CN110359097A - The method that On-DNA aromatic compound is obtained by Suzuki coupling reaction in the building of DNA encoding compound library - Google Patents
The method that On-DNA aromatic compound is obtained by Suzuki coupling reaction in the building of DNA encoding compound library Download PDFInfo
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Abstract
The invention discloses the methods that the On-DNA aryl halides in a kind of building of DNA encoding compound library obtain On-DNA aromatic compound by Suzuki coupling reaction with organic trifluoroborate reagent: using On-DNA aryl halides as substrate, in the presence of Pd catalyst, ligand and alkali, is reacted with organic three potassium fluoborates reagent and On-DNA aromatic compound is made.Reaction method provided by the present invention provides new thinking for the functional group conversion of On-DNA aryl halides and nut cap method, the diversity of the DNA encoding compound library of On-DNA aryl halides can be dramatically increased, the reaction method yield is high, substrate universality is wide, mild condition, it is easy to operate, it is suitable for the synthesis of the DNA encoding compound library of porous plate progress.
Description
Technical field
The invention belongs to DNA encoding compound library technical fields, and in particular in a kind of building of DNA encoding compound library
The method that On-DNA virtue halogen and three potassium fluoborate class reagents obtain On-DNA aromatic compound by Suzuki coupling reaction.
Background technique
U.S. Scripps graduate Sydney Brenner and Richard Lerner professor proposed in 1992
DNA encoding compound library (DNA Encoded Library, vehicle economy L) concept (bibliography:
Proc.Natl.Acad.Sci., 1992,89,5381, patent: US5573905), this method is by by a small organic molecule
Reagent and the DNA of one section of unique sequences are attached in molecular level and (carry out DNA marker to small organic agents), utilize combination
" combination-fractionation " strategy of chemistry rapidly constructs the compound library of enormous amount, the compound by two to more circulations
Each compound is made of different small organic molecule reagent residues in library, and is marked by the DNA of corresponding unique base sequence
Know, minimal amount of DNA encoding compound library and target are subjected to affine screening, the compound library molecule not adsorbed with target is first
It is washed off, what is left has the compound library molecule of absorption to elute again with target, the compound library molecular concentration at this moment obtained
Very low, conventional means are difficult to analyze and identify, but polymerase chain reaction (the Polymerase Chain exclusive by DNA
Reaction, abbreviation PCR) there can be the part DNA in the compound library molecule of absorption to carry out duplication expansion with target what is obtained
Increase until obtained amount of DNA can be identified by DNA sequencer, when the data after sequencing pass through building DNA encoding compound library again
Relation table between the small organic molecule reagent of creation and each specific DNA base sequence decodes, and then finds and can identify
With the corresponding small organic molecule reagent of the corresponding particular compound of potential activity molecule, we pass through traditional organic conjunction again
These small organic molecule reagents are combined the target molecule screened at method, then detects and confirms it to target
Physiological activity.
There are mainly three types of the construction methods of DNA encoding compound library, the first is sharp based on Ensemble company, the U.S.
DNA guide molecule library (DNA-Templated Chemical Library Synthesis, the letter obtained with DNA mould plate technique
Claim DTCL), it is for second that DNA marker skill is utilized based on X-Chem company and domestic Chengdu guide company with GSK company, the U.S.
The DNA that art obtains records library of molecules (DNA-Recorded Chemical Library, abbreviation DRCL), the third is with Switzerland
Drug based on Philogen company based on segment designs (Fragment-based drug discovery, abbreviation FBDD) skill
Coding self assembly molecule library (Encoded Self-Assembling Chemical Libraries, the abbreviation that art obtains
ESAC), at present industrially by largely with the method for building DNA encoding compound library be mainly second, this method operation
Simply, cost is lower, can obtain the DNA encoding compound of the compound containing magnanimity using combinational chemistry more quickly
Library.
In addition to DNA Start Fragment (being detailed in our company's patent of invention: CN201711263372.3, CN201711318894.9)
Outside, the small organic molecule reagent that needs a large amount of DNA label and can be reacted according to certain sequence.The volume of DNA label
Code can be obtained by certain computer program and (be detailed in our company's patent of invention: CN201711247220.4), then be passed through
DNA synthesizer obtains the primer of specific DNA base sequence.Certain calculating can be used in the acquisition of small organic molecule reagent
Machine program to the reagent inventory of acquisition is screened to obtain and (be detailed in our company's patent of invention: CN201810378969.0).
The most important work at present of the library DEL field first is that the exploitation chemically reacted on DNA, abbreviation On-DNA chemistry is anti-
It answers.Because DNA must just be able to maintain stabilization in certain water phase, under pH, temperature, concentration of metal ions and inorganic salt concentration,
Therefore, small to DNA damage, have the On-DNA of the preferable rate of recovery and substrate wide adaptability chemical reaction, be only large-scale application
Required for the synthesis of DNA encoding compound library.The On-DNA chemical reaction type of open report has more than 50 kinds, every kind at present
Reaction condition it is few then a kind of, it is how then ten several, it may be said that in the case where other situations are the same, On-DNA chemical reaction
Type is more, and condition is abundanter, and the selectivity in the design of DNA encoding compound library is just more, the synthesis success in final library
Rate is just higher, and the diversity in obtained library is just abundanter.
Table 1 can be used for the On-DNA chemical reaction type and actual conditions of DRCL building
In On-DNA chemical reaction, the selection of buffer is particularly significant, we determined that several common buffers
Preparation and quality detecting method (being detailed in our company's patent of invention: CN201811181396.9), and provide under the buffer conditions
Several specific On-DNA chemical reactions (be detailed in our company's patent of invention: CN201811181396.9,
CN201811546746.7)。
There is most-often used bonding chemical reaction in DNA encoding compound library building at present: formed amido bond reaction, other
The nut cap reaction (reduction amination, substitution, the formation of (sulphur) urea, formation, the sulfonylation of carbamate etc.) of amine, Suzuki are even
Connection reaction, Buchwald coupling reaction, Click reaction etc. (bibliography: Angew.Chem.Int.Ed., 2019,58,
10.1002/anie.201902489).Wherein, Suzuki coupling reaction is mild with reaction condition, functional group tolerance is high, ginseng
With the boric acid or borate ester small organic agents type reacted it is more, stablize and be easy to get, be easy to the advantages that storing, be current DNA encoding
One of the coupling reaction being most widely used in compound library synthesis.
What disclosure was reported at present is suitable for On-DNA Suzuki coupling reaction used in the synthesis of DNA encoding compound library
There are mainly four types of conditions: Ding of GSK company etc. uses Pd (PPh in report in 20153)4And Na2CO3In 80 DEG C in water phase
Under the conditions of be catalyzed the Suzuki-Miyaura coupling reaction that On-DNA aryl bromide or iodide are reacted with aryl boric acid or borate
(bibliography: ACS.Med.Chem.Lett., 2015,6,919；ACS Comb.Sci., 2015,17,1-4), Roche company
Satz etc. use Pd (OAc) in report in 20152, TPPTS and Na2CO3On-DNA is catalyzed under the conditions of 65 DEG C in water phase
Suzuki-Miyaura coupling reaction that aryl iodide is reacted with aryl boric acid or borate (bibliography:
Bioconjugate Chem., 2015,26,1623-1632), Ding of GSK company etc. report in 2016 using POPd,
SSPhos and KOH is catalyzed On-DNA aryl chloride under the conditions of 80-100 DEG C in water phase and reacts with aryl boric acid or borate
Suzuki-Miyaura coupling reaction (bibliography: Bioconjugate Chem., 2016,27,2597), Baylor College Medicine
Li et al. report in 2018 using sSPhos-Pd-G2 pre-catalyst and CsOH in water phase in 80 DEG C in a short time
Suzuki-Miyaura coupling reaction (the ginseng that catalysis On-DNA aryl chloride, bromine or iodine compound are reacted with aryl boric acid or borate
Examine document: Bioconjugate Chem., 2018,29,3841-3846).
But the above On-DNA Suzuki coupling reaction is both for aryl boric acid or borate, obtained product master
If On-DNA biaryl cyclics, when these methods are applied to alkyl/alkylene/alkynes ylboronic acid or borate, yield
Lower, substrate applicability is also limited, and main cause may be that this kind of boric acid or boronate reagent are unstable, apt to deteriorate.
It is as above in order to solve the problems, such as, it is intended that develop it is a kind of it is easy, quick, can be by the halogen of On-DNA aryl halides
Plain functional group converted in-situ be other non-aromatic ring class functional groups method, so as to can rapid expansion DNA encoding compound library it is more
Sample, and adapt to the demand of the DNA encoding compound library production of high-volume porous plate.And trifluoroborate class reagent can pass through
Alleviate as stable, protected form boric acid hydro carbons boric acid or borate such issues that, and in small organic agents
Suzuki coupling reaction field obtains wide application, and therefore, our research is with three potassium fluoborate salt reagents and On-DNA
Aryl halides Suzuki coupling reaction be starting point.
Summary of the invention
The first technical problem to be solved by the present invention is to provide a kind of in the building of DNA encoding compound library
Participated in by three potassium fluoborates, On-DNA aryl halides are the Suzuki coupling reaction of substrate.Wherein, the On-DNA aryl
The structural formula of halides are as follows: DNA-Ar-X, the structural formula of three potassium fluoborate of hydro carbons are as follows: R-BF3K；
Wherein, the DNA in structural formula is the list by polymerizeing through manually modified and/or unmodified nucleotide monomer
The nucleotide chain of chain or double-strand；X is chlorine, bromine or iodine；
Wherein, the Ar in structural formula is monocycle or bicyclic aromatic rings；X in the On-DNA aryl halides is connected to
On the ring of Ar；
Wherein, the DNA in structural formula and Ar is keyed by a chemical bond or multiple chemistry.When one chemical bond, it is
Refer to that the DNA and Ar in structural formula is connected directly；When multiple chemical bonds, refers to and be spaced multiple chemistry between DNA and Ar in structural formula
Key is connected, for example, passing through a methylene (- CH between DNA and Ar2) be connected, that is, pass through two chemistry key connections；Or DNA with
Ar connects the amino of DNA by a carbonyl (- CO-), and passes through two chemistry key connections；Or DNA and Ar passes through an Asia
Methyl carbonyl (- CH2CO- the amino for) connecting DNA is by three continuous chemistry key connections.
Specifically, Ar can be selected from following group:
R1For hydrogen, halogen, amino, nitro, cyano, hydroxyl, sulfydryl, aryl ketone, alkylphenones, C1-C12Alkyl, C1-
C6Alkylene, C1-C6Alkynes base, C3-C8Naphthenic base, C1-C6Alkyl oxy, C1-C6Any one in alkyl amino is to a variety of
Random combine, Ar is upper can one or more R1Group；R2For the functional group for connecting the part DNA, specifically one can be with
The functional group of functional group complementary interaction on DNA can be amino, carboxyl, aldehyde radical, any one in fragrant halogen, R2It can be straight
It connects and is connected with Ar, multiple chemical bonds can also be spaced and be connected；Y is any one in O, S, NH or alkyl-substituted amino.
Wherein, three potassium fluoborate R-BF3K be commercially, or pass through R-B (OH)2With KHF2Fabricated in situ；
R is aldehyde radical, carboxyl, ester group, azido, hydroxyl, amino, nitro, C1-C6Alkyl, C1-C6Alkylene, C1-C6Alkynes
Base, C3-C8Naphthenic base, aryl ketone, any one in alkylphenones are to a variety of random combines.
The second technical problem to be solved by the present invention, being to provide one kind can be by On-DNA aryl halides in-situ transesterification
The method for turning to On-DNA aromatic compound.
Using On-DNA aryl halides as raw material, with acetonitrile, dimethylformamide, dimethyl acetamide, N- methylpyrrole
Alkanone, dimethyl sulfoxide, methanol, ethyl alcohol, the tert-butyl alcohol, isopropanol, tetrahydrofuran, 1,4- dioxane, water, inorganic salt buffer
Liquid, organic acid buffer liquid, any one in organic base buffer or several are solvent, in the presence of palladium catalyst and ligand
Under, it is reacted 0.5~24 hour under conditions of 20~100 DEG C with three potassium fluoborate reagents and alkali, specific reaction equation is as follows:
The On-DNA aryl halides are On-DNA aryl chloride complex, On-DNA aryl bromo-derivative, On-DNA aryl
Iodo object；It preferably, is On-DNA aryl bromo-derivative；
The palladium catalyst is palladium chloride, palladium bromide, palladium iodide, bis- (acetonitrile) palladium chlorides, ethylenediamine palladium chloride, trifluoro
Acid chloride, acid chloride, palladium sulfate, palladium nitrate, dipropionic acid palladium, palladium acetylacetonate, hexafluoroacetylacetone palladium, dichloro (norborneol two
Alkene) palladium, (1,5- cyclo-octadiene) palladium chloride, dichloro (N, N, N, N- tetramethylethylenediamine) palladium, dichloro (1,10- phenanthroline)
Palladium, bis- (dibenzalacetone) palladiums, tris(dibenzylideneacetone) dipalladium, four (acetonitrile) two (trifluoromethanesulfonic acid) palladiums, four (triphenyls
Phosphine) palladium, four (tri-o-tolyl phosphine) palladiums, triphenylphosphine palladium acetate, bis- (three-o- toluene phosphorus) palladiums, bis- [1,2- bis- (diphenylphosphines)
Ethane] palladium, bis- (tri-tert-butylphosphine) palladiums, bis- (di-t-butyl phosphinoso) palladiums of dihydro dichloro, bis- (triphenylphosphine) palladium chlorides,
(bis- (diphenylphosphine) propane of 1,3-) palladium chloride, [bis- (diphenylphosphine) ferrocene of 1,1'-] palladium chloride, the [bis- (hexichol of 1,1'-
Base phosphine) ferrocene] palladium chloride dichloromethane complex, bis- (tri-tert-butylphosphine) two palladiums of dibromo, the bis- (di-t-butyls of 1,1'-
Phosphine) ferrocene palladium chloride, one or more of bis- (tricyclohexyl phosphine) palladium chlorides mixture；Preferably, the palladium
Catalyst is acid chloride.
The ligand is triphenylphosphine, three [bis- (trifluoromethyl) phenyl of 3,4-] phosphines, three (4- fluorophenyl) phosphines, three (3- bromines
Phenyl) phosphine, three (2- methoxyphenyl) phosphines, three (4- methoxyl group -3,5- xylyl) phosphines, three (4- dimethylamino phenyl) phosphines,
Three (4- chlorphenyl) phosphines, three (3- chlorphenyl) phosphines, triphenylphosphine -3,3,3- trisulfonic acid trisodium salt, three (2,5- xylyl) phosphines,
Three p-methylphenyl phosphines, 4- diphenylphosphine benzoic acid, 2- diphenylphosphine benzoic acid, diphenyl (o-methoxyphenyl) phosphine, 4- hexichol
Base phosphino- benzene sulfonic acid sodium salt, 4- (dimethylamino) triphenylphosphine, 3- diphenylphosphine fluorobenzene, 2- diphenylphosphino cyanophenyl, bis- (4- methoxies
Base phenyl) Phenylphosphine, bis- (p- sulfonyl-phenyl) the Phenylphosphine di-potassiums of two hydrations, bis- (3- sulphenyl) (bis--fluoroforms of 3,5-
Base phenyl) phosphonic acids disodium monohydrate, bis- (4- trifluoromethyls) (3- sulphenyl) phosphine, 3- diphenylphosphine benzene sulfonic acid sodium salt two
Bis- (diphenylphosphine) methane of hydrate, 1,1-, bis- (dimethyl phosphine) ethane of 1,2-, bis- (diphenylphosphine) ethane of 1,2-, 1,3- are bis-
Bis- (diphenylphosphine) butane of (diphenylphosphine) propane, 1,4-, bis- (diphenylphosphine) butane of 2,3-, diphenylcyclohexyl phosphine, hexichol
Base oxethyl phosphine, methyldiphenyl base phosphine, ethyl diphenyl phosphine, carboxymethyl group diphenylphosphine, phenyldicyclohexylphosphine, 3,5-dimethylphenyl
Phosphine, di-tert-butyl-phenyl phosphine, 2- (di-t-butyl phosphine) biphenyl, 1,1'- dinaphthalene -2,2'- double diphenyl phosphines, dicyclohexylphosphontetrafluoroborate -2 2-,
4,6- tri isopropyl biphenyl, 2- dicyclohexylphosphontetrafluoroborate -2'- methyl biphenyl, diisopropoxy -1 2- dicyclohexylphosphontetrafluoroborate -2', 6'-,
1'- biphenyl, 2- dicyclohexyl phosphino--o-2', 6'- dimethoxy-biphenyl, tri- isopropyl of 2- di-t-butyl phosphino- -2', 4', 6'-
Base biphenyl, 2- di-t-butyl phosphino- -2'- methyl biphenyl, 2- di-t-butyl phosphino- -2'- (N, N- dimethylamino) biphenyl,
2- dicyclohexyl phosphino--o-2'- (N, N- dimethylamino) biphenyl, 2- (di-t-butyl phosphino-) biphenyl, 2- diphenylphosphino-
2'- (N, N- dimethylamino) biphenyl, the hydration of 2- dicyclohexylphosphontetrafluoroborate -2,6- diisopropyl -3- sulfonic group -1,1- biphenyl sodium salt
Object, 4- (2,6- Dimethoxyphenyl) -3- (1,1- dimethyl ethyl) -2,3- dihydro -1,3- benzo oxygen phospha cycloheptatriene, 2-
(dicyclohexyl phosphino-) biphenyl, [4- (N, N- dimethylamino) phenyl] di-t-butyl phosphine, three (2- carboxyethyl) phosphines, three (3-
Hydroxypropyl) phosphine, tricyclohexyl phosphine, the bis- diphenylphosphine -9,9- xanthphos of 4,5- or the bis- (di-t-butyls of 1,1'-
Phosphine) one or more of ferrocene mixture, it is preferable that the ligand is dialkyl phosphine biphenyl class ligand；It is highly preferred that
The ligand is 2'- dicyclohexyl phosphino- -2,6- dimethoxy -1,1'- xenyl -3- sulfonic acid sodium hydrate or 4- (2,6- bis-
Methoxyphenyl) -3- (1,1- dimethyl ethyl) -2,3- dihydro -1,3- benzo oxygen phospha cycloheptatriene.
The alkali is Boratex, potassium borate, potassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, sodium acetate, sodium fluoride, fluorination
Potassium, cesium fluoride, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, carbon
The mixture of one or more of sour hydrogen sodium or saleratus；Preferably, the alkali is carbonate.
On-DNA aryl halides in the present invention can be by DNA-NH2It contracts in situ with containing carboxylic acid virtue halogen binary compound
Reaction is closed to be made.
The present invention provides new method for On-DNA Suzuki coupling reaction in the building of DNA encoding compound library, the present invention
Use trifluoroborate class reagent cheap and easy to get, that stability is good as reaction raw materials, reaction condition is mild, easy to operate, can
It, can the aryl halides of On-DNA to be quickly converted to other On-DNA aromatic compounds that can continue nut cap reaction
To quickly increase the diversity of the DNA encoding compound library, it is suitble to the production of the DNA encoding compound library of high-volume porous plate.
Detailed description of the invention
Fig. 1 is method for preparing raw material of the invention, by DNA-NH2Be made On-DNA aryl bromo-derivative chemical equation and
Conversion profile (conversion ratio be subject to the TIC peak area on LCMS-LTQ), wherein ordinate is reagent number, and abscissa is
Conversion ratio section, as 0-30% indicates 0% < conversion ratio≤30%.
Fig. 2 is that present invention On-DNA aryl bromo-derivative is made the chemical equation of On-DNA aryl ethylene compound and turns
Rate distribution (conversion ratio be subject to the TIC peak area on LCMS-LTQ), wherein ordinate is reagent number, and abscissa is to turn
Rate section, as 0-30% indicates 0% < conversion ratio≤30%.
Fig. 3 is the representative that On-DNA aryl ethylene compound is made for two step of carboxylic acid binary compound for aryl bromide of the invention
Structural formula and two-step reaction yield.
Fig. 4 is the two step chemical equations that On-DNA benzylamine compound is made with On-DNA aryl bromo-derivative by the present invention.
Fig. 5 is the conversion ratio point that the boc-protected benzylamine compound of On-DNA is made in present invention On-DNA aryl bromo-derivative
Cloth (conversion ratio be subject to the TIC peak area on LCMS-LTQ), wherein ordinate is reagent number, and abscissa is conversion ratio area
Between, as 0-30% indicates 0% < conversion ratio≤30%.
Specific embodiment
Clear, complete description is carried out to technical solution of the present invention below in conjunction with attached drawing, it is clear that described implementation
Example is a part of the embodiments of the present invention, instead of all the embodiments.Based on the embodiments of the present invention, the common skill in this field
Art personnel every other embodiment obtained without making creative work belongs to the model that the present invention protects
It encloses.
Embodiment 1, the synthesis of On-DNA aryl bromo-derivative
DNA-NH2(such as the starting head segment of patent CN108070009A referred to) is dissolved in 250mM, the boron of pH=9.5
Acid buffer is configured to 1mM strength solution, is dispensed into 96 orifice plates, with bromo aryl carboxyl binary compound (total 569
It is a) use EDCI to react to obtain corresponding On-DNA aryl bromo-derivative and (be abbreviated as condensing agent and s-NHS condensation activator
DNA-Ar-Br, bibliography: Nat.Chem., 2015,7,3,241), this only does ethanol precipitation processing after the reaction was completed, concentration
Reduction reaction (the conversion ratio of the chemical equation and On-DNA aryl bromo-derivative obtained point of next step is directly used in after drying
Cloth is shown in Fig. 1).
We, which amount to, has reacted 589 different bromo aryl carboxyl binary compounds, but in order to reduce first step contracting
The inconsistent influence to second step Suzuki coupling reaction calculation of yield of reaction yield is closed, we only count the 419 of purity > 70%
The subsequent Suzuki coupling reaction yield distribution situation of a On-DNA aryl bromo-derivative.
Embodiment 2, the synthesis of On-DNA aryl olefin compound
Generated in-situ DNA-Ar-Br is redissolved in ultrapure water, is configured to 1mM strength solution, takes out two parts, respectively
Be dispensed into 96 new orifice plates (5 μ L, 5nmol, 1mM aqueous solution), sequentially add vinyl potassium trifluoborate (1.25 μ L, 250
Nmol, 200mM dimethylacetamide solution, 50eq.), and cesium carbonate solution (3.75 μ L, 750nmol, 200mM aqueous solutions, 150
Eq.), centrifugation allows solution to sink to the bottom, and is vortexed and mixes, and after being centrifuged again, replaces nitrogen 3 times, acid chloride (Pd (OAc) is added again2)
It is molten with being pre-mixed for 2'- dicyclohexyl phosphino- -2,6- dimethoxy -1,1'- xenyl -3- sulfonic acid sodium hydrate (sSPhos)
Liquid (dimethylacetamide solution of 1.5 μ L, volume ratio=2/1,10mM dimethylacetamide solution/40mM, 2eq./
4eq.), it replaces nitrogen 3 times again, sealer, 96 orifice plates react 2 hours (Gai Wen: 100 DEG C) in PCR instrument at 80 DEG C.
Palladium removing: after completion of the reaction, sodium diethyldithiocarbamate solution (3.0 μ are added into each hole of 96 orifice plates
L, 300 nmol, 100mM aqueous solution, 60eq.), centrifugation allows solution to sink to the bottom, and is vortexed and mixes, and after being centrifuged again, 96 orifice plates are in PCR
It is reacted at 80 DEG C 30 minutes (Gai Wen: 105 DEG C) in instrument, end of reaction, a large amount of precipitatings is generated, with the centrifugal force 5 of 4000G
Minute, supernatant is transferred in 96 new orifice plates and carries out ethanol precipitation.
Ethanol precipitation: the 5M sodium chloride solution of reaction solution volume 10%, sealer being added to each hole of 96 orifice plates, and oscillation mixes
After even, be added 3 times of total volume -20 DEG C store cold dehydrated alcohol, in -80 DEG C refrigerator freezing 2 hours, taken out later 4
DEG C with centrifugal force 30 minutes of 4000G, supernatant is absorbed, in -40 DEG C of vacuum freeze-dryings after precipitating deionized water dissolving, obtain
To product, OD is detected by microplate reader and confirms the rate of recovery, while detecting the conversion ratio that LC-MS confirms each small molecule.
The On-DNA aryl bromo-derivative of purity > 70% is converted into On-DNA aryl ethylene compound, and > 50% conversion ratio reaches
To 77% (see Fig. 2), substrate universality is fine, and part representative structure formula is shown in Fig. 3.Obtained On-DNA aryl ethylene compound
Heck reaction, Michale addition, Diels-Alder cycloaddition etc. can be directly used to react as nut cap, compared to original
(Suzuki coupling reaction, Sonogashira coupling reaction, Heck coupling are anti-for the nut cap reaction that On-DNA aryl halides carry out
Answer, Buchwald coupling reaction, Ullmann coupling reaction) the word bank synthesis that carries out, word bank number can increase by 60%, can be with
Dramatically increase the diversity of the DNA encoding compound library.
With the method for the present embodiment, the three potassium fluoborate salt containing alkynes base can be used, as trimethyl silane is protected
Three potassium fluoborate of acetenyl is reacted with On-DNA aryl halides, obtains On-DNA aryl ethane based compound, such compound
The reactions such as Click reaction, Sonogashira coupling, Michale addition can be used to react as nut cap, can also significantly increase
Add the diversity of the DNA encoding compound library.
Embodiment 3, the synthesis of On-DNA benzylamine compound
Into 96 orifice plates, DNA-Ar-Br (5 μ L, 5nmol, 1mM aqueous solution), sequentially adds N-Boc- amino methyl trifluoro boron
Sour potassium (3.75 μ L, 750nmol, 200mM dimethylacetamide solutions, 150eq.), solution of potassium carbonate (7.5 μ L, 1500nmol,
200mM aqueous solution, 300eq.), centrifugation allows solution to sink to the bottom, and is vortexed and mixes, and after being centrifuged again, replaces nitrogen 3 times, second is added again
Sour palladium (Pd (OAc)2) and 4- (2,6- Dimethoxyphenyl) -3- (1,1- dimethyl ethyl) -2,3- dihydro -1,3- benzo oxygen phosphorus
(5.0 μ L, volume ratio=1/1,10mM dimethyl acetamide are molten for the solution that is pre-mixed of heterocycle heptantriene (rac-BI-DIME)
Liquid/40 mM dimethylacetamide solution, 5eq./20eq.), it replaces nitrogen 3 times again, sealer, 96 orifice plates are in PCR instrument
It is reacted at 95 DEG C 2 hours (Gai Wen: 105 DEG C).
After completion of the reaction, into each hole of 96 orifice plates be added sodium diethyldithiocarbamate solution (3.0 μ L,
300nmol, 100mM aqueous solution, 60eq.), centrifugation allows solution to sink to the bottom, and is vortexed and mixes, and after being centrifuged again, 96 orifice plates are in PCR instrument
It is reacted at 80 DEG C 30 minutes (Gai Wen: 105 DEG C) in device, end of reaction, a large amount of precipitatings is generated, with the centrifugal force 5 of 4000G
Minute, supernatant is transferred in 96 new orifice plates and carries out ethanol precipitation.
The boc-protected benzylamine compound of obtained On-DNA is dissolved in the aqueous solution that ultrapure water is configured to 1mM, then to each
NaOAc aqueous solution (5 μ L, 75mM aqueous solutions, 75eq.) and MgCl are added in hole2Aqueous solution (2.5 μ L, 1mM aqueous solutions, 0.5
Eq.), centrifugation allows solution to sink to the bottom, and is vortexed and mixes, and after being centrifuged again, sealer, reaction 16 is small at 90 DEG C in PCR instrument for 96 orifice plates
When (Gai Wen: 105 DEG C), ethanol precipitation obtains target product.
The On-DNA aryl bromo-derivative of purity > 70% is converted into On-DNA Boc benzylamine compound, and > 50% conversion ratio reaches
On-DNA benzylamine compound, > 50% conversion are obtained after further removing tertbutyloxycarbonyl protecting group to 55% (see Fig. 4)
Rate reaches 49% (see Fig. 4), and the substrate universality of reaction is good, and part representative structure formula is shown in Fig. 5.Obtained On-DNA benzylamine chemical combination
Object can be used the common nut cap method in DNA amino coded compounds library (amidation, reduction amination, at urea, at thiocarbamide, amino
Formic acid esters formation, substitution, sulfonylation, Michale addition etc.) synthesis that carries out corresponding word bank, compared to original On-DNA virtue
Base halides carry out nut cap reaction (Suzuki coupling reaction, Sonogashira coupling reaction, Heck coupling reaction,
Buchwald coupling reaction, Ullmann coupling reaction) it synthesizes, word bank number can increase by 160%, can dramatically increase the DNA
The diversity in coded compounds library.
In conclusion the various embodiments described above and attached drawing are only presently preferred embodiments of the present invention, not to limit this
The protection scope of invention, all within the spirits and principles of the present invention, any modification, equivalent substitution, improvement and etc. done all are answered
It is included within the scope of the present invention.
Claims (16)
1. the side for preparing On-DNA aromatic compound by On-DNA aryl halides in a kind of DNA encoding compound library building
Method, which is characterized in that the structural formula of the On-DNA aryl halides are as follows: DNA-Ar-X is urged in the palladium of 1~100 molar equivalent
In the presence of the ligand of agent and 1~100 molar equivalent, molar concentration is the DNA-Ar-X solution of 0.1~5.0mM, 10~1000
It is small that organic three potassium fluoborates reagent of molar equivalent and the alkali of 10~2000 molar equivalents react 0.5~24 at 20~100 DEG C
Shi Zhizhi reaction terminates；
Wherein, the DNA in structural formula be by through polymerize single-stranded of manually modified and/or unmodified nucleotide monomer or
The nucleotide chain of double-strand；X is chlorine, bromine or iodine；
Wherein, the Ar in structural formula is monocycle or bicyclic aromatic rings, and the halogen of the On-DNA aryl halides is connected to Ar
Ring on；
Wherein, the DNA in structural formula and Ar is keyed by one or more chemistry.
2. the method as described in claim 1, which is characterized in that the Ar can be selected from following group:
R1For hydrogen, halogen, amino, nitro, cyano, hydroxyl, sulfydryl, aryl ketone, alkylphenones, C1-C12Alkyl, C1-C6Alkene
Base, C1-C6Alkynes base, C3-C8Naphthenic base, C1-C6Alkyl oxy, C1-C6Any one in alkyl amino is to a variety of random groups
It closes, Ar is upper can one or more R1Group；R2For connect the part DNA functional group, specifically one can on DNA
The functional group of functional group complementary interaction can be amino, carboxyl, aldehyde radical, any one in fragrant halogen, R2Can directly with Ar phase
Even, multiple chemical bonds can also be spaced to be connected；Y is any one in O, S, NH or alkyl-substituted amino.
3. the method as described in claim 1, which is characterized in that the molar concentration of the DNA-Ar-X aqueous solution is 0.1~
5.0mM；Preferably, the molar concentration of the DNA-Ar-X be 0.1mM, 0.2mM, 0.3mM, 0.4mM, 0.5mM, 0.6mM,
0.7mM, 0.8mM, 0.9mM, 1.0mM, 1.5mM, 2.0mM, 2.5mM, 3.0mM, 3.5mM, 4.0mM, 4.5mM or 5.0mM；It is more excellent
Selection of land, the molar concentration of the DNA-Ar-X are 1.0mM.
4. the method as described in claim 1, which is characterized in that the reaction solution is containing acetonitrile, dimethylformamide, diformazan
Yl acetamide, N-Methyl pyrrolidone, dimethyl sulfoxide, methanol, ethyl alcohol, the tert-butyl alcohol, isopropanol, tetrahydrofuran, 1,4- dioxy
Six rings, inorganic salt buffer, organic acid buffer liquid, any one or a few the aqueous mixing in organic base buffer are molten
Agent, and the content of water is not less than 20% in end reaction liquid；Preferably, the DNA-Ar-X is dissolved in water, inorganic salt buffer, has
Machine acid buffer or organic base buffer.
5. the method as described in claim 1, which is characterized in that the palladium catalyst is palladium chloride, palladium bromide, palladium iodide, double
(acetonitrile) palladium chloride, ethylenediamine palladium chloride, palladium trifluoroacetate, acid chloride, palladium sulfate, palladium nitrate, dipropionic acid palladium, acetylacetone,2,4-pentanedione
Palladium, hexafluoroacetylacetone palladium, dichloro (norbornadiene) palladium, (1,5- cyclo-octadiene) palladium chloride, dichloro (N, N, N, N- tetramethyl
Base ethylenediamine) palladium, dichloro (1,10- phenanthroline) palladium, bis- (dibenzalacetone) palladiums, tris(dibenzylideneacetone) dipalladium, four (second
Nitrile) two (trifluoromethanesulfonic acid) palladiums, tetrakis triphenylphosphine palladium, four (tri-o-tolyl phosphine) palladiums, triphenylphosphine palladium acetate, bis- (three-o-
Toluene phosphorus) palladium, bis- [bis- (diphenylphosphine) ethane of 1,2-] palladiums, bis- (tri-tert-butylphosphine) palladiums, bis- (the di-t-butyl hydroxyl Asias of dihydro dichloro
Phosphino-) palladium, bis- (triphenylphosphine) palladium chlorides, (bis- (diphenylphosphine) propane of 1,3-) palladium chloride, [1,1'- bis- (diphenylphosphines)
Ferrocene] palladium chloride, [bis- (diphenylphosphine) ferrocene of 1,1'-] palladium chloride dichloromethane complex, bis- (the three tertiary fourths of dibromo
Base phosphine) two palladiums, bis- (di-t-butyl phosphine) the ferrocene palladium chlorides of 1,1'-, one of bis- (tricyclohexyl phosphine) palladium chlorides or
Several mixtures；Preferably, the palladium catalyst is acid chloride.
6. the method as described in claim 1, which is characterized in that the molar equivalent of the palladium catalyst is 1~100 equivalent；It is excellent
Choosing, the molar equivalent of the palladium catalyst be 1 equivalent, 2 equivalents, 3 equivalents, 4 equivalents, 5 equivalents, 6 equivalents, 7 equivalents, 8 equivalents,
9 equivalents, 10 equivalents, 20 equivalents, 30 equivalents, 40 equivalents, 50 equivalents, 60 equivalents, 70 equivalents, 80 equivalents, 90 equivalents or 100 are worked as
Amount.
7. the method as described in claim 1, which is characterized in that the ligand is triphenylphosphine, three [3,4- bis- (trifluoromethyls)
Phenyl] phosphine, three (4- fluorophenyl) phosphines, three (3- bromophenyl) phosphines, three (2- methoxyphenyl) phosphines, three (4- methoxyl group -3,5- diformazans
Phenyl) phosphine, three (4- dimethylamino phenyl) phosphines, three (4- chlorphenyl) phosphines, three (3- chlorphenyl) phosphines, triphenylphosphine -3,3,3- three
Sulfonic acid trisodium salt, three (2,5- xylyl) phosphines, three p-methylphenyl phosphines, 4- diphenylphosphine benzoic acid, 2- diphenylphosphine benzoic acid,
Diphenyl (o-methoxyphenyl) phosphine, 4- diphenylphosphino benzene sulfonic acid sodium salt, 4- (dimethylamino) triphenylphosphine, 3- diphenylphosphine fluorine
Benzene, 2- diphenylphosphino cyanophenyl, bis- (4- methoxyphenyl) Phenylphosphines, two bis- (p- sulfonyl-phenyl) the Phenylphosphine di-potassiums of hydration,
Bis- (3- sulphenyls) (3,5- di-trifluoromethyl phenyl) phosphonic acids disodium monohydrate, bis- (4- trifluoromethyl) (3- sulfonic acid
Phenyl) phosphine, 3- diphenylphosphine benzene sulfonic acid sodium salt dihydrate, bis- (diphenylphosphine) methane of 1,1-, bis- (dimethyl phosphine) ethane of 1,2-,
Bis- (diphenylphosphine) ethane of 1,2-, bis- (diphenylphosphine) propane of 1,3-, bis- (diphenylphosphine) butane of 1,4-, the bis- (diphenyl of 2,3-
Phosphine) butane, diphenylcyclohexyl phosphine, hexichol base oxethyl phosphine, methyldiphenyl base phosphine, ethyl diphenyl phosphine, carboxymethyl group diphenyl
Phosphine, phenyldicyclohexylphosphine, dimethylphenylphosphine, di-tert-butyl-phenyl phosphine, 2- (di-t-butyl phosphine) biphenyl, dinaphthalene -2 1,1'-,
The bis- diphenyl phosphines of 2'-, 2- dicyclohexylphosphontetrafluoroborate -2,4,6- tri isopropyl biphenyl, 2- dicyclohexylphosphontetrafluoroborate -2'- methyl biphenyl, bis- hexamethylene of 2-
Base phosphine -2', 6'- diisopropoxy -1,1'- biphenyl, 2- dicyclohexyl phosphino--o-2', 6'- dimethoxy-biphenyl, 2- bis--tertiary fourth
Base phosphino- -2', 4', 6'- tri isopropyl biphenyl, 2- di-t-butyl phosphino- -2'- methyl biphenyl, 2- di-t-butyl phosphino- -2'-
(N, N- dimethylamino) biphenyl, 2- dicyclohexyl phosphino--o-2'- (N, N- dimethylamino) biphenyl, 2- (di-t-butyl phosphine
Base) biphenyl, 2- diphenylphosphino -2'- (N, N- dimethylamino) biphenyl, 2- dicyclohexylphosphontetrafluoroborate -2,6- diisopropyl -3- sulfonic acid
Base -1,1- biphenyl sodium salt hydrate, 4- (2,6- Dimethoxyphenyl) -3- (1,1- dimethyl ethyl) -2,3- dihydro -1,3- benzene
And oxygen phospha cycloheptatriene, 2- (dicyclohexyl phosphino-) biphenyl, [4- (N, N- dimethylamino) phenyl] di-t-butyl phosphine, three
(2- carboxyethyl) phosphine, three (3- hydroxypropyl) phosphines, tricyclohexyl phosphine, the bis- diphenylphosphine -9,9- xanthphos of 4,5- or
The mixture of one or more of bis- (di-t-butyl phosphine) ferrocene of 1,1'-；Preferably, the ligand is dialkyl phosphine biphenyl
Class ligand.
8. the method as described in claim 1, which is characterized in that the molar equivalent of the ligand is 1~100 equivalent；Preferably,
The molar equivalent of the ligand is 1 equivalent, 2 equivalents, 3 equivalents, 4 equivalents, 5 equivalents, 6 equivalents, 7 equivalents, 8 equivalents, 9 equivalents, 10
Equivalent, 20 equivalents, 30 equivalents, 40 equivalents, 50 equivalents, 60 equivalents, 70 equivalents, 80 equivalents, 90 equivalents or 100 equivalents.
9. the method as described in claim 1, which is characterized in that the three potassium fluoborates agent structure formula is R-BF3K, R are aldehyde
Base, carboxyl, ester group, azido, hydroxyl, amino, nitro, C1-C6Alkyl, C1-C6Alkylene, C1-C6Alkynes base, C3-C8Cycloalkanes
Base, aryl ketone, C1-C6Any one in alkylphenones is to a variety of random combines.
10. the method as described in claim 1, which is characterized in that the molar equivalent of the three potassium fluoborates reagent is 10~
1000 equivalents；Preferably, the equivalent of the three potassium fluoborates reagent be 10 equivalents, 20 equivalents, 30 equivalents, 40 equivalents, 50 equivalents,
60 equivalents, 70 equivalents, 80 equivalents, 90 equivalents, 100 equivalents, 150 equivalents, 200 equivalents, 250 equivalents, 300 equivalents, 350 equivalents,
400 equivalents, 450 equivalents, 500 equivalents, 550 equivalents, 600 equivalents, 650 equivalents, 700 equivalents, 750 equivalents, 800 equivalents, 850 are worked as
Amount, 900 equivalents, 950 equivalents or 1000 equivalents.
11. the method as described in claim 1, which is characterized in that the alkali is Boratex, potassium borate, potassium phosphate, biphosphate
Potassium, dipotassium hydrogen phosphate, sodium acetate, sodium fluoride, potassium fluoride, cesium fluoride, lithium hydroxide, sodium hydroxide, potassium hydroxide, hydroxide
The mixture of one or more of caesium, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate or saleratus；It is preferred that
Ground, the alkali are carbonate.
12. the method as described in claim 1, which is characterized in that the molar equivalent of the alkali is 10~2000 equivalents；It is preferred that
, the equivalent of the palladium catalyst is 10 equivalents, 20 equivalents, 30 equivalents, 40 equivalents, 50 equivalents, 60 equivalents, 70 equivalents, 80 works as
Amount, 90 equivalents, 100 equivalents, 200 equivalents, 300 equivalents, 400 equivalents, 500 equivalents, 600 equivalents, 700 equivalents, 800 equivalents, 900
Equivalent, 1000 equivalents, 1100 equivalents, 1200 equivalents, 1300 equivalents, 1400 equivalents, 1500 equivalents, 1600 equivalents, 1700 equivalents,
1800 equivalents, 1900 equivalents or 2000 equivalents.
13. the method as described in claim 1, which is characterized in that the reaction temperature of the reaction is 20~100 DEG C；Preferably,
The reaction temperature of the reaction is 20 DEG C, 25 DEG C, 30 DEG C, 35 DEG C, 40 DEG C, 45 DEG C, 50 DEG C, 55 DEG C, 60 DEG C, 65 DEG C, 70 DEG C, 75
DEG C, 80 DEG C, 85 DEG C, 90 DEG C, 95 DEG C or 100 DEG C.
14. the method as described in claim 1, which is characterized in that the reaction time of the reaction is 0.5~24 hour；It is preferred that
Ground, reaction time of the reaction is 0.5 hour, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, it is 8 small
When, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, it is 19 small
When, 20 hours, 21 hours, 22 hours, 23 hours or 24 hours；It is highly preferred that the reaction time of the reaction is 2 hours.
15. the method as described in claim 1, which is characterized in that porous plate of the method for batch operates；Preferably,
Synthesis of the method for the DNA encoding compound library of porous plate.
16. the method as described in claim 1, which is characterized in that the three potassium fluoborates class reagent is commercially, or to pass through
Corresponding boric acid and KHF2It is generated in-situ.
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