CN110066308B - Synthetic method of On-DNA sulfonamide compound for constructing DNA coding compound library - Google Patents
Synthetic method of On-DNA sulfonamide compound for constructing DNA coding compound library Download PDFInfo
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Abstract
The invention relates to a method for synthesizing an On-DNA sulfonamide compound in the construction of a DNA coding compound library, which takes a DNA amino compound as a substrate and reacts with sulfinate in the presence of halogen or analogues thereof to obtain the On-DNA sulfonamide compound. The method for synthesizing the On-DNA sulfonamide compounds does not need metal participation, has cheap and easily obtained reaction reagents, stable and easily stored raw materials, mild reaction conditions, high yield and good substrate universality, is suitable for synthesizing a DNA coding compound library by using a porous plate, can quickly convert the DNA amino compound library into the DNA sulfonamide compound library through one-step reaction, and can obviously improve the success rate of the synthesis.
Description
Technical Field
The invention belongs to the technical field of DNA coding compound libraries, and particularly relates to a method for preparing On-DNA sulfonamide compounds from DNA amino compounds in a DNA coding compound library.
Background
The teaching of Sydney Brenner and Richard Lerner of the research institute of Scripps, USA, in 1992, proposed the concept of DNA Encoded Library of compounds (DEL) (reference: Proc. Natl. Acad. Sci.,1992,89,5381, U.S. Pat. No. 4,5573905) by linking an organic small molecule agent to a unique sequence of DNA at the molecular level (i.e., DNA labeling of small molecule agents), rapidly constructing a large Library of compounds by two to many cycles using the "combinatorial-resolution" strategy of combinatorial chemistry, in which each compound in the Library consists of residues of a different small organic molecule agent and is labeled with DNA of the corresponding unique base sequence, affinity-screening a very small Library of DNA-encoding compounds with a target, washing away the Library molecules of compounds that are not adsorbed to the target, washing away the remaining Library molecules of compounds that are adsorbed to the target, the concentration of the molecules of the obtained compound library is low, and the molecules are difficult to analyze and identify by a conventional method, but the DNA part in the obtained compound library molecules adsorbed to a target can be copied and amplified by a Polymerase Chain Reaction (PCR) unique to DNA until the obtained DNA quantity can be identified by a DNA sequencer, the sequenced data is decoded by a relation table between an organic small molecule reagent and each specific DNA base sequence which are created when a DNA coding compound library is constructed, so that the organic small molecule reagent corresponding to a specific compound capable of identifying the molecules with potential activity is found, the organic small molecule reagents are combined together by a traditional organic synthesis method to obtain a screened target molecule, and the physiological activity of the target molecule is detected and confirmed.
The method for constructing DNA coding compound Library mainly includes three kinds, the first kind is DNA-guided Chemical Library Synthesis (DTCL) mainly obtained by using DNA template technology from Ensemble corporation in America, the second kind is DNA-Recorded Chemical Library (DRCL) mainly obtained by using DNA marking technology from GSK corporation in America, X-Chem corporation and domestic leader corporation, the third kind is coding Self-assembly molecule Library (ESAC) mainly obtained by Fragment-based drug design (Fragment-based drug discovery, FBDD) technology from Philogen corporation in Switzerland, the method for constructing DNA coding compound Library which is industrially applied in large quantity at present is mainly the second kind, the method is simple to operate and lower in cost, and can quickly obtain a DNA coding compound library containing massive compounds by using a combinatorial chemistry method.
Besides the DNA starting fragment (see the invention patents of the present company: CN201711263372.3, CN201711318894.9), a large number of DNA tags and small organic molecule reagents which can be reacted in a certain order are required. The DNA tag code can be obtained by a computer program (see the present invention: CN201711247220.4), and a primer of a specific DNA base sequence can be obtained by a DNA synthesizer. The small organic molecule reagent can be obtained by screening the obtained reagent list by using a certain computer program (see the invention patent of the company: CN 201810378969.0).
One of the most important works in the field of DEL libraries at present is the development of chemical reactions on DNA, referred to as on-DNA chemistry. Because DNA must be kept stable in a certain aqueous phase, pH, temperature, metal ion concentration and inorganic salt concentration, on-DNA chemical reactions with less DNA damage, better recovery rate and wide substrate adaptability are required for large-scale application in the synthesis of DNA coding compound libraries.
There are more than 50 kinds of On-DNA chemical reactions reported in the prior art, each reaction condition is one kind or more than ten kinds, so that under the same other conditions, the more the kinds of On-DNA chemical reactions are, the more the conditions are, the more the selectivity is in designing the DNA coding compound library, the higher the synthesis success rate of the final DNA coding compound library is, and the more the diversity of the obtained DNA coding compound library is.
TABLE 1 On-DNA chemistry reaction types and specific conditions that can be used for DRCL construction
In the On-DNA chemical reaction, the selection of buffer solution is very important, and we have determined several commonly used buffer solution preparation and quality inspection methods (see the invention patent of the company: CN201811181396.9 for details) and provided several specific On-DNA chemical reactions under the condition of the buffer solution (see the invention patent of the company: CN201811181396.9 for details).
The sulfonamide compound has various biological activities, and the sulfonamide compound and a series of organic compounds derived from the sulfonamide compound have wide application in the aspects of clinical medicines, pesticides, dyes, materials and the like. At present, in the field of DNA coding compound libraries, the main method for synthesizing On-DNA sulfonamide compounds is to directly react On-DNA amino compounds and small-molecule sulfonyl chloride reagents under alkaline conditions (reference: ACS Med. chem.Lett.,2015,919), but because the DNA coding compound libraries are operated in batches, sulfonyl chloride solutions have poor stability and are not easy to store, excessive sulfonyl chloride is not easy to remove and is easy to cause DNA degradation, and the like, in actual production, the small-molecule sulfonyl chloride reagents are used as capping reagents of the DNA coding amino compound libraries, and the preparation of the DNA coding sulfonamide compound libraries by the small-molecule sulfonyl chloride reagents is not ideal.
In order to solve the above problems, it is desirable to develop a method for synthesizing a DNA-encoding compound library, which has the advantages of stable and easily-stored raw materials, mild reaction conditions, high yield, good substrate universality, small DNA damage, and suitability for batch operation using a multi-well plate, and can rapidly convert a DNA-encoding amino compound library into a DNA-encoding sulfonamide compound library through one-step reaction.
Disclosure of Invention
One of the technical problems to be solved by the present invention is to provide an On-DNA amino compound (DNA-NHR) for use in the construction of a library of DNA encoding compounds1Compound) into an On-DNA sulfonamide compound, wherein the structural formula of the prepared On-DNA sulfonamide compound is shown in the specificationShown in the figure: DNA-NR1-SO2-R2；
Wherein, DNA-NHR1Is a single-chain or double-chain nucleotide chain with naked primary amine or secondary amine groups, which is obtained by the polymerization of artificially modified and/or unmodified nucleotide monomers; wherein R is1Hydrogen, alkyl, substituted alkyl, aryl or substituted aryl; wherein alkyl is C1～C20Alkyl groups such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, and the like; the number of the substituent groups of the substituted alkyl is one or more, and the substituent groups of the substituted alkyl are one or more independently selected from halogen, nitro, alkoxy, benzyloxy, vinyl and alkynyl; the number of the substituent groups of the substituted aromatic group is one or more, and the substituent groups of the substituted alkyl group are one or more of the substituent groups which are mutually independent and selected from halogen, nitryl, alkoxy, benzyloxy, vinyl, alkynyl or alkyl, and the like;
wherein, DNA-NR1-SO2-R2R in the structural formula2Is alkyl, substituted alkyl, aryl or substituted aryl; wherein alkyl is C1～C20Alkyl groups such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, and the like; the number of the substituent groups of the substituted alkyl is one or more, and the substituent groups of the substituted alkyl are one or more independently selected from halogen, nitro, alkoxy, benzyloxy, vinyl and alkynyl; the number of the substituent groups of the substituted aromatic group is one or more, and the substituent groups of the substituted alkyl group are one or more independently selected from halogen, nitro, alkoxy, benzyloxy, vinyl, alkynyl or alkyl.
Furthermore, the second technical problem to be solved by the present invention is to provide a DNA-NHR which is stable and easy to store, mild in reaction conditions, simple, convenient and fast, and suitable for mass production of DNA coding compound libraries of multi-well plates1Methods for converting to On-DNA sulfonamides.
In particular to an On-DNA amino compound (DNA-NHR)1Compound) as substrate, sulfinate as raw material, acetonitrile and dimethyl formamideOne or more of dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, ethanol, methanol, tert-butyl alcohol, isopropanol, tetrahydrofuran, 1, 4-dioxane, water, inorganic salt buffer solution (borate, phosphate and carbonate), organic acid buffer solution (acetic acid, HEPES, TAPS and MES) and organic base buffer solution (triethylamine and tris) are used as solvents, and the On-DNA sulfonamide compound is obtained by reacting at 0-100 ℃ for 0.5-24 hours in the presence of halogen or analogues thereof, wherein the specific reaction equation is as follows:
the DNA-NHR1Is a single-chain or double-chain nucleotide chain with naked primary amine or secondary amine obtained by the polymerization of artificially modified and/or unmodified nucleotide monomers; wherein R is1Hydrogen, alkyl, substituted alkyl, aryl or substituted aryl; wherein alkyl is C1～C20Alkyl groups such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, and the like; the substituted alkyl is halogen, nitro, alkoxy, benzyloxy, vinyl, alkynyl and other substituted alkyl, and the number of the substituent groups is one or more; the substituted aryl is aryl with halogen, nitryl, alkoxy, benzyloxy, vinyl, alkynyl or alkyl and other substituents, and the number of the substituents is one or more;
the sulfinate is lithium sulfinate, sodium sulfinate, potassium sulfinate, cesium sulfinate, magnesium sulfinate, calcium sulfinate, aluminum sulfinate, copper sulfinate, iron sulfinate, cobalt sulfinate, nickel sulfinate, copper sulfinate, zinc sulfinate, palladium sulfinate and ruthenium sulfinate; preferably, sodium sulfenate;
wherein, DNA-NR1-SO2-R2R in the structural formula2Is alkyl, substituted alkyl, aryl or substituted aryl. Wherein alkyl is C1～C20Alkyl groups such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, and the like; the substituted alkyl is halogen,Nitro, alkoxy, benzyloxy, vinyl, alkynyl and other substituted alkyl groups, and the number of the substituent groups is one or more; the substituted aryl is halogen, nitryl, alkoxy, benzyloxy, vinyl, alkynyl or alkyl substituted aryl, and the number of the substituted aryl is one or more.
The halogen or the analogue thereof is one or a mixture of more of elementary bromine, elementary iodine, N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, ammonium chloride, ammonium bromide, ammonium iodide, tetrabutylammonium chloride, m-chloroperoxybenzoic acid, tetrabutylammonium bromide, m-chloroperoxybenzoic acid, tetrabutylammonium iodide, m-chloroperoxybenzoic acid, tetrabutylammonium chloride, tert-butyl hydroperoxide, tetrabutylammonium bromide, tert-butyl hydroperoxide, tetrabutylammonium iodide and tert-butyl hydroperoxide; preferably, the halogen or analog thereof is elemental iodine.
Compared with the traditional DNA-NHR, the synthesis method of the On-DNA sulfonamide compound provided by the invention1The method has the advantages of stable and easily-stored reaction raw materials, mild reaction conditions, high yield, high substrate universality and small damage to DNA under the reaction conditions, is suitable for synthesizing a DNA coding compound library by using a porous plate, can quickly convert the DNA amino compound library into the DNA sulfonamide compound library through one-step reaction, and can obviously improve the success rate of synthesizing the DNA sulfonamide compound library.
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FIG. 1 shows DNA-NH of the present invention2And the obtained product is mixed with sodium sulfinate to react to obtain a corresponding On-DNA sulfonamide compound.
FIG. 2 shows DNA-NH of the present invention2The representative structural formula of sodium sulfinate and the yield of the prepared product are obtained by mixing and reacting with sodium sulfinate to obtain the corresponding On-DNA sulfonamide compounds (the yield is based On the area of TIC peak On LCMS-LTQ).
Detailed Description
The technical solutions of the present invention will be described clearly and completely with reference to the accompanying drawings, and it should be understood that the described embodiments are some, but not all embodiments of the present invention. All other embodiments, which can be obtained by a person skilled in the art without any inventive step based on the embodiments of the present invention, are within the scope of the present invention.
In the case of the example 1, the following examples are given,
1) synthesis of On-DNA sulfonamide compounds
Reacting DNA-NH2(for example, the initial head fragment mentioned in patent CN 108070009A) was dissolved in a 250mM boric acid buffer solution with pH 9.5 to prepare a 1mM concentration solution, which was dispensed into 26 wells (10. mu.L, 10nmol,1mM) of a 96-well plate, and then a sodium sulfinate solution (5. mu.L, 1000nmol,200mM in water, 100 equivalents) and an elemental iodine solution (1.25. mu.L, 500nmol,400mM in ethanol, 50 equivalents) were added to each well of the 96-well plate in this order, and the solution was centrifuged, and the mixture was vortexed, centrifuged again, and then the membrane was sealed, and the 96-well plate was reacted at 20 ℃ and 150rpm in a shaker for 16 hours.
Ethanol precipitation after the reaction is finished:
adding a 5M sodium chloride solution with the volume of 10% of the total reaction solution into each hole of a 96-hole plate, sealing a membrane, oscillating and uniformly mixing, adding cold absolute ethyl alcohol with the volume of 3 times of the total volume and stored at the temperature of 20 ℃ below zero, freezing the mixture in a refrigerator at the temperature of 80 ℃ below zero for 2 hours, taking out the mixture, centrifuging the mixture for 30 minutes at the temperature of 4 ℃ by using a centrifugal force of 4000G, sucking and removing a supernatant, dissolving a precipitate in deionized water, freeze-drying the dissolved precipitate to obtain a product, detecting OD (optical density) by using an enzyme labeling instrument to confirm the recovery rate, and detecting LCMS (liquid crystal display system) to confirm the conversion rate of each small molecule.
We have verified a total of 26 sodium sulfites and DNA-NH2The structure and yield of the representative reagent of the On-DNA sulfonamide compound prepared by the reaction in the presence of elemental iodine and sodium sulfinate are shown in figure 2.
In order to expand the diversity of a DNA coding compound library, a sulfonyl chloride micromolecule reagent is used for capping the DNA amino compound library, but the sulfonyl chloride has poor stability, the solution of the sulfonyl chloride is difficult to store, and excessive added sulfonyl chloride has a certain degradation effect on DNA.
In summary, the above embodiments and drawings are only preferred embodiments of the present invention and are not intended to limit the scope of the present invention, and any modifications, equivalent substitutions, improvements and the like made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (12)
1. A method for converting On-DNA amino compounds into On-DNA sulfonamide compounds used in the construction of DNA coding compound libraries, wherein the On-DNA amino compounds have the structural formula: DNA-NHR1The structural formula of the prepared On-DNA sulfonamide compound is shown as follows: DNA-NR1-SO2-R2(ii) a Dissolving an On-DNA amino compound in 250mM boric acid buffer solution with the pH value of 9.5 to the molar concentration of 0.1-5.0 mM, mixing with 10-1000 molar equivalents of sodium sulfinate and 10-1000 molar equivalents of simple substance iodine, and reacting at 0-100 ℃ for 0.5-24 hours until the reaction is finished;
wherein, DNA-NHR1Is a single-chain or double-chain nucleotide chain with primary amino or secondary amino obtained by the polymerization of artificially modified and/or unmodified nucleotide monomers; wherein R is1Hydrogen, alkyl, substituted alkyl, aryl or substituted aryl; wherein alkyl is C1～C20An alkyl group; the number of the substituent groups of the substituted alkyl is one or more, and the substituent groups of the substituted alkyl are one or more independently selected from halogen, nitro, alkoxy, benzyloxy, vinyl and alkynyl; 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 mutually independent and are selected from one or more of halogen, nitryl, alkoxy, benzyloxy, vinyl, alkynyl or alkyl;
wherein, DNA-NR1-SO2-R2R in the structural formula2Is alkyl, substituted alkyl, aryl or substituted aryl; wherein alkyl is C1～C20An alkyl group; getThe number of the substituent groups of the substituted alkyl is one or more, and the substituent groups of the substituted alkyl are one or more independently selected from halogen, nitro, alkoxy, benzyloxy, vinyl and alkynyl; the number of the substituent groups of the substituted aromatic group is one or more, and the substituent groups of the substituted alkyl group are one or more independently selected from halogen, nitro, alkoxy, benzyloxy, vinyl, alkynyl or alkyl.
2. The method according to claim 1, wherein the molar concentration of the On-DNA amino compound after dissolving in the reaction solution is 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 5.0 mM.
3. The method of claim 2, wherein the molar concentration is 1.0 mM.
4. The method of claim 1, wherein the molar equivalent of the sulfinate is 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 equivalents, 900 equivalents, 950 equivalents, or 1000 equivalents.
5. The method of claim 4, wherein the molar equivalent of the sulfinate is 100 equivalents.
6. The method of claim 1, wherein the molar equivalents of elemental iodine are 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 equivalents, 900 equivalents, 950 equivalents, or 1000 equivalents.
7. The method of claim 6, wherein the molar equivalent of elemental iodine is 50 equivalents.
8. The method of claim 1, wherein the reaction temperature is 0 ℃,20 ℃, 25 ℃, 30 ℃, 35 ℃,40 ℃, 45 ℃,50 ℃, 55 ℃, 60 ℃, 65 ℃, 70 ℃, 75 ℃, 80 ℃, 85 ℃, 90 ℃, 95 ℃, or 100 ℃.
9. The method of claim 8, wherein the reaction temperature is 20 ℃.
10. The method of claim 1, wherein the reaction time is 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours.
11. The method of claim 10, wherein the reaction time is 16 hours.
12. The method of claim 1, wherein the method is used for the synthesis of a library of DNA-encoding compounds for multi-well plates.
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| CN113735916B (en) * | 2021-09-17 | 2023-11-14 | 康龙化成(宁波)科技发展有限公司 | Method for converting terminal alkyne into amide and application of method in construction of gene coding library |
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