleic acids Human genes 0.000 description 15
• 238000003556 assay Methods 0.000 description 12
• 239000002253 acid Substances 0.000 description 11
• 239000000203 mixture Substances 0.000 description 11
• MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 10
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
• 239000000047 product Substances 0.000 description 10
• 238000011160 research Methods 0.000 description 10
• 239000000126 substance Substances 0.000 description 10
• 229910001868 water Inorganic materials 0.000 description 10
• 101150073006 HOT13 gene Proteins 0.000 description 9
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
• 238000010828 elution Methods 0.000 description 9
• 238000000746 purification Methods 0.000 description 9
• 238000001042 affinity chromatography Methods 0.000 description 7
• 238000004128 high performance liquid chromatography Methods 0.000 description 7
• OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 7
• 239000011780 sodium chloride Substances 0.000 description 7
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
• VNDYJBBGRKZCSX-UHFFFAOYSA-L zinc bromide Chemical compound Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 description 7
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
• 239000003153 chemical reaction reagent Substances 0.000 description 6
• 125000000524 functional group Chemical group 0.000 description 6
• WZFUQSJFWNHZHM-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)CC(=O)N1CC2=C(CC1)NN=N2 WZFUQSJFWNHZHM-UHFFFAOYSA-N 0.000 description 5
• YJLUBHOZZTYQIP-UHFFFAOYSA-N 2-[5-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-1,3,4-oxadiazol-2-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1=NN=C(O1)CC(=O)N1CC2=C(CC1)NN=N2 YJLUBHOZZTYQIP-UHFFFAOYSA-N 0.000 description 5
• SFYDWLYPIXHPML-UHFFFAOYSA-N 3-nitro-1-(2,4,6-trimethylphenyl)sulfonyl-1,2,4-triazole Chemical compound CC1=CC(C)=CC(C)=C1S(=O)(=O)N1N=C([N+]([O-])=O)N=C1 SFYDWLYPIXHPML-UHFFFAOYSA-N 0.000 description 5
• CONKBQPVFMXDOV-QHCPKHFHSA-N 6-[(5S)-5-[[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]methyl]-2-oxo-1,3-oxazolidin-3-yl]-3H-1,3-benzoxazol-2-one Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C[C@H]1CN(C(O1)=O)C1=CC2=C(NC(O2)=O)C=C1 CONKBQPVFMXDOV-QHCPKHFHSA-N 0.000 description 5
• 229920000936 Agarose Polymers 0.000 description 5
• 229920005654 Sephadex Polymers 0.000 description 5
• 239000012507 Sephadex™ Substances 0.000 description 5
• 238000009833 condensation Methods 0.000 description 5
• 230000005494 condensation Effects 0.000 description 5
• 230000000875 corresponding effect Effects 0.000 description 5
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 5
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
• VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 4
• OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 4
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 4
• 235000011114 ammonium hydroxide Nutrition 0.000 description 4
• 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 4
• 239000000872 buffer Substances 0.000 description 4
• 230000000694 effects Effects 0.000 description 4
• 238000002955 isolation Methods 0.000 description 4
• 239000007790 solid phase Substances 0.000 description 4
• 230000002194 synthesizing effect Effects 0.000 description 4
• 238000012360 testing method Methods 0.000 description 4
• QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 3
• 238000004587 chromatography analysis Methods 0.000 description 3
• 239000003446 ligand Substances 0.000 description 3
• 239000007791 liquid phase Substances 0.000 description 3
• 239000000463 material Substances 0.000 description 3
• PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 3
• UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 3
• 229920000642 polymer Polymers 0.000 description 3
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
• 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 3
• 238000005406 washing Methods 0.000 description 3
• NTNKNFHIAFDCSJ-UHFFFAOYSA-N (2-nitrophenyl) thiohypochlorite Chemical compound [O-][N+](=O)C1=CC=CC=C1SCl NTNKNFHIAFDCSJ-UHFFFAOYSA-N 0.000 description 2
• HMUNWXXNJPVALC-UHFFFAOYSA-N 1-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C(CN1CC2=C(CC1)NN=N2)=O HMUNWXXNJPVALC-UHFFFAOYSA-N 0.000 description 2
• HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
• 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 2
• SUTWPJHCRAITLU-UHFFFAOYSA-N 6-aminohexan-1-ol Chemical compound NCCCCCCO SUTWPJHCRAITLU-UHFFFAOYSA-N 0.000 description 2
• 108090000790 Enzymes Proteins 0.000 description 2
• 102000004190 Enzymes Human genes 0.000 description 2
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
• 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
• 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
• 229910021529 ammonia Inorganic materials 0.000 description 2
• 230000000052 comparative effect Effects 0.000 description 2
• 239000012043 crude product Substances 0.000 description 2
• 238000010511 deprotection reaction Methods 0.000 description 2
• DNJIEGIFACGWOD-UHFFFAOYSA-N ethyl mercaptane Natural products CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 description 2
• 239000000706 filtrate Substances 0.000 description 2
• 229920001519 homopolymer Polymers 0.000 description 2
• 150000002430 hydrocarbons Chemical group 0.000 description 2
• 108020004999 messenger RNA Proteins 0.000 description 2
• 238000002515 oligonucleotide synthesis Methods 0.000 description 2
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• 150000002923 oximes Chemical class 0.000 description 2
• 235000011007 phosphoric acid Nutrition 0.000 description 2
• 229960004838 phosphoric acid Drugs 0.000 description 2
• 230000002633 protecting effect Effects 0.000 description 2
• 102000004169 proteins and genes Human genes 0.000 description 2
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
• OENLEHTYJXMVBG-UHFFFAOYSA-N pyridine;hydrate Chemical compound [OH-].C1=CC=[NH+]C=C1 OENLEHTYJXMVBG-UHFFFAOYSA-N 0.000 description 2
• 239000011369 resultant mixture Substances 0.000 description 2
• 150000003839 salts Chemical class 0.000 description 2
• 239000002904 solvent Substances 0.000 description 2
• 238000010189 synthetic method Methods 0.000 description 2
• HWCKGOZZJDHMNC-UHFFFAOYSA-M tetraethylammonium bromide Chemical compound [Br-].CC[N+](CC)(CC)CC HWCKGOZZJDHMNC-UHFFFAOYSA-M 0.000 description 2
• DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 2
• 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
• OHVLMTFVQDZYHP-UHFFFAOYSA-N 1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-2-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]ethanone Chemical compound N1N=NC=2CN(CCC=21)C(CN1CCN(CC1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)=O OHVLMTFVQDZYHP-UHFFFAOYSA-N 0.000 description 1
• KZEVSDGEBAJOTK-UHFFFAOYSA-N 1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-2-[5-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]-1,3,4-oxadiazol-2-yl]ethanone Chemical compound N1N=NC=2CN(CCC=21)C(CC=1OC(=NN=1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)=O KZEVSDGEBAJOTK-UHFFFAOYSA-N 0.000 description 1
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• VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
• JQMFQLVAJGZSQS-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-N-(2-oxo-3H-1,3-benzoxazol-6-yl)acetamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)CC(=O)NC1=CC2=C(NC(O2)=O)C=C1 JQMFQLVAJGZSQS-UHFFFAOYSA-N 0.000 description 1
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• 239000004215 Carbon black (E152) Substances 0.000 description 1
• 102100025027 E3 ubiquitin-protein ligase TRIM69 Human genes 0.000 description 1
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