CN113387990A - Method for synthesizing DNA coding selenide compound by light-promoted on-DNA free radical reaction - Google Patents
Method for synthesizing DNA coding selenide compound by light-promoted on-DNA free radical reaction Download PDFInfo
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- -1 selenide compound Chemical class 0.000 title claims abstract description 42
- 238000000034 method Methods 0.000 title claims abstract description 28
- 150000003254 radicals Chemical class 0.000 title abstract description 10
- 238000007348 radical reaction Methods 0.000 title abstract description 5
- 230000002194 synthesizing effect Effects 0.000 title abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims abstract description 35
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims abstract description 19
- 150000001875 compounds Chemical class 0.000 claims abstract description 17
- XIMIGUBYDJDCKI-UHFFFAOYSA-N diselenium Chemical compound [Se]=[Se] XIMIGUBYDJDCKI-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000003960 organic solvent Substances 0.000 claims abstract description 12
- 230000003100 immobilizing effect Effects 0.000 claims abstract description 3
- 108020004414 DNA Proteins 0.000 claims description 41
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 19
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 150000001555 benzenes Chemical class 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 239000000460 chlorine Substances 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 239000011737 fluorine Substances 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- 239000007810 chemical reaction solvent Substances 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical class C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical class C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 4
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical class C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical class C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 4
- 125000000304 alkynyl group Chemical group 0.000 claims description 4
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 125000001072 heteroaryl group Chemical group 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 125000003729 nucleotide group Chemical group 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 3
- 230000001376 precipitating effect Effects 0.000 claims description 3
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 2
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical group C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- 108091028043 Nucleic acid sequence Proteins 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 125000003172 aldehyde group Chemical group 0.000 claims description 2
- 125000003368 amide group Chemical group 0.000 claims description 2
- 125000003277 amino group Chemical group 0.000 claims description 2
- 229960003328 benzoyl peroxide Drugs 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 239000007853 buffer solution Substances 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 2
- 125000005331 diazinyl group Chemical group N1=NC(=CC=C1)* 0.000 claims description 2
- 150000003959 diselenides Chemical class 0.000 claims description 2
- 125000004185 ester group Chemical group 0.000 claims description 2
- 150000002240 furans Chemical class 0.000 claims description 2
- 125000002541 furyl group Chemical group 0.000 claims description 2
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 2
- 125000002883 imidazolyl group Chemical group 0.000 claims description 2
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Chemical class CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 2
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Chemical class C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 2
- 125000001041 indolyl group Chemical group 0.000 claims description 2
- 229910017053 inorganic salt Inorganic materials 0.000 claims description 2
- 125000000468 ketone group Chemical group 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 239000000178 monomer Substances 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 125000002560 nitrile group Chemical group 0.000 claims description 2
- 239000002773 nucleotide Substances 0.000 claims description 2
- 125000002971 oxazolyl group Chemical group 0.000 claims description 2
- 230000000379 polymerizing effect Effects 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 2
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 2
- 125000005493 quinolyl group Chemical group 0.000 claims description 2
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 2
- 125000000335 thiazolyl group Chemical group 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 2
- 229930192474 thiophene Chemical class 0.000 claims description 2
- 125000004306 triazinyl group Chemical group 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 2
- 229920002554 vinyl polymer Polymers 0.000 claims description 2
- 150000003384 small molecules Chemical class 0.000 claims 1
- 239000002904 solvent Substances 0.000 claims 1
- 238000010189 synthetic method Methods 0.000 claims 1
- 238000010276 construction Methods 0.000 abstract description 7
- 238000005859 coupling reaction Methods 0.000 abstract description 6
- 239000000758 substrate Substances 0.000 abstract description 5
- 239000011941 photocatalyst Substances 0.000 abstract description 4
- 229910052723 transition metal Inorganic materials 0.000 abstract description 3
- 150000003624 transition metals Chemical class 0.000 abstract description 3
- 230000027756 respiratory electron transport chain Effects 0.000 abstract description 2
- 238000010532 solid phase synthesis reaction Methods 0.000 abstract 1
- 150000003343 selenium compounds Chemical class 0.000 description 12
- 239000002994 raw material Substances 0.000 description 8
- 229940065287 selenium compound Drugs 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 239000000047 product Substances 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 239000011347 resin Substances 0.000 description 4
- 229920005989 resin Polymers 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- ROGHUJUFCRFUSO-UHFFFAOYSA-N 1h-indole-4-carboxylic acid Chemical compound OC(=O)C1=CC=CC2=C1C=CN2 ROGHUJUFCRFUSO-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- 150000001491 aromatic compounds Chemical class 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 238000006268 reductive amination reaction Methods 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- SWFCZJVRWYZLPW-UHFFFAOYSA-N 2-(1h-indol-6-yl)acetic acid Chemical compound OC(=O)CC1=CC=C2C=CNC2=C1 SWFCZJVRWYZLPW-UHFFFAOYSA-N 0.000 description 1
- BMTZEAOGFDXDAD-UHFFFAOYSA-M 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium;chloride Chemical compound [Cl-].COC1=NC(OC)=NC([N+]2(C)CCOCC2)=N1 BMTZEAOGFDXDAD-UHFFFAOYSA-M 0.000 description 1
- 241001156002 Anthonomus pomorum Species 0.000 description 1
- 238000006161 Suzuki-Miyaura coupling reaction Methods 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910021538 borax Inorganic materials 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000006757 chemical reactions by type Methods 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000006880 cross-coupling reaction Methods 0.000 description 1
- 238000006352 cycloaddition reaction Methods 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- YWWZCHLUQSHMCL-UHFFFAOYSA-N diphenyl diselenide Chemical compound C=1C=CC=CC=1[Se][Se]C1=CC=CC=C1 YWWZCHLUQSHMCL-UHFFFAOYSA-N 0.000 description 1
- 238000007877 drug screening Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 238000013032 photocatalytic reaction Methods 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 239000002265 redox agent Substances 0.000 description 1
- 238000006479 redox reaction Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 239000004328 sodium tetraborate Substances 0.000 description 1
- 235000010339 sodium tetraborate Nutrition 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance 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
- C07H21/04—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids with deoxyribosyl as saccharide radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
Abstract
A method for synthesizing DNA coding selenide compounds by light-promoted on-DNA free radical reaction. The invention provides a new method for synthesizing a DNA coding selenide compound promoted by visible light. The method adopts an electron donor-acceptor compound electron transfer and solid-phase synthesis strategy to complete free radical coupling reaction of DNA coding aromatic hydrocarbon and diselenide under the condition of organic solvent under the promotion of light. Immobilizing DNA coding aromatic hydrocarbon, adding an organic solvent and diselenide, and reacting for a certain time under the irradiation of a light source with a certain wavelength to obtain the DNA coding diselenide compound. The method has the advantages of no transition metal photocatalyst participation in the reaction, mild conditions, convenient operation, good substrate universality and high product yield, and is suitable for the construction of a DNA coding compound library.
Description
Technical Field
The invention belongs to the technical field of DNA coding compound libraries, and particularly relates to a strategy for converting electrons of an electron donor-acceptor compound promoted by visible light, which realizes the activation of DNA coding electron-rich aromatic compounds, completes the double-free-radical coupling reaction of micromolecule diselenide and DNA coding aromatic hydrocarbons, and develops a new synthesis method of DNA coding selenide compounds.
Background
The concept of libraries of DNA-encoding compounds (professor Sydney Brenner and Richard Lerner, proc.natl.acad.sci.u.s.a.1992, 89, 5381, from Scripps research institute, usa) has led to great progress in both banking strategies and new drug screening, but the development of DNA-compatible chemical approaches remains a bottleneck that limits this technology. Because DNA must exist stably in a water phase, the concentration is extremely low, and the DNA is sensitive to pH, temperature, metal ions, redox reagents and the like, the on-DNA compatible chemical reaction type is insufficient, and the coverage rate of a compound structure is low. Therefore, the method solves the problem of insufficient reaction activity caused by low water solubility and concentration of DNA, and has application prospect in developing various on-DNA compatible chemical reactions with mild conditions. At present, the synthesis reaction of DNA coding compound library which can occur is mainly aqueous phase reaction in which amine compounds participate. Reactions that have been successfully applied to the construction of libraries of DNA-encoding compounds include: acid-amine condensation reaction, reductive amination reaction, nucleophilic substitution reaction, cross-coupling reaction, cycloaddition reaction, redox reaction (weak redox agent), Suzuki-Miyaura reaction and the like, wherein the reactions are all carried out in a water phase, and the universality of reaction substrates is influenced by the solubility of organic matters, so that the types of DNA coding compound library compounds are influenced.
The photo-promoted free radical reaction has the characteristics of extremely mild conditions and high reactivity at low concentration, and many research teams try to develop the construction reaction of a DNA coding compound library by adopting the reaction. Since the David Liu group reports that metal Ru is used as a photocatalyst, and a reaction for reducing an azide compound promoted by visible light into amine (nat. chem.2011, 3 and 146) is carried out for the first time, research teams and companies such as the fevered and Molander groups, GSK cooperation and Yamingkudard develop various visible light-promoted free radical reactions (ChemMedchem 2018, 13 and 2159; J.Am.chem.Soc.2019, 141 and 3723; org.Lett.2020, 22 and 1046; CN 111909232A). In 2019, professor Dawson and Baran of the research institute of Scripps, USA develops a method for constructing organic phase DNA coding compounds based on resin reversible adsorption (J.Am.chem.Soc.2019, 141, 9998; Angew.chem.int. Ed.2020, 59, 7377), and decarboxylation free radical coupling reaction, electrochemically promoted C-N bond construction reaction, reductive amination reaction and various C-S bond construction reactions are completed. Solves the problem that the DNA can not be stably existed in the organic solvent, and expands the universality of the organic substrate.
The project provides a novel synthesis method of a DNA coding selenide compound based on electron donor-acceptor compound electron transfer free radical coupling reaction promoted by visible light under the condition of an organic solvent. The method adopts ion exchange resin to carry on-DNA electron-rich aromatic hydrocarbon, completes the on-DNA free radical coupling reaction of diselenide in organic solvent under the promotion of light with a certain wavelength, and synthesizes the DNA selenide compound. The method solves the problems of insufficient reaction activity and insufficient solubility of the water-phase organic raw material caused by extremely low concentration of the on-DNA raw material, and has the advantages of no participation of a transition metal photocatalyst in the reaction process, mild conditions, convenient operation, good substrate universality and high product yield. The development of the method provides an effective solution to the problems of insufficient reaction activity caused by the solubility of reaction raw materials and extremely low DNA raw materials and metal residues caused by photocatalytic reaction, and provides a new method with industrial application prospect for the rational construction of a DNA coding compound library.
Disclosure of Invention
The invention aims to provide a novel method for synthesizing a DNA coding selenide compound shown as a formula (III) promoted by visible light under the condition of an organic solvent.
The specific technical scheme is as follows:
1) immobilizing a DNA-encoded aromatic hydrocarbon compound having the structure of formula (I) on a resin, and washing the resin with an organic solvent;
2) dissolving immobilized DNA encoding aromatic hydrocarbon compound (molar concentration is 0.1-0.2mM) and diselenide (molar concentration is 10-1500mM) with a structure of formula (II) in an organic solvent, reacting for 5-24 hours at 0-80 ℃ under the irradiation of light with a certain wavelength, removing the reaction solvent, and washing for multiple times;
3) adding an Elute buffer to Elute the DNA coding selenide compound with the structure of the formula (III), precipitating and centrifuging the product to obtain the DNA coding selenide compound with the structure of the formula (III).
Wherein:
the DNA coded aromatic hydrocarbon compound shown in the formula (I) is obtained by connecting an amine compound containing a DNA sequence with electron-rich aromatic hydrocarbon containing carboxyl through an amide bond;
the DNA is a double-stranded nucleotide sequence obtained by polymerizing artificially modified/unmodified nucleotide monomers.
Specifically, the method comprises the following steps:
the electron-rich aromatic hydrocarbon shown in the formula (I) is benzene, substituted benzene, aromatic heterocycle and substituted aromatic heterocycle containing one or more electron-donating groups; wherein the electron-donating groups comprise hydroxyl, C1-C6 alkoxy, C1-C6 cycloalkoxy, amino, substituted amino, sulfydryl, methyl, ethyl, C3-C10 straight chain and branched chain alkyl and cycloalkyl; the substituted benzene can be mono-substituted benzene or poly-substituted benzene, and the substituent can be methyl, ethyl, C3-C6 alkyl, cycloalkyl, vinyl, fluorine, chlorine, methoxy, amino, acetoxyl (-OAc), ester (-OCOR), and amine (-NHCOR); the aromatic heterocyclic ring can be mono-substituted or poly-substituted furan, thiophene, pyrrole, indole or naphthalene, and the substituent on the aromatic heterocyclic ring can be methyl, ethyl, C3-C6 alkyl, cycloalkyl, alkenyl, alkynyl, fluorine, chlorine, methoxy, amino, hydroxyl, sulfydryl, acetoxyl (-OAc), ester (-OCOR), amino (-NHCOR);
the diselenide with the structure shown in the formula (II) is phenyl, substituted phenyl, heteroaryl and alkyl substituted diselenide, wherein the substituted phenyl can be mono-substituted phenyl or multi-substituted phenyl, and the substituent can be methyl, ethyl, C3-C6 alkyl, cycloalkyl, fluorine, chlorine, bromine, iodine, nitro, trifluoromethyl, nitrile group, aldehyde group, acetyl, alkyl ketone group, ester group, amide group, methoxy group, amino group, hydroxyl group, mercapto group, alkenyl group, alkynyl and phenyl; the heteroaryl is furyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidyl, indolyl, naphthyl, quinolyl, diazinyl or triazinyl; the alkyl is methyl, ethyl, benzyl, hydroxymethyl, straight-chain and branched-chain alkyl of C3-C10, cycloalkyl of C3-C8, substituted cycloalkyl, benzyl and allyl;
the organic solvent is one or a mixture of more of N, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, methanol, ethanol, isopropanol, acetone, 1, 4-dioxane, acetonitrile, tetrahydrofuran, toluene, dichloromethane, 1, 2-dichloroethane, chloroform and an inorganic salt buffer solution; preferably, the on-DNA reaction solvent is DMSO.
The light with certain wavelength is as follows: 13w CFL light, white light, 365nm-650nm LED light; preferably, the on-DNA reaction light source is 13w CFL light, 427nm LED light and 455nm LED light.
The molarity of the small molecular compound diselenide shown in the formula (II) is 10mM, 50mM, 100mM, 200mM, 500mM, 1M and 1.5M; preferably, the molar concentration of the diselenide of the small molecule compound shown in the formula (II) is 0.5M.
The reaction temperature is room temperature, 20 ℃, 30 ℃, 40 ℃, 60 ℃ and 80 ℃; preferably, the reaction temperature is room temperature.
The reaction time is 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 16 hours, 20 hours and 24 hours; preferably, the reaction time is 16 hours.
The method has the advantages of no transition metal photocatalyst, mild conditions, convenient operation, good substrate universality and high product yield, and provides a new method with industrial application prospect for the reasonable construction of the DNA coding compound library selenide compounds.
Detailed Description
The present invention is further illustrated by the following examples, which are not intended to limit the scope of the invention.
Example 1
Step 1: synthesis of DNA-encoded aromatic Compound (I)
Reacting DNA-NH2(4. mu. mol), DMTMM (1M, 3mL), indole-4-carboxylic acid (1M, 0.4mL) were added to borax buffer (pH 9.5, 100mM, 3mL), reacted at room temperature for 2h, and after completion of the reaction, ethanol (15mL) and NaCl solution (5M, 0.4mL) were added to precipitate DNA. Adding water, acetonitrile and DIPEA into a sample tube containing the obtained precipitate, reacting at 70 ℃ for 12h, adding ethanol (15mL) and NaCl solution (5M, 0.4mL) to precipitate DNA encoding aromatic hydrocarbon compound (I-a) after the reaction is finished, and determining the structure of the compound by LC-MS with the yield of 92%.
Step 2: free radical coupling reaction of DNA encoding aromatic hydrocarbon compound (I-a) and diselenide compound (II-a)
DNA encoding aromatic hydrocarbon compounds (I-a, 10nmol) are immobilized on resin, DMSO is washed, DMSO (0.2mL) and diphenyl diselenide (II-a, 0.5M) are respectively added, the reaction is carried out for 16h at room temperature under the irradiation of a 13w CFL light source, reaction solvents are removed after the reaction is finished, the washing is carried out for multiple times, Elutebauffer (0.25 mL) is finally added for elution, NaCl solution (5M, 0.025mL) and ethanol (1.5mL) are added into the eluent for precipitating DNA encoding selenium compounds (III-a), the structure of the product is determined by LC-MS, and the yield is 77%.
Example 2
Using the same procedure as in example 1, DMSO was replaced with DMA as the reaction solvent in the second reaction step, to obtain on-DNA selenium compound (III-a) in a yield of 46%.
Example 3
The same procedure as in example 1 was followed, using a 365nm light source instead of 455nm light source as the light source in the second reaction step, to obtain DNA-encoded selenium compound (III-a) with a yield of 27%.
Example 4
Using the same procedure as in example 1, the air in the second reaction step was replaced with oxygen, to obtain DNA-encoded selenium compound (III-a) in a yield of 65%.
Example 5
The same method as that in example 1 is adopted, the diselenide in the second step of reaction takes II-b to replace II-a as raw material, and 455nm light replaces 13w CFL light, so that the DNA coded selenium compound (III-b) is obtained, and the yield is 73%.
Example 6
The same method as that in example 1 is adopted, the diselenide in the second step reaction takes II-c to replace II-a as raw material, and 427nm light replaces 13w CFL light, so that the DNA coding selenium compound (III-c) is obtained, and the yield is 68%.
Example 7
The same method as that in example 1 is adopted, the diselenide in the second step of reaction takes II-d to replace II-a as raw material, and 455nm light replaces 13w CFL light, so that the DNA coded selenium compound (III-d) is obtained, and the yield is 73%.
Example 8
Step 1:
in the same manner as in example 1, in the first reaction step, indole-6-acetic acid was used in place of indole-4-carboxylic acid as a starting material to give DNA-encoded aromatic hydrocarbon compound (I-b) in a yield of 99%.
Step 2:
the same method as that in example 1 was adopted, and in the second step, the aromatic hydrocarbon compound coded by DNA was prepared by using I-b instead of I-a and diselenide II-e instead of II-a as raw material and using 455nm light instead of 13w CFL light, to obtain on-DNA selenium compound (III-e) with a yield of 99%.
The specific structural formula of the DNA-header is as follows:
Claims (6)
1. a synthetic method of a DNA coding selenide compound shown as a formula (III) is characterized in that:
1) immobilizing a DNA encoding an aromatic hydrocarbon compound represented by the formula (I), and washing the immobilized DNA with an organic solvent;
2) adding immobilized DNA encoding aromatic hydrocarbon compound (molar concentration is 0.1-0.2mM) and diselenide (molar concentration is 10-1500mM) with the structure of formula (II) into an organic solvent, reacting for 5-24 hours at 0-80 ℃ under the irradiation of single-wavelength LED light with the wavelength range of 365nm-650nm and white light, removing the reaction solvent, and washing for multiple times;
3) adding Elutebauffer to elute the DNA coding selenide compound with the structure of formula (III), precipitating and centrifuging the product to obtain the DNA coding selenide compound with the structure of formula (III).
Wherein:
the DNA coded aromatic hydrocarbon compound shown in the formula (I) is obtained by connecting an amine compound containing a DNA sequence with electron-rich aromatic hydrocarbon containing carboxyl through an amide bond;
the DNA is a double-stranded nucleotide sequence obtained by polymerizing artificially modified/unmodified nucleotide monomers.
The electron-rich aromatic hydrocarbon shown in the formula (I) is benzene, substituted benzene, aromatic heterocycle and substituted aromatic heterocycle containing one or more electron-donating groups; wherein the electron-donating groups comprise hydroxyl, C1-C6 alkoxy, C1-C6 cycloalkoxy, amino, substituted amino, sulfydryl, methyl, ethyl, C3-C10 straight chain and branched chain alkyl and cycloalkyl; the substituted benzene can be mono-substituted benzene or poly-substituted benzene, and the substituent can be methyl, ethyl, C3-C6 alkyl, cycloalkyl, vinyl, fluorine, chlorine, methoxy, amino, acetoxyl (-OAc), ester (-OCOR), and amine (-NHCOR); the aromatic heterocyclic ring can be mono-substituted or poly-substituted furan, thiophene, pyrrole, indole or naphthalene, and the substituent on the aromatic heterocyclic ring can be methyl, ethyl, C3-C6 alkyl, cycloalkyl, alkenyl, alkynyl, fluorine, chlorine, methoxy, amino, hydroxyl, sulfydryl, acetoxyl (-OAc), ester (-OCOR), amino (-NHCOR);
the diselenide with the structure shown in the formula (II) is phenyl, substituted phenyl, heteroaryl and alkyl substituted diselenide, wherein the substituted phenyl can be mono-substituted phenyl or multi-substituted phenyl, and the substituent can be methyl, ethyl, C3-C6 alkyl, cycloalkyl, fluorine, chlorine, bromine, iodine, nitro, trifluoromethyl, nitrile group, aldehyde group, acetyl, alkyl ketone group, ester group, amide group, methoxy group, amino group, hydroxyl group, mercapto group, alkenyl group, alkynyl and phenyl; the heteroaryl is furyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidyl, indolyl, naphthyl, quinolyl, diazinyl or triazinyl; the alkyl is methyl, ethyl, benzyl, hydroxymethyl, straight-chain and branched-chain alkyl of C3-C10, cycloalkyl of C3-C8, substituted cycloalkyl, benzyl and allyl;
the organic solvent is one or a mixture of more of N, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, methanol, ethanol, isopropanol, acetone, 1, 4-dioxane, acetonitrile, tetrahydrofuran, toluene, dichloromethane, 1, 2-dichloroethane, chloroform and an inorganic salt buffer solution.
2. The method of claim 1, wherein the solvent for the on-DNA reaction is DMSO.
3. The method of claim 1, wherein the on-DNA reaction light source is 13w CFL light, white light, 365nm-650nm single wavelength LED light; preferably, the light source for the on-DNA reaction is 13w CFL light, 427nm light and 455nm light.
4. The method according to claim 1, wherein the small molecule compound diselenide represented by formula (II) is present in a molar concentration of 10mM, 50mM, 100mM, 200mM, 500mM, 1M, 1.5M; preferably, the molar concentration of the diselenide of the small molecule compound shown in the formula (II) is 0.5M.
5. The method of claim 1, wherein the reaction temperature is room temperature, 20 ℃, 30 ℃, 40 ℃, 60 ℃, 80 ℃; preferably, the reaction temperature is room temperature.
6. The method of claim 1, wherein the reaction time is 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 16 hours, 20 hours, 24 hours; preferably, the reaction time is 16 hours.
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