CN114411267A - Method for constructing beta-fat substituted ketone compound through On-DNA reaction - Google Patents
Method for constructing beta-fat substituted ketone compound through On-DNA reaction Download PDFInfo
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- CN114411267A CN114411267A CN202011161395.5A CN202011161395A CN114411267A CN 114411267 A CN114411267 A CN 114411267A CN 202011161395 A CN202011161395 A CN 202011161395A CN 114411267 A CN114411267 A CN 114411267A
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- 238000000034 method Methods 0.000 title claims abstract description 44
- -1 ketone compound Chemical class 0.000 title claims abstract description 41
- 238000006243 chemical reaction Methods 0.000 title claims abstract description 33
- 150000001875 compounds Chemical class 0.000 claims abstract description 28
- 239000004327 boric acid Substances 0.000 claims abstract description 22
- 150000001728 carbonyl compounds Chemical class 0.000 claims abstract description 22
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims abstract description 13
- PBIMIGNDTBRRPI-UHFFFAOYSA-N trifluoro borate Chemical compound FOB(OF)OF PBIMIGNDTBRRPI-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000003504 photosensitizing agent Substances 0.000 claims abstract description 11
- 125000001931 aliphatic group Chemical group 0.000 claims abstract description 10
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 8
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 8
- 239000003513 alkali Substances 0.000 claims abstract description 6
- 239000002994 raw material Substances 0.000 claims abstract description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 26
- 125000000217 alkyl group Chemical group 0.000 claims description 23
- 239000000243 solution Substances 0.000 claims description 19
- 125000001424 substituent group Chemical group 0.000 claims description 15
- 229910052757 nitrogen Inorganic materials 0.000 claims description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 12
- 239000000126 substance Substances 0.000 claims description 11
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 10
- 125000003118 aryl group Chemical group 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 6
- TXNLQUKVUJITMX-UHFFFAOYSA-N 4-tert-butyl-2-(4-tert-butylpyridin-2-yl)pyridine Chemical compound CC(C)(C)C1=CC=NC(C=2N=CC=C(C=2)C(C)(C)C)=C1 TXNLQUKVUJITMX-UHFFFAOYSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 6
- 239000007853 buffer solution Substances 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- 125000003729 nucleotide group Chemical group 0.000 claims description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 125000005037 alkyl phenyl group Chemical group 0.000 claims description 4
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000002773 nucleotide Substances 0.000 claims description 4
- 239000012074 organic phase Substances 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 claims description 3
- 229910000396 dipotassium phosphate Inorganic materials 0.000 claims description 3
- 125000000623 heterocyclic group Chemical group 0.000 claims description 3
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 125000005493 quinolyl group Chemical group 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 125000000335 thiazolyl group Chemical group 0.000 claims description 3
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 claims description 2
- PRWATGACIORDEL-UHFFFAOYSA-N 2,4,5,6-tetra(carbazol-9-yl)benzene-1,3-dicarbonitrile Chemical group C12=CC=CC=C2C2=CC=CC=C2N1C1=C(C#N)C(N2C3=CC=CC=C3C3=CC=CC=C32)=C(N2C3=CC=CC=C3C3=CC=CC=C32)C(N2C3=CC=CC=C3C3=CC=CC=C32)=C1C#N PRWATGACIORDEL-UHFFFAOYSA-N 0.000 claims description 2
- MFGOFGRYDNHJTA-UHFFFAOYSA-N 2-amino-1-(2-fluorophenyl)ethanol Chemical compound NCC(O)C1=CC=CC=C1F MFGOFGRYDNHJTA-UHFFFAOYSA-N 0.000 claims description 2
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical group [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims description 2
- 229910021538 borax Inorganic materials 0.000 claims description 2
- 229910052796 boron Inorganic materials 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Inorganic materials [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 235000019797 dipotassium phosphate Nutrition 0.000 claims description 2
- 229910000397 disodium phosphate Inorganic materials 0.000 claims description 2
- 235000019800 disodium phosphate Nutrition 0.000 claims description 2
- 229910017053 inorganic salt Inorganic materials 0.000 claims description 2
- 239000000178 monomer Substances 0.000 claims description 2
- 150000007524 organic acids Chemical class 0.000 claims description 2
- 150000007530 organic bases Chemical class 0.000 claims description 2
- 230000000379 polymerizing effect Effects 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 2
- 235000011009 potassium phosphates Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 239000001488 sodium phosphate Substances 0.000 claims description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 2
- 235000011008 sodium phosphates Nutrition 0.000 claims description 2
- 235000010339 sodium tetraborate Nutrition 0.000 claims description 2
- 125000003107 substituted aryl group Chemical group 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical group [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 claims description 2
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims 1
- 239000000203 mixture Substances 0.000 claims 1
- 229960005222 phenazone Drugs 0.000 claims 1
- 239000008346 aqueous phase Substances 0.000 abstract description 6
- 239000003960 organic solvent Substances 0.000 abstract description 3
- 108020004414 DNA Proteins 0.000 description 33
- 235000010338 boric acid Nutrition 0.000 description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 150000002611 lead compounds Chemical class 0.000 description 4
- 230000002194 synthesizing effect Effects 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 3
- 239000008367 deionised water Substances 0.000 description 3
- 229910021641 deionized water Inorganic materials 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 125000001183 hydrocarbyl group Chemical group 0.000 description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 238000012917 library technology Methods 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 238000012216 screening Methods 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 102000053602 DNA Human genes 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 239000007821 HATU Substances 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 235000011089 carbon dioxide Nutrition 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 2
- 238000009509 drug development Methods 0.000 description 2
- 230000008014 freezing Effects 0.000 description 2
- 238000007710 freezing Methods 0.000 description 2
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 2
- 238000013537 high throughput screening Methods 0.000 description 2
- 238000002372 labelling Methods 0.000 description 2
- 125000005647 linker group Chemical group 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000011002 quantification Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical group CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 description 2
- WLWNRAWQDZRXMB-YLFCFFPRSA-N (2r,3r,4r,5s)-n,3,4,5-tetrahydroxy-1-(4-phenoxyphenyl)sulfonylpiperidine-2-carboxamide Chemical compound ONC(=O)[C@H]1[C@@H](O)[C@H](O)[C@@H](O)CN1S(=O)(=O)C(C=C1)=CC=C1OC1=CC=CC=C1 WLWNRAWQDZRXMB-YLFCFFPRSA-N 0.000 description 1
- VQNDBXJTIJKJPV-UHFFFAOYSA-N 2h-triazolo[4,5-b]pyridine Chemical compound C1=CC=NC2=NNN=C21 VQNDBXJTIJKJPV-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 229930024421 Adenine Natural products 0.000 description 1
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 1
- 108020004682 Single-Stranded DNA Proteins 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 229960000643 adenine Drugs 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000006757 chemical reactions by type Methods 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 229940104302 cytosine Drugs 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 238000012869 ethanol precipitation Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 230000004907 flux Effects 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 125000006357 methylene carbonyl group Chemical group [H]C([H])([*:1])C([*:2])=O 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 230000010355 oscillation Effects 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 238000007146 photocatalysis Methods 0.000 description 1
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- 125000003367 polycyclic group Chemical group 0.000 description 1
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- 238000002360 preparation method Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- QIPHSSYCQCBJAX-UHFFFAOYSA-N propan-2-ylboronic acid Chemical compound CC(C)B(O)O QIPHSSYCQCBJAX-UHFFFAOYSA-N 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 229940113082 thymine Drugs 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C40—COMBINATORIAL TECHNOLOGY
- C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
- C40B50/00—Methods of creating libraries, e.g. combinatorial synthesis
- C40B50/08—Liquid phase synthesis, i.e. wherein all library building blocks are in liquid phase or in solution during library creation; Particular methods of cleavage from the liquid support
-
- 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
- C40—COMBINATORIAL TECHNOLOGY
- C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
- C40B30/00—Methods of screening libraries
- C40B30/04—Methods of screening libraries by measuring the ability to specifically bind a target molecule, e.g. antibody-antigen binding, receptor-ligand binding
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Health & Medical Sciences (AREA)
- Structural Engineering (AREA)
- Immunology (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Saccharide Compounds (AREA)
Abstract
The invention relates to a method for constructing beta-aliphatic substituted ketone compounds by an On-DNA reaction, which takes an On-DNA alpha, beta-unsaturated carbonyl compound as a raw material to react with aliphatic boric acid/boric acid ester or trifluoroborate in the presence of a photosensitizer and alkali to obtain the beta-aliphatic substituted ketone compounds. The method of the invention can be carried out in the mixed aqueous phase of organic solvent/aqueous phase, has simple post-treatment and mild conditions, can obtain a highly diversified DNA coding compound library in a short time and high yield, and is suitable for the synthesis of DNA coding compounds by a multi-well plate.
Description
Technical Field
The invention belongs to the technical field of coding compound libraries, and particularly relates to a method for constructing On-DNA beta-aliphatic substituted ketone compounds in a DNA coding compound library.
Background
In drug development, especially new drug development, high-throughput screening for biological targets is one of the main means for rapidly obtaining lead compounds. However, traditional high throughput screening based on single molecules requires long time, large equipment investment, limited number of library compounds (millions), and the building of compound libraries requires decades of accumulation, limiting the efficiency and possibility of discovery of lead compounds. The recent DNA-encoded compound library technologies (WO2005058479, WO2018166532, CN103882532) combine the technologies of combinatorial chemistry and molecular biology, add a DNA tag to each compound on the molecular level, and synthesize up to hundred million levels of compound libraries in a very short time, which is a trend of the next generation compound library screening technology, and begin to be widely applied in the pharmaceutical industry, resulting in many positive effects (Accounts of Chemical Research,2014,47, 1247-.
The DNA coding compound library can rapidly generate a giant compound library through combinatorial chemistry, and can screen out a lead compound with high flux, so that the screening of the lead compound becomes unprecedented rapidness and high efficiency. One of the challenges in constructing libraries of DNA-encoding compounds is the need to synthesize chemically diverse small molecules on DNA in high yields. Because DNA can be kept stable under certain conditions (solvent, pH, temperature and ion concentration), the On-DNA reaction applied to the construction of the DNA coding compound library also needs higher yield. Therefore, the reagent type, reaction type and reaction condition of the chemical reaction (On-DNA reaction for short) carried out On DNA directly influence the richness and selectivity of the DNA coding compound library. Therefore, the development of chemical reactions compatible with DNA is also a long-term research and research direction of the current DNA coding compound library technology, and the application and commercial value of the DNA coding compound library are directly influenced.
Alpha, beta unsaturated carbonyl compound and aliphatic boric acid/boric acid ester are added in beta position of carbonyl through photocatalysis to form sp3The hybridized carbon atom connecting sites can enrich the topological structure of the pharmaceutical compounds, and the introduction of the beta-aliphatic substituted ketone compounds into the DNA coding compound library can further expand the diversity of the compound library and is beneficial to improving the probability of screening effective compounds. However, no method for synthesizing On-DNA beta-aliphatic substituted ketone compounds by using On-DNA alpha, beta-unsaturated carbonyl compounds is reported at present. Therefore, it is desired to develop a new method for synthesizing On-DNA beta-fat substituted ketone compounds suitable for large-scale multi-well plate operation, so as to increase the diversity of DNA coding compound libraries and further improve the DNA coding compoundsThe application value of the library technology.
Disclosure of Invention
In order to solve the problems, the invention develops a synthesis method of a DNA coding compound library, which has stable storage of raw materials, mild reaction conditions, good substrate universality and small damage to DNA and is suitable for batch operation by using a porous plate, and can quickly convert an On-DNA alpha, beta-unsaturated carbonyl compound into an On-DNA beta-aliphatic substituted ketone compound through one-step reaction.
The technical scheme adopted by the invention is as follows:
a method for constructing beta-fat substituted ketone compounds by On-DNA reaction takes On-DNA alpha, beta-unsaturated carbonyl compounds as raw materials, and reacts with fatty boric acid/boric acid ester or trifluoroborate in the presence of photosensitizer and alkali to obtain On-DNA beta-fat substituted ketone compounds; wherein the structural formula of the On-DNA alpha, beta-unsaturated carbonyl compound is shown in the specification
The structural formula of the fatty boric acid/boric acid ester is shown in the specification
The structural formula of the On-DNA beta-fat substituted ketone compound is shown as
Wherein the DNA in the structural formula comprises a single-stranded or double-stranded nucleotide chain obtained by polymerizing artificially modified and/or unmodified nucleotide monomers, and the nucleotide chain is connected with a nitrogen atom through one or more chemical bonds or groups; the length of the DNA is 10-200 bp.
Wherein, the DNA in the structural formula is connected with the nitrogen atom through one chemical bond or a plurality of chemical bonds. One chemical bond means that the DNA in the structural formula is directly connected with a nitrogen atom; multiple chemical bonds means that the DNA is linked to the nitrogen atom in the structural formula with multiple chemical bonds spaced apart, for example, the DNA is linked to the nitrogen atom via a methylene group (-CH)2-) are linked, i.e. linked by two chemical bonds; or between DNA and nitrogen atomsThe amino group of the DNA is connected through a carbonyl group (-CO-) and is also connected through two chemical bonds; or DNA and nitrogen atom through a methylene carbonyl group (-CH)2CO-) is attached to the amino group of the DNA, again by three consecutive chemical bonds.
R1Selected from hydrogen or a group having a molecular weight of 1000 or less directly bonded to a carbon atom alpha to the alpha, beta-unsaturated carbonyl group;
R2selected from groups having a molecular weight of 1000 or less which are directly attached to the boron atom in the aliphatic boronic acid/boronic ester;
R3、R4each independently selected from hydrogen or a group with the molecular weight of below 1000 and directly connected with an oxygen atom in the borate; or R3、R4Are connected to form a ring.
Preferably, the method comprises the following steps: the R is1Selected from alkyl, substituted alkyl, aryl or substituted aryl; wherein the alkyl is C1～C20Alkyl or C3～C8A cycloalkyl group; the number of substituents of the substituted alkyl group is one or more; the substituent of the substituted alkyl is one or more independently selected from halogen, nitro, alkoxy, halogenated phenyl, alkyl phenyl and heterocyclic radical; the aryl is selected from pyridyl, quinolyl, thiazolyl, thienyl or phenyl; the number of the substituent groups of the substituted aromatic group is one or more, and the substituent groups of the substituted aromatic group are independently selected from halogen, cyano, nitro, alkoxy and C1～C20One or more of alkyl;
the R is2Selected from alkyl, substituted alkyl; wherein the alkyl is C1～C20Alkyl or C3～C8A cycloalkyl group; the number of substituents of the substituted alkyl group is one or more; the substituent of the substituted alkyl is one or more independently selected from halogen, nitro, alkoxy, halogenated phenyl, alkyl phenyl and heterocyclic radical;
the R is3、R4Is selected from C1～C20An alkyl group; or R3、R4Are connected to form a ring.
Further, the method comprises the following steps of; said R1Is selected from C1～C6Alkyl, substituted C1～C6Alkyl, phenyl, said C1～C6The alkyl is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl and hexyl; substituted C1～C6The substituent of the alkyl is selected from phenyl and 5-6-membered saturated heterocyclic radical; the 5-6 membered saturated heterocyclic group is a saturated monocyclic hydrocarbon group carrying at least one atom of 3 to 6 selected from O, N.
Said R2Is selected from C1～C6Alkyl, substituted C1～C6Alkyl, saturated C3～C8Cycloalkyl radical, said C1～C6The alkyl is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl and hexyl; the saturation C3～C8Cycloalkyl is specifically selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; substituted C1～C6The substituent of the alkyl is selected from phenyl and amino.
The R is3、R4Is selected from C1～C6Alkyl, or R3、R4Are connected to form a ring, C1～C6The alkyl group is specifically selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl and hexyl.
Preferably, the method comprises the following steps: the On-DNA alpha, beta-unsaturated carbonyl compound is specifically selected from:
preferably, the method comprises the following steps: the boronic acid/boronic ester is in particular selected from:
preferably, the method comprises the following steps: the trifluoroborate is
Further, the trifluoroborate is
A method for constructing beta-aliphatic substituted ketone compounds by an On-DNA reaction comprises the following steps: adding 10-1000 times of molar equivalent of aliphatic boric acid/boric acid ester or trifluoroborate and 10-1000 times of molar equivalent of alkali into an On-DNA alpha, beta-unsaturated carbonyl compound solution with the molar equivalent of 1 and the molar concentration of 0.5-5mM, adding 0.1-1000 times of molar equivalent of photosensitizer, and reacting for 0.1-24 hours at 10-100 ℃.
Further, the method comprises the following steps of; the base is selected from sodium borate, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, potassium phosphate, sodium hydrogen phosphate, potassium hydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, N-methylmorpholine, triethylamine, diisopropylethylamine, DBU (1, 8-diazabicycloundecen-7-ene), 4-dimethylaminopyridine, 2, 6-dimethylpyridine, or N-methylimidazole; preferably, the base is dipotassium hydrogen phosphate.
Further, the method comprises the following steps of; the photosensitizer is selected from 2,4,5, 6-tetra (9-carbazolyl) -isophthalonitrile, Ir [ p-F (Me) ppy]2(dtbbpy)PF6、[Ir(dtbbpy)(ppy)2][PF6]、(Ir[dF(CF3)ppy]2(dtbpy))PF6、Ir[dF(Me)ppy]2(dtbbpy)PF6、[Ir{dFCF3ppy}2(bpy)]PF6(2,2' -bipyridine) bis (2-phenylpyridine) iridium (III) hexafluorophosphate; preferably, the photosensitizer is (Ir [ dF (CF)3)ppy]2(dtbpy))PF6。
Further, the method comprises the following steps of; the reaction is carried out in a solvent, and the solvent is a water-containing mixed solvent of any one or more of water, methanol, ethanol, acetonitrile, dimethyl sulfoxide, an inorganic salt buffer solution, an organic acid buffer solution and an organic base buffer solution; preferably, the reaction solvent comprises water, dimethyl sulfoxide. More preferably, the volume ratio of the organic phase in the solvent is 60-80%. Even more preferably, the organic phase in the solvent is 70% by volume.
Further, the method comprises the following steps of; the reaction temperature of the reaction is 10-100 ℃; preferably, the reaction temperature is 20 deg.C, 30 deg.C, 40 deg.C, 50 deg.C, 60 deg.C, 70 deg.C, 80 deg.C, 90 deg.C, 100 deg.C.
Further, the method comprises the following steps of; the reaction time is 0.1-24 hours; preferably, the reaction time is 0.1 hour, 0.5 hour, 1 hour, 2 hours, 4 hours, 8 hours, 10 hours, 16 hours, 18 hours, 20 hours, 24 hours.
Further, the method comprises the following steps of; in the method, the molar equivalent of the On-DNA alpha, beta-unsaturated carbonyl compound is 1, and the molar equivalents of the aliphatic boric acid/boric acid ester or trifluoroborate are 50 equivalents, 100 equivalents, 200 equivalents, 300 equivalents, 400 equivalents, 500 equivalents, 600 equivalents, 800 equivalents and 1000 equivalents; the equivalent of the base is 50 equivalents, 100 equivalents, 120 equivalents, 150 equivalents, 200 equivalents, 300 equivalents, 400 equivalents, 500 equivalents, 600 equivalents, 800 equivalents, 1000 equivalents; the molar equivalent of the photosensitizer is 0.1 equivalent, 0.5 equivalent, 1 equivalent, 5 equivalents, 10 equivalents, 20 equivalents, 50 equivalents, 80 equivalents; most preferably, the molar equivalent of the aliphatic boronic acid/boronic ester or trifluoroborate is 100, the molar equivalent of the base is 120, and the molar equivalent of the photosensitizer is 1.
Further, the reaction is carried out under nitrogen.
Further, the reaction is carried out under the irradiation of blue light, wherein the wavelength of the blue light is 420-460 nm; preferably, the blue light wavelength is 440 nm.
Further, the method comprises the following steps of; the method is used for batch multi-well plate operations.
Further, the method comprises the following steps of; the method is used for the synthesis of libraries of DNA-encoding compounds for multi-well plates.
The method can realize the acquisition of the On-DNA beta-aliphatic substituted ketone compound in a DNA coding compound library through the On-DNA alpha, beta-unsaturated carbonyl compound, can be widely applied to various On-DNA alpha, beta-unsaturated carbonyl substrates, and can introduce various substituted aliphatic boric acid/borate compounds as synthesis modules in a large scale. The method has single product, can be carried out in the mixed aqueous phase of an organic solvent/aqueous phase, has simple operation and environmental protection, and is suitable for synthesizing the DNA coding compound library by using a porous plate.
Definitions of terms used in connection with the present invention: the initial definitions provided herein for a group or term apply to that group or term throughout the specification unless otherwise indicated; for terms not specifically defined herein, the meanings that would be given to them by a person skilled in the art are to be given in light of the disclosure and the context.
"substituted" means that a hydrogen atom in a molecule is replaced by a different atom or molecule.
The minimum and maximum values of the carbon atom content in the hydrocarbon group are indicated by a prefix, e.g. prefix (Ca-C)b) Alkyl means any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, C1～C20The alkyl group is a straight-chain or branched alkyl group having 1 to 20 carbon atoms.
Alkyl means a straight or branched chain hydrocarbon radical substituted by H in the alkane molecule, e.g. methyl CH3-, ethyl CH3CH2-, methylene-CH2-。
Cycloalkyl groups: refers to a saturated or unsaturated cycloalkyl group wherein H is substituted; the halogen is fluorine, chlorine, bromine or iodine.
An aromatic group: refers to a group in which a part of H on the aromatic ring is substituted, such as pyridyl, quinolyl, thiazolyl, or phenyl.
Alkoxy groups: means that the alkyl radical is bound to an oxygen atom to form a substituent, e.g. methoxy is-OCH3。
Halogenated phenyl group: refers to a group formed by substituting H on a phenyl group with a halogen.
Alkyl phenyl: refers to a group formed by substituting H on a phenyl group with an alkyl group.
Heterocyclic group: is a saturated or unsaturated monocyclic or polycyclic hydrocarbon group carrying at least one atom of 3 to 8 selected from O, S, N.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples, but it should not be construed that the scope of the above subject matter is limited to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Drawings
FIGS. 1 to 2: the corresponding transformation rate distribution diagram of 30 On-DNA beta-aliphatic substituted ketone compounds prepared in example 2.
Detailed Description
The raw materials and equipment used in the invention are known products and are obtained by purchasing commercial products.
In the invention, the term "room temperature" means 20-25 ℃.
DMA: dimethylacetamide (Dimethylacetamide); DMF: dimethylformamide (DMF).
HATU: 2- (7-azabenzotriazole) -N, N' -tetramethyluronium hexafluorophosphate;
DIPEA: n, N-diisopropylethylamine;
DMSO, DMSO: dimethyl sulfoxide; THF: tetrahydrofuran.
DNA-NH in the present invention2Is formed by single-stranded or double-stranded DNA and a linker group and has-NH2DNA constructs for linkers, e.g. DNA-NH of "compound 1" in WO20050584792And (5) structure. Also for example the following DNA structure:
wherein A is adenine, T is thymine, C is cytosine, and G is guanine.
Example 1 Synthesis of On-DNA beta-aliphatic substituted Ketone Compounds
Reacting DNA-NH2(A) Dissolved in 250mM, pH 9.4 boric acid buffer to make a 1mM concentration solution (20 μ L,20 nmol); 2-methacrylic acid (25 eq, 500nmol,0.2M DMA solution) and DIPEA (25 eq, 500nmol,0.2M DMA solution) were mixed well, then HATU (25 eq, 500nmol,0.2M DMA solution) was added, mixed well, activated at 0 ℃ for 5 minutes; the activating solution was added to the DNA solution in 2 portions, reacted at 0 ℃ for 5 minutes and then at 25 ℃ for 30 minutes.
And (3) performing ethanol precipitation after the reaction is finished: adding a 5M sodium chloride solution with the total volume of 10% into the reacted solution, continuously adding anhydrous ethanol with the total volume of 3 times, uniformly oscillating, placing the reaction in dry ice for freezing for 0.5 hour, centrifuging for half an hour at low temperature (4 ℃) at the rotating speed of 12000rpm, pouring out supernatant, dissolving the rest precipitate with deionized water to obtain a solution of the On-DNA alpha, beta-unsaturated carbonyl compound (1), and sending LC-MS to confirm that the conversion rates of the compound1 are 97% respectively after the quantification by an enzyme labeling instrument OD.
On-DNA alpha, beta-unsaturated carbonyl compound (1) was made into a 1mM concentration solution (20. mu.L, 20nmol) with deionized water, and to the solution was added in sequence isopropylboronic acid (2000nmol,100 equiv., 0.5M in DMSO), K2HPO4(2400nmol,120 equivalents, 0.3M in DMSO), (Ir [ dF (CF)3)ppy]2(dtbpy))PF6(20nmol,1 equivalent, 0.01M DMSO solution), then 59 μ L DMSO was added to make the volume ratio of the organic phase in the reaction system 70%, mixed uniformly, purged with nitrogen gas for 2 hours, oxygen removed, and then irradiated with LED blue light (λ 440nm) for 1 hour.
After the reaction is finished, adding a 5M sodium chloride solution with the total volume of 10% into the solution after the reaction, then continuously adding absolute ethyl alcohol with the total volume of 3 times of the total volume, after the uniform oscillation, putting the reaction into dry ice for freezing for 0.5 hour, then centrifuging for half an hour at low temperature (4 ℃) at the rotating speed of 12000rpm, pouring out supernatant, dissolving the rest precipitate with deionized water to obtain a solution of the On-DNA beta-aliphatic substituted ketone compound (1a), and after the quantification is carried out by an enzyme labeling instrument OD, sending LC-MS to confirm that the conversion rates of the compound 1a are 81% respectively.
Example 2 Synthesis of On-DNA beta-aliphatic substituted Ketone Compounds
According to the preparation method of the example 1, 5 alpha, beta-unsaturated carbonyl compounds (1-5) are respectively reacted with 6 aliphatic boric acids/boric acid esters or trifluoroborate (a-f) under the same conditions, and the specific reaction product yield is shown in the figure.
In conclusion, the On-DNA beta-aliphatic substituted ketone compound can be obtained by controlling the conditions of solvent, temperature, pH and the like during the reaction and reacting the On-DNA alpha, beta-unsaturated carbonyl compound with aliphatic boric acid/boric acid ester or trifluoroborate in the presence of alkali. The method has wide substrate application range, can be carried out in a mixed aqueous phase of an organic solvent and an aqueous phase, is simple to operate, is environment-friendly, and is suitable for synthesizing a DNA coding compound library by using a porous plate.
Claims (13)
1. A method for constructing beta-aliphatic substituted ketone compounds by On-DNA reaction is characterized in that: the method takes an On-DNA alpha, beta-unsaturated carbonyl compound as a raw material, and the On-DNA beta-unsaturated carbonyl compound reacts with fatty boric acid/boric acid ester or trifluoroborate in the presence of a photosensitizer and alkali to obtain an On-DNA beta-fatty substituted ketone compound; wherein the structural formula of the On-DNA alpha, beta-unsaturated carbonyl compound is shown in the specification
The structural formula of the fatty boric acid/boric acid ester is shown in the specification
On-DNA beta-fat substituted ketone compoundHas the structural formula
Wherein the DNA in the structural formula comprises a single-stranded or double-stranded nucleotide chain obtained by polymerizing artificially modified and/or unmodified nucleotide monomers, and the nucleotide chain is connected with a nitrogen atom through one or more chemical bonds or groups;
R1selected from hydrogen or a group having a molecular weight of 1000 or less directly bonded to a carbon atom alpha to the alpha, beta-unsaturated carbonyl group;
R2selected from groups having a molecular weight of 1000 or less which are directly attached to the boron atom in the aliphatic boronic acid/boronic ester;
R3、R4each independently selected from hydrogen or a group with the molecular weight of below 1000 and directly connected with an oxygen atom in the borate; or R3、R4Are connected to form a ring.
2. The method of claim 1, wherein: the R is1Selected from alkyl, substituted alkyl, aryl or substituted aryl; wherein the alkyl is C1～C20Alkyl or C3～C8A cycloalkyl group; the number of substituents of the substituted alkyl group is one or more; the substituent of the substituted alkyl is one or more independently selected from halogen, nitro, alkoxy, halogenated phenyl, alkyl phenyl and heterocyclic radical; the aryl is selected from pyridyl, quinolyl, thiazolyl, thienyl or phenyl; the number of the substituent groups of the substituted aromatic group is one or more, and the substituent groups of the substituted aromatic group are independently selected from halogen, cyano, nitro, alkoxy and C1～C20One or more of alkyl;
the R is2Selected from alkyl, substituted alkyl; wherein the alkyl is C1～C20Alkyl or C3～C8A cycloalkyl group; the number of substituents of the substituted alkyl group is one or more; the substituents of the substituted alkyl are independently selected from halogen, nitro, alkoxy, halogenated phenyl, phenyl and alkyl phenylOne or more of a heterocyclic group;
the R is3、R4Is selected from C1～C20An alkyl group; or R3、R4Are connected to form a ring.
3. The method of claim 1, wherein: adding 10-1000 times of molar equivalent of aliphatic boric acid/boric acid ester or trifluoroborate and 10-1000 times of molar equivalent of alkali into an On-DNA alpha, beta-unsaturated carbonyl compound solution with the molar equivalent of 1 and the molar concentration of 0.5-5mM, adding 0.1-100 times of molar equivalent of photosensitizer, and reacting for 0.1-24 hours at 10-100 ℃.
4. The method of claim 3, wherein: the base is selected from sodium borate, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, potassium phosphate, sodium hydrogen phosphate, potassium hydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, N-methylmorpholine, triethylamine, diisopropylethylamine, 1, 8-diazabicycloundecen-7-ene, 4-dimethylaminopyridine, 2, 6-dimethylpyridine or N-methylimidazole.
5. The method of claim 3, wherein: the photosensitizer is selected from 2,4,5, 6-tetra (9-carbazolyl) -isophthalonitrile, Ir [ p-F (Me) ppy]2(dtbbpy)PF6、[Ir(dtbbpy)(ppy)2][PF6]、(Ir[dF(CF3)ppy]2(dtbpy))PF6、Ir[dF(Me)ppy]2(dtbbpy)PF6、[Ir{dFCF3ppy}2(bpy)]PF6Or (2,2' -bipyridine) bis (2-phenylpyridine) iridium (III) hexafluorophosphate.
6. The method of claim 3, wherein: the reaction is carried out in a solvent, and the solvent is one or a mixture of water, methanol, ethanol, acetonitrile, dimethyl sulfoxide, an inorganic salt buffer solution, an organic acid buffer solution and an organic base buffer solution. Preferably, the volume of the organic phase in the solvent accounts for 60-80%.
7. The method of claim 3, wherein: the reaction temperature of the reaction is 20 ℃, 30 ℃, 40 ℃,50 ℃, 60 ℃, 70 ℃, 80 ℃, 90 ℃ and 100 ℃.
8. The method of claim 3, wherein: the reaction time of the reaction was 0.1 hour, 0.5 hour, 1 hour, 2 hours, 4 hours, 8 hours, 10 hours, 16 hours, 18 hours, 20 hours.
9. The method of claim 3, wherein: when the molar equivalent of the On-DNA alpha, beta-unsaturated carbonyl compound is 1, the molar equivalent of the aliphatic boric acid/borate or the trifluoroborate is 50 equivalents, 100 equivalents, 200 equivalents, 300 equivalents, 400 equivalents, 500 equivalents, 600 equivalents, 800 equivalents, 1000 equivalents; the molar equivalents of the base are 50 equivalents, 100 equivalents, 120 equivalents, 150 equivalents, 200 equivalents, 300 equivalents, 400 equivalents, 500 equivalents, 600 equivalents, 800 equivalents, 1000 equivalents; the molar equivalents of the photosensitizer are 0.1 equivalent, 0.5 equivalent, 1 equivalent, 5 equivalents, 10 equivalents, 20 equivalents, 50 equivalents, and 80 equivalents.
10. The method of claim 3, wherein: the reaction was carried out under nitrogen.
11. The method of claim 3, wherein: the reaction is carried out under the irradiation of blue light, wherein the wavelength of the blue light is 420-460 nm; preferably, the blue light wavelength is 440 nm.
12. The method according to any one of claims 1 to 11, wherein the method is used for a batch multi-well plate operation.
13. The method of any one of claims 1 to 11, wherein the method is used for the synthesis of libraries of DNA-encoding compounds for multi-well plates.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20150321164A1 (en) * | 2012-12-20 | 2015-11-12 | Hitgen Ltd. | Method for synthesizing and screening lead compound and reagent testing kit |
| CN109680342A (en) * | 2018-12-18 | 2019-04-26 | 上海药明康德新药开发有限公司 | The method that On-DNA virtue nitro compound is reduced into On-DNA aromatic amine compound in DNA encoding compound library |
| CN110359097A (en) * | 2019-07-08 | 2019-10-22 | 上海药明康德新药开发有限公司 | The method that On-DNA aromatic compound is obtained by Suzuki coupling reaction in the building of DNA encoding compound library |
| US20200040326A1 (en) * | 2018-08-02 | 2020-02-06 | Tu Dresden | Method for providing a dna-encoded library, dna-encoded library and method of decoding a dna-encoded library |
-
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20150321164A1 (en) * | 2012-12-20 | 2015-11-12 | Hitgen Ltd. | Method for synthesizing and screening lead compound and reagent testing kit |
| US20200040326A1 (en) * | 2018-08-02 | 2020-02-06 | Tu Dresden | Method for providing a dna-encoded library, dna-encoded library and method of decoding a dna-encoded library |
| CN109680342A (en) * | 2018-12-18 | 2019-04-26 | 上海药明康德新药开发有限公司 | The method that On-DNA virtue nitro compound is reduced into On-DNA aromatic amine compound in DNA encoding compound library |
| CN110359097A (en) * | 2019-07-08 | 2019-10-22 | 上海药明康德新药开发有限公司 | The method that On-DNA aromatic compound is obtained by Suzuki coupling reaction in the building of DNA encoding compound library |
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