AU2017354876A1 - Thiol-containing cleave reagents and oxidative wash - Google Patents

Info

Publication number

AU2017354876A1

AU2017354876A1 AU2017354876A AU2017354876A AU2017354876A1 AU 2017354876 A1 AU2017354876 A1 AU 2017354876A1 AU 2017354876 A AU2017354876 A AU 2017354876A AU 2017354876 A AU2017354876 A AU 2017354876A AU 2017354876 A1 AU2017354876 A1 AU 2017354876A1

Authority

AU

Australia

Prior art keywords

compound

group

synthesis

pct

nucleobase

Prior art date

2016-11-04

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.)

Abandoned

Links

• Espacenet
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• 239000003153 chemical reaction reagent Substances 0.000 title claims description 94
• 230000001590 oxidative effect Effects 0.000 title claims description 41
• 125000003396 thiol group Chemical class [H]S* 0.000 title description 27
• 150000001875 compounds Chemical class 0.000 claims abstract description 266
• 239000000203 mixture Substances 0.000 claims abstract description 115
• 239000001226 triphosphate Substances 0.000 claims abstract description 109
• 235000011178 triphosphate Nutrition 0.000 claims abstract description 108
• 238000000034 method Methods 0.000 claims abstract description 96
• 125000006239 protecting group Chemical group 0.000 claims abstract description 77
• 150000003573 thiols Chemical class 0.000 claims abstract description 49
• XJLXLCWHYSPAJZ-UHFFFAOYSA-N dithiirane Chemical compound C1SS1 XJLXLCWHYSPAJZ-UHFFFAOYSA-N 0.000 claims abstract description 40
• 125000003729 nucleotide group Chemical group 0.000 claims description 176
• 239000002773 nucleotide Substances 0.000 claims description 153
• 238000006243 chemical reaction Methods 0.000 claims description 125
• UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical compound OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 0.000 claims description 93
• 239000011541 reaction mixture Substances 0.000 claims description 92
• 239000000243 solution Substances 0.000 claims description 83
• MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical group OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 54
• 239000000872 buffer Substances 0.000 claims description 48
• 150000007523 nucleic acids Chemical class 0.000 claims description 39
• 108020004707 nucleic acids Proteins 0.000 claims description 35
• 102000039446 nucleic acids Human genes 0.000 claims description 35
• 238000009396 hybridization Methods 0.000 claims description 30
• 239000002516 radical scavenger Substances 0.000 claims description 27
• 108010014303 DNA-directed DNA polymerase Proteins 0.000 claims description 25
• 102000016928 DNA-directed DNA polymerase Human genes 0.000 claims description 25
• 235000000346 sugar Nutrition 0.000 claims description 24
• 239000008000 CHES buffer Substances 0.000 claims description 18
• 238000001712 DNA sequencing Methods 0.000 claims description 18
• 239000007983 Tris buffer Substances 0.000 claims description 18
• VEVZDKMDCHTMIA-UHFFFAOYSA-N oxadithietane Chemical compound O1CSS1 VEVZDKMDCHTMIA-UHFFFAOYSA-N 0.000 claims description 17
• MKWKNSIESPFAQN-UHFFFAOYSA-N N-cyclohexyl-2-aminoethanesulfonic acid Chemical group OS(=O)(=O)CCNC1CCCCC1 MKWKNSIESPFAQN-UHFFFAOYSA-N 0.000 claims description 16
• GKJQHSSYBJHANH-UHFFFAOYSA-N 1,1-bis(sulfanyl)propane-1-sulfonic acid Chemical compound CCC(S)(S)S(O)(=O)=O GKJQHSSYBJHANH-UHFFFAOYSA-N 0.000 claims description 14
• 108091028043 Nucleic acid sequence Proteins 0.000 claims description 12
• LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims description 7
• LSXWFXONGKSEMY-UHFFFAOYSA-N di-tert-butyl peroxide Chemical group CC(C)(C)OOC(C)(C)C LSXWFXONGKSEMY-UHFFFAOYSA-N 0.000 claims description 5
• 150000004662 dithiols Chemical group 0.000 claims description 4
• 238000004891 communication Methods 0.000 claims description 2
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• 238000003786 synthesis reaction Methods 0.000 abstract description 187
• 238000012163 sequencing technique Methods 0.000 abstract description 80
• 238000005516 engineering process Methods 0.000 abstract description 20
• 125000002264 triphosphate group Chemical class [H]OP(=O)(O[H])OP(=O)(O[H])OP(=O)(O[H])O* 0.000 abstract description 9
• 125000000446 sulfanediyl group Chemical group *S* 0.000 abstract description 2
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 334
• 125000005647 linker group Chemical group 0.000 description 152
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• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 95
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 89
• 239000000047 product Substances 0.000 description 68
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• -1 nucleoside triphosphates Chemical class 0.000 description 66
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• 238000005481 NMR spectroscopy Methods 0.000 description 41
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• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 32
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• 238000003818 flash chromatography Methods 0.000 description 32
• HWCKGOZZJDHMNC-UHFFFAOYSA-M tetraethylammonium bromide Chemical compound [Br-].CC[N+](CC)(CC)CC HWCKGOZZJDHMNC-UHFFFAOYSA-M 0.000 description 31
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• 210000004027 cell Anatomy 0.000 description 24
• WQOXQRCZOLPYPM-UHFFFAOYSA-N dimethyl disulfide Chemical compound CSSC WQOXQRCZOLPYPM-UHFFFAOYSA-N 0.000 description 24
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 23
• BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 21
• WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 20
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 18
• 150000001412 amines Chemical class 0.000 description 18
• 239000003638 chemical reducing agent Substances 0.000 description 18
• HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 description 18
• 239000012153 distilled water Substances 0.000 description 18
• 150000003833 nucleoside derivatives Chemical class 0.000 description 18
• 239000000843 powder Substances 0.000 description 18
• FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 18
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• 239000004215 Carbon black (E152) Substances 0.000 description 17
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• NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 16
• 125000000547 substituted alkyl group Chemical group 0.000 description 16
• 229910052799 carbon Inorganic materials 0.000 description 15
• NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 14
• 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 14
• 238000000746 purification Methods 0.000 description 14
• 229940126062 Compound A Drugs 0.000 description 13
• NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 13
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• 239000012043 crude product Substances 0.000 description 13
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• 239000002808 molecular sieve Substances 0.000 description 13
• 235000021317 phosphate Nutrition 0.000 description 13
• URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 13
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• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 12
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