CN112851732B - Method for synthesizing On-DNA 2-carboxyl-3-amino arylthiophene compound - Google Patents
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Abstract
The invention relates to a method for synthesizing an On-DNA 2-carboxyl-3-amino arylthiophene compound, which takes an On-DNA ortho-halogen aryl carbonitrile compound and thioglycolic acid/thioglycolic acid ester as raw materials to react in the presence of alkali to obtain the On-DNA 2-carboxyl-3-amino arylthiophene compound. The method has the advantages of wide substrate application range, capability of being carried out in a mixed aqueous phase of an organic solvent/aqueous phase, simple operation, no introduction of a metal reagent, environmental friendliness and suitability for synthesis of a DNA coding compound library by using a porous plate.
Description
Technical Field
The invention belongs to the technical field of coding compound libraries, and particularly relates to a method for synthesizing On-DNA 2-carboxyl-3-amino arylthiophene compounds in the construction of a DNA coding compound library.
Background
In drug development, especially new drug development, high-throughput screening for biological targets is one of the main means for rapidly obtaining lead compounds. However, traditional high throughput screening based on single molecules requires long time, large equipment investment, limited number of library compounds (millions), and the building of compound libraries requires decades of accumulation, limiting the efficiency and possibility of finding lead compounds. The recent emergence of DNA-encoded compound library technologies (WO 2005058479, WO2018166532, CN 103882532), combining combinatorial chemistry and molecular biology technologies, adding a DNA tag to each compound on a molecular level, and being able to synthesize up to one hundred million-class compound libraries in a very short time, is a trend toward the next-generation compound library screening technology, and is beginning to be widely applied in pharmaceutical industry, producing many positive effects (Accounts of Chemical Research,2014,47, 1247-1255).
The DNA coding compound library can rapidly generate a giant compound library through combinatorial chemistry, and can screen out a lead compound with high flux, so that the screening of the lead compound becomes unprecedented rapidness and high efficiency. One of the challenges in constructing libraries of DNA-encoding compounds is the need to synthesize chemically diverse small molecules on DNA in high yields. Because DNA can be kept stable under certain conditions (solvent, pH, temperature and ion concentration), the On-DNA reaction applied to the construction of the DNA coding compound library also needs higher yield. Therefore, the reagent type, reaction type and reaction condition of the chemical reaction (On-DNA reaction for short) carried out On DNA directly influence the richness and selectivity of the DNA coding compound library. Therefore, the development of chemical reactions compatible with DNA is also a long-term research and research direction of the current DNA coding compound library technology, and the application and commercial value of the DNA coding compound library are directly influenced.
The aromatic ring bithiophene compound is an important pharmaceutical compound skeleton structure, and the introduction of the aromatic ring bithiophene skeleton into a DNA coding compound library can further expand the diversity of the compound library and is beneficial to improving the probability of screening effective compounds. However, no method for constructing On-DNA arylthiophene compounds by using On-DNA aryl compounds has been reported. Therefore, it is desirable to develop a new method for synthesizing On-DNA arylthiophene compounds in the construction of DNA coding compound libraries suitable for large-scale multi-well plates, so as to increase the diversity of the DNA coding compound libraries and further improve the application value of the DNA coding compound library technology.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a method for synthesizing On-DNA 2-carboxyl-3-amino arylthiophene compounds, which has mild reaction conditions and simple post-treatment, is suitable for the production of DNA coding compound libraries and can obviously improve the diversity of molecules of the compound libraries.
The technical scheme of the invention is as follows:
a method for synthesizing On-DNA 2-carboxyl-3-amino arylthiophene compounds is characterized in that an On-DNA ortho halogen aryl carbonitrile compound and thioglycolic acid/thioglycolic acetate are used as raw materials and react in the presence of alkali to obtain an On-DNA product; wherein the structural formula of the On-DNA ortho halogen aryl carbonitrile compound is shown as
The structural formula of thioglycolic acid/thioglycolic ester is shown in the specification
The structural formula of the On-DNA product is shown as
Wherein, the DNA in the structural formula comprises a single-stranded or double-stranded nucleotide chain obtained by polymerizing artificially modified and/or unmodified nucleotide monomers, and the nucleotide chain is connected with Ar through one or more chemical bonds or groups; the length of the DNA is 10-200 bp.
Wherein, the DNA in the structural formula is connected with Ar through one chemical bond or a plurality of chemical bonds or groups. When the chemical bond is one, the DNA in the structural formula is directly connected with Ar; multiple chemical bonds mean that the DNA and Ar are connected at intervals of multiple chemical bonds in the structural formula, for example, the DNA and Ar are connected through a methylene (-CH) 2 -) are linked, i.e. linked by two chemical bonds; or the DNA and the Ar are connected with the amino of the DNA through a carbonyl (-CO-) and are also connected through two chemical bonds; or DNA and Ar through a methylene carbonyl group (-CH) 2 CO-) is attached to the amino group of the DNA, again by three consecutive chemical bonds.
Ar is selected from aromatic ring or aromatic heterocyclic ring with the molecular weight less than 1000;
x is selected from fluorine, chlorine, bromine and iodine;
r is selected from hydrogen or a group with molecular weight below 1000 which can be directly connected with an ester oxygen atom.
Preferably, the method comprises the following steps: ar is selected from the following groups:
R 1 is any one or more of hydrogen, halogen, cyano, hydroxyl, carboxyl, amino, alkyl, substituted alkyl and alkoxy, and one or more R can be arranged on Ar 1 Y is any one of O, S, NH or alkyl substituted imino; the alkyl group is C 1 -C 12 Straight or branched alkyl or C 3 -C 8 A cycloalkyl group; the alkoxy is C 1 -C 12 A straight or branched alkoxy group of (a); 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, cyano, carboxyl, phenyl and amino;
r is selected from hydrogen or C 1 -C 12 Linear or branched alkyl.
Further: ar is
R 1 Selected from hydrogen, halogen, C 1 -C 6 Any one or more random combinations of alkoxy groups.
Preferably, the method comprises the following steps: the On-DNA ortho halogen aryl carbonitrile compound is specifically selected from:
x is selected from fluorine, chlorine, bromine and iodine.
A method of synthesizing an On-DNA 2-carboxy-3-aminoarylthiophene compound, the method comprising the steps of: adding mercaptoacetic acid/mercaptoacetic ester with 20-1000 times of molar equivalent and alkali with 20-1000 times of molar equivalent into an On-DNA ortho-halogen aryl carbonitrile compound solution with the molar equivalent of 1 and the molar concentration of 0.1-5 mM in sequence, and reacting at 10-100 ℃ for 0.5-24 hours until the reaction is finished.
Further, the base is selected from sodium borate, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, potassium phosphate, sodium hydrogen phosphate, potassium hydrogen phosphate, N-methylmorpholine, triethylamine, diisopropylethylamine, DBU (1, 8-diazabicycloundecen-7-ene), 4-dimethylaminopyridine, 2, 6-dimethylpyridine or N-methylimidazole; preferably, the base is selected from sodium hydroxide.
Further, the reaction is carried out in a solvent, wherein the solvent is a water-containing mixed solvent of any one or more of water, methanol, ethanol, acetonitrile, dimethyl sulfoxide, DMA (direct memory access), an inorganic salt buffer solution, an organic acid buffer solution and an organic base buffer solution; preferably, the reaction solvent contains a boric acid buffer, DMA.
Further, the pH value of the boric acid buffer solution is 7-11; preferably, the pH is 9.4.
Further, the reaction temperature of the reaction is 10-100 ℃; preferably, the reaction temperature is 20 ℃,30 ℃, 40 ℃, 50 ℃ or 60 ℃.
Further, the reaction time of the reaction is 0.5 to 24 hours; preferably, the reaction time is 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours or 8 hours.
Further, in the method, the molar equivalent of the On-DNA ortho-halogen aryl carbonitrile compound is 1, the molar equivalent of thioglycolic acid/thioglycolate is 20-1000 equivalents, and the molar equivalent of alkali is 20-1000 equivalents; preferably, the molar equivalents of thioglycolic acid/thioglycolate are 20 equivalents, 40 equivalents, 100 equivalents, 200 equivalents, 400 equivalents, 800 equivalents, 1000 equivalents, and the molar equivalents of base are 20 equivalents, 40 equivalents, 100 equivalents, 200 equivalents, 400 equivalents, 800 equivalents, 1000 equivalents.
Furthermore, the feeding sequence of the reaction is that the On-DNA ortho halogen aryl carbonitrile compound is added firstly, then thioglycolic acid/thioglycolic ester is added, and finally alkali is added. Preferably, the reaction base is added in two portions: the reaction was carried out at 30 ℃ for 2 hours after the first addition of 1/3 equivalent of the base, and at 60 ℃ for 2 hours after the second addition of 2/3 equivalent of the base.
Further, the above method is used for multi-well plate operations in batches.
Further, the above method is used for the synthesis of libraries of DNA encoding compounds for multiwell plates.
The method can realize the construction of the On-DNA 2-carboxyl-3-amino arylthiophene in a DNA coding compound library, and can be widely applied to various On-DNA aryl substrates. The method has high yield and single product, can be carried out in the mixed water phase of an organic solvent/water phase, has simple operation, does not introduce metal reagents, is environment-friendly, and is suitable for synthesizing the DNA coding compound library by using a porous plate.
In the preferred embodiment of the invention, the reaction yield is improved and the accuracy of the method applied to library construction of the DNA coding compound is improved by controlling the proportion of reaction raw materials and reagents and the feeding sequence.
Definitions of terms used in relation to the present invention: unless otherwise indicated, the initial definitions provided for by a group or term herein apply to that group or term throughout the specification; for terms not specifically defined herein, the meanings that would be given to them by a person skilled in the art are to be given in light of the disclosure and the context.
"substituted" means that a hydrogen atom in a molecule is replaced with a different atom or molecule.
The minimum and maximum values of the carbon atom content in the hydrocarbon group are indicated by a prefix, e.g. the prefix (Ca-C) b ) Alkyl means any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, C 1 ～C 12 Alkyl refers to a straight or branched chain alkyl group containing 1 to 12 carbon atoms.
Alkyl is a straight or branched chain hydrocarbon radical derived from an alkane molecule by the removal of one hydrogen atom, e.g. methyl-CH 3 Ethyl radical-CH 2 CH 3 (ii) a The alkyl group may also be part of other groups, such as C1-C6 alkoxy, C1-C6 alkylamino.
Cycloalkyl groups: refers to saturated or partially saturated cyclic groups having multiple carbon atoms and no ring heteroatoms and having a single ring or multiple rings, including fused, bridged, and spiro ring systems.
The halogen is fluorine, chlorine, bromine or iodine.
Alkoxy group: means that the alkyl radical is bound to an oxygen atom to form a substituent, e.g. methoxy is-OCH 3 。
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Drawings
FIG. 1: the corresponding conversion rate distribution map of 5 On-DNA 2-carboxyl-3-amino arylthiophene compounds obtained in the embodiment 2 of the invention.
Detailed Description
The raw materials and equipment used in the invention are known products and are obtained by purchasing commercial products.
DMA: n, N-dimethylacetamide.
DNA-NH in the present invention 2 DNA constructs with an-NH 2 linker formed by single-or double-stranded DNA and linker groups, e.g.DNA-NH of "compound1" in WO2005058479 2 And (5) structure. Also for example the following DNA structure:
wherein A is adenine, T is thymine, C is cytosine, and G is guanine.
Example 1 Synthesis of On-DNA 2-carboxy-3-aminobenzothiophene
The On-DNA o-fluorophenylcarbonitrile compound (1) was dissolved in a 250mM boric acid buffer solution having a pH of 9.4 to prepare a 1mM concentration solution (20. Mu.L, 20 nmol), ethyl thioglycolate (100 equivalents, 200mM DMA solution) and sodium hydroxide (100 equivalents, 1000mM double distilled water solution) were sequentially added to the solution, the mixture was mixed well, reacted at 30 ℃ for 2 hours, then added to the reaction mixture (200 equivalents, 1000mM double distilled water solution), and reacted at 60 ℃ for 2 hours.
And (3) after the reaction is finished, carrying out ethanol precipitation: and adding a 5M sodium chloride solution with the total volume of 10% into the solution after the reaction, then continuously adding absolute ethyl alcohol with the total volume of 3 times of the total volume, after uniformly oscillating, placing the reaction in dry ice for freezing for 2 hours, then centrifuging for half an hour at the rotating speed of 12000rpm, pouring out a supernatant, dissolving the rest precipitate with deionized water to obtain a solution of an On-DNA product, and after quantifying by an enzyme labeling instrument OD (optical density measurement) and sending to LCMS (liquid crystal display system) to confirm that the conversion rate of the reaction is 95%.
Example 2 Synthesis of On-DNA 2-carboxy-3-aminobenzothiophene
5 different On-DNA o-fluorophenylcarbonitrile compounds were dissolved in 250mM boric acid buffer solution having a pH of 9.4 to prepare a 1 mM-concentration solution (20. Mu.L, 20 nmol), ethyl thioglycolate (100 equivalents, 200mM DMA), sodium hydroxide (100 equivalents, 1000mM double distilled water) were sequentially added to the solution, and the mixture was mixed well, reacted at 30 ℃ for 2 hours, further added to the reaction mixture, and reacted at 60 ℃ for 2 hours.
And (3) after the reaction is finished, carrying out ethanol precipitation: and adding a 5M sodium chloride solution accounting for 10% of the total volume of the solution after the reaction, continuously adding absolute ethyl alcohol accounting for 3 times of the total volume of the solution, uniformly oscillating, placing the reaction in dry ice for freezing for 2 hours, centrifuging at 12000rpm for half an hour, pouring out a supernatant, dissolving the rest precipitate with deionized water to obtain a solution of an On-DNA product, quantifying by an enzyme labeling instrument OD, and sending to LCMS to confirm the conversion rate of the reaction.
In conclusion, the On-DNA 2-carboxyl-3-aminobenzothiophene compound can be obtained by controlling the conditions of solvent, temperature, pH and the like in the reaction and reacting the On-DNA o-fluorophenylcarbonitrile compound with thioglycolic acid/thioglycolic ester in the presence of alkali. The method has wide substrate application range, can be carried out in the mixed aqueous phase of an organic solvent/aqueous phase, has simple operation, does not introduce a metal reagent, is environment-friendly, and is suitable for synthesizing a DNA coding compound library by using a porous plate.
Claims (9)
1. A method for synthesizing an On-DNA 2-carboxyl-3-amino arylthiophene compound is characterized in that: the method takes On-DNA ortho halogen aryl formonitrile compound and thioglycolic acid/thioglycolic acetate as raw materials, and the On-DNA product is obtained by reaction in the presence of alkali; wherein, the structural formula of the On-DNA ortho-halogen aryl carbonitrile compound is shown as
The structural formula of thioglycolic acid/thioglycolic ester is shown in the specification
The structural formula of the On-DNA product is shown as
Wherein, the DNA in the structural formula comprises a single-stranded or double-stranded nucleotide chain obtained by polymerizing artificially modified and/or unmodified nucleotide monomers, and the nucleotide chain is connected with Ar through one or more chemical bonds or groups;
x is selected from fluorine;
ar is selected from the following groups:
R 1 is any one or more of hydrogen, halogen, alkyl and alkoxy, and one or more R on Ar 1 The radical(s) is (are),
the alkyl group is C 1 -C 12 Straight or branched alkyl or C 3 -C 8 A cycloalkyl group; the alkoxy is C 1 -C 12 A straight or branched alkoxy group of (a);
r is selected from hydrogen or C 1 -C 12 Linear or branched alkyl of (a);
the method comprises the following steps: dissolving an On-DNA ortho-halogen aryl carbonitrile compound into a boric acid buffer solution with pH =9.4, adding thioglycolic acid/thioglycolate in an amount of 20-1000 times the molar equivalent and alkali in an amount of 20-1000 times the molar equivalent to an On-DNA ortho-halogen aryl carbonitrile compound solution with a molar concentration of 0.1-5 mM and having a molar equivalent of 1, and reacting at 10-100 ℃ for 0.5-24 hours.
2. The method of claim 1, wherein: the base is selected from the group consisting of sodium borate, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, potassium phosphate, sodium hydrogen phosphate, potassium hydrogen phosphate, N-methylmorpholine, triethylamine, diisopropylethylamine, 1, 8-diazabicycloundecen-7-ene, 4-dimethylaminopyridine, 2, 6-dimethylpyridine, and N-methylimidazole.
3. The method of claim 1, wherein: the reaction is carried out in a solvent, and the solvent is one or a mixture of water, methanol, ethanol, acetonitrile, dimethyl sulfoxide, DMA, an inorganic salt buffer solution, an organic acid buffer solution and an organic base buffer solution.
4. The method of claim 1, wherein: the reaction temperature of the reaction is 20 ℃,30 ℃, 40 ℃, 50 ℃ or 60 ℃.
5. The method of claim 1, wherein: the reaction time of the reaction is 0.5 hour, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, or 8 hours.
6. The method of claim 1, wherein: in the method, the molar equivalent of the On-DNA ortho-halogen aryl carbonitrile compound is 1, and the molar equivalents of thioglycolic acid/thioglycolate are 20 equivalents, 40 equivalents, 100 equivalents, 200 equivalents, 400 equivalents, 800 equivalents and 1000 equivalents; the molar equivalent of the base is 20 equivalents, 40 equivalents, 100 equivalents, 200 equivalents, 400 equivalents, 800 equivalents, or 1000 equivalents.
7. The method of claim 1, wherein: the reaction base is added in two times: the reaction was carried out at 30 ℃ for 2 hours after the first addition of 1/3 equivalent of the base, and at 60 ℃ for 2 hours after the second addition of 2/3 equivalent of the base.
8. The method according to any one of claims 1 to 7, wherein the method is used for a batch multi-well plate operation.
9. The method of any one of claims 1 to 7, wherein the method is used for the synthesis of libraries of DNA encoding compounds for multi-well plates.
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