CN112920246A - Method for synthesizing On-DNA1, 4-thiazepine compound - Google Patents
Method for synthesizing On-DNA1, 4-thiazepine compound Download PDFInfo
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Abstract
The invention relates to a method for synthesizing an On-DNA1, 4-thiazepine compound, which is characterized in that an On-DNA alpha, beta-unsaturated carbonyl compound reacts with an o-mercaptoamine compound to obtain an On-DNA product. The reaction method can be carried out in the mixed aqueous phase of an organic solvent/aqueous phase, is simple to operate, does not introduce a metal reagent, is environment-friendly, and is suitable for synthesizing 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 an On-DNA1, 4-thiazepine compound 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 discovery of lead compounds. The recent DNA-encoded compound library technologies (WO2005058479, WO2018166532, CN103882532) combine the technologies of combinatorial chemistry and molecular biology, add a DNA tag to each compound on the molecular level, and synthesize up to hundred million levels of compound libraries in a very short time, which is a trend of the next generation compound library screening technology, and begin to be widely applied in the pharmaceutical industry, resulting in many positive effects (Accounts of Chemical Research,2014,47, 1247-.
The DNA coding compound library can rapidly generate a giant compound library through combinatorial chemistry, and can screen out a lead compound with high flux, so that the screening of the lead compound becomes unprecedented rapidness and high efficiency. One of the challenges in constructing libraries of DNA-encoding compounds is the need to synthesize chemically diverse small molecules on DNA in high yields. Because DNA can be kept stable under certain conditions (solvent, pH, temperature and ion concentration), the On-DNA reaction applied to the construction of the DNA coding compound library also needs higher yield. Therefore, the reagent type, reaction type and reaction condition of the chemical reaction (On-DNA reaction for short) carried out On DNA directly influence the richness and selectivity of the DNA coding compound library. Therefore, the development of chemical reactions compatible with DNA is also a long-term research and research direction of the current DNA coding compound library technology, and the application and commercial value of the DNA coding compound library are directly influenced.
The 1, 4-thiazepine compound is an important medicine compound skeleton structure, and the introduction of the 1, 4-thiazepine compound skeleton into a DNA coding compound library can further expand the diversity of the compound library, and is favorable for improving the probability of screening effective compounds. However, no method for synthesizing the On-DNA1, 4-thiazepine compound by using the On-DNA alpha, beta-unsaturated carbonyl compound is reported at present. Therefore, it is desirable to develop a new method for synthesizing the On-DNA1, 4-thiazepine compound suitable for large-scale multi-well plate operation, so as to increase the diversity of the DNA coding compound library and further improve the application value of the DNA coding compound library technology.
Disclosure of Invention
The invention provides a method for synthesizing a DNA coding compound, which has the advantages of stable storage of raw materials, mild reaction conditions, good substrate universality and small DNA damage and is suitable for batch operation by using a porous plate, and an On-DNA alpha, beta-unsaturated carbonyl compound can be quickly converted into an On-DNA1, 4-thiazepine compound through one-step reaction.
The invention provides a method for synthesizing an On-DNA1, 4-thiazepine compound, which takes an On-DNA alpha, beta-unsaturated carbonyl compound and an o-mercaptoamine compound as raw materials and reacts in the presence of a reducing agent to obtain an On-DNA product; wherein the structural formula of the On-DNA alpha, beta-unsaturated carbonyl compound is shown in the specification
The structural formula of the o-mercaptoamine compound is shown in the specification
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 the rest part in the compound through one or more chemical bonds or groups; the length of the DNA is 10-200 bases.
Wherein, the DNA and R in the structural formula1Or R3Linked by a chemical bond or multiple chemical bonds. When a chemical bond is present, it means DNA and R in the structural formula1Or R3Directly connecting; when multiple chemical bonds are present, they refer to DNA and R in the structural formula1Or R3Are connected with a plurality of chemical bonds at intervals, e.g. DNA andR1or R3Through a methylene group (-CH)2-) are linked, i.e. linked by two chemical bonds; or DNA and R1Or R3The amino group of the DNA is connected with the amino group of the DNA through a carbonyl (-CO-) and is also connected through two chemical bonds; or DNA and R1Or R3Through a methylene carbonyl group (-CH)2CO-) is attached to the amino group of the DNA, again by three consecutive chemical bonds.
R1Selected from the group consisting of groups having a molecular weight of 1000 or less which are directly attached to the DNA and carbonyl carbon atoms or are absent;
R2selected from groups having a molecular weight of 1000 or less directly bonded to an alkenyl carbon atom;
R3selected from the group consisting of groups having a molecular weight of 1000 or less directly attached to the DNA and to the alkenyl carbon atom or are absent;
R4selected from groups having a molecular weight below 1000 directly attached to the carbonyl carbon atom;
R5selected from hydrogen or a group having a molecular weight of 1000 or less directly bonded to an alkenyl carbon atom;
or R5Are each independently of R1、R2、R3Or R4Looping;
R6、R6' is selected from hydrogen or a group having a molecular weight of 1000 or less; or R6、R6' are linked to form optionally substituted cycloalkyl, heterocycle, aromatic ring, aromatic heterocycle having a molecular weight of 1000 or less.
Preferably, R is1、R2、R3、R4Are respectively selected from alkyl, substituted alkyl, carboxyl, 5-10-membered aryl, substituted 5-10-membered aryl, 5-10-membered aromatic heterocyclic group and substituted 5-10-membered aromatic heterocyclic group; wherein the alkyl is C1～C20Alkyl or C3～C8A cycloalkyl group; the number of substituents of the substituted alkyl group is one or more; the substituent of the substituted alkyl is one or more independently selected from halogen, carboxyl, nitro, alkoxy, halogenated phenyl, alkyl phenyl and heterocyclic radical; the number of the substituent(s) for substituting the 5-to 10-membered aryl group is one or more, and the 5-to 10-membered aryl group is substitutedThe substituents are independently selected from halogen, cyano, nitro, carboxyl, alkoxy, C1～C20One or more of alkyl and trifluoromethyl; the number of the substituent(s) for substituting the 5-to 10-membered aromatic heterocyclic group is one or more, and the substituent(s) for substituting the 5-to 10-membered aromatic heterocyclic group are independently selected from the group consisting of halogen, cyano, nitro, carboxyl, alkoxy, C1～C20One or more of alkyl and trifluoromethyl;
the R is5Selected from hydrogen, C1～C20An alkyl group; the R is6、R6' selected from C1～C20An alkyl group; or R6、R6' are linked to form an aromatic ring.
Further on;
said R1Selected from phenyl, thienyl;
said R2Selected from phenyl, substituted phenyl, C1～C6Alkyl, carboxyl, pyridyl, substituted pyridyl, furyl; the substituent of the substituted phenyl is selected from carboxyl and C1～C6Alkoxy, trifluoromethyl, C1～C6An alkyl group; the substituent of the substituted pyridyl is selected from C1～C6Alkyl radical, C1～C6An alkoxy group;
said R3Selected from phenyl, thienyl;
said R4Selected from phenyl, substituted phenyl, C1～C6Alkyl, carboxyl, pyridyl, substituted pyridyl, furyl; the substituent of the substituted phenyl is selected from carboxyl and C1～C6Alkoxy, trifluoromethyl, C1～C6An alkyl group; the substituent of the substituted pyridyl is selected from C1～C6Alkyl radical, C1～C6An alkoxy group;
the R is5Selected from hydrogen, C1～C6An alkyl group; the R is6、R6' selected from C1～C6An alkyl group; or R6、R6The linkage forms a benzene ring. .
The On-DNA alpha, beta-unsaturated carbonyl compound is specifically selected from
The o-mercaptoamine compound is specifically selected from
A method for synthesizing an On-DNA1, 4-thiazepine compound comprises the steps of adding an o-mercaptoamine compound with the molar equivalent of 10-1000 times of the molar equivalent into an On-DNA alpha, beta-unsaturated carbonyl compound solution with the molar equivalent of 1 and the molar concentration of 0.5-5mM, then adding a reducing agent with the molar equivalent of 10-500 times of the molar equivalent, and reacting for 0.5-24 hours at the temperature of 10-100 ℃.
Further, the reducing agent is selected from sodium borohydride, sodium cyanoborohydride or lithium aluminum hydride; preferably, the reducing agent is sodium cyanoborohydride.
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, N-dimethylformamide, N-dimethylacetamide, an inorganic salt buffer solution, an organic acid buffer solution and an organic base buffer solution; preferably, the reaction solvent contains a phosphate buffer.
Furthermore, the pH value of the phosphate buffer solution is 5-7; preferably, the pH is 5.5.
Further, the reaction temperature of the reaction is 10-100 ℃; preferably, the reaction temperature is 20 ℃, 30 ℃, 40 ℃, 50 ℃, 60 ℃, 70 ℃ or 80 ℃.
Further, the reaction time of the reaction is 0.5-24 hours; preferably, the reaction time of the reaction is 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours or 16 hours.
Further, in the method, the molar equivalent of the On-DNA alpha, beta-unsaturated carbonyl compound is 1, and the molar equivalent of the o-mercaptoamine compound is 50 equivalents, 100 equivalents, 200 equivalents, 300 equivalents, 400 equivalents, 500 equivalents, 600 equivalents, 800 equivalents and 1000 equivalents; the molar equivalent of the reducing agent is 20 equivalents, 60 equivalents, 80 equivalents, 100 equivalents, 200 equivalents, or 400 equivalents.
Most preferably, the molar equivalents of the ortho-mercaptoamine compound are 400 and the equivalents of the reducing agent are 100.
Furthermore, the charging sequence of the reaction is that the On-DNA alpha, beta-unsaturated carbonyl compound is firstly added, the o-mercaptoamine compound is then added, after the reaction is carried out for 16 hours at 30 ℃, the sodium cyanoborohydride is added, and the reaction is carried out for 1 hour at 60 ℃.
Further, the above method is used for batch multi-well plate operations.
Further, the above method is used for the synthesis of libraries of DNA-encoding compounds for multi-well plates.
The method can realize the acquisition of the On-DNA1, 4-thiazepine compound in a DNA coding compound library through the On-DNA alpha, beta-unsaturated carbonyl compound, can be widely applied to various On-DNA alpha, beta-unsaturated carbonyl substrates, and can introduce various substituted o-mercaptoamine compounds as synthesis modules in a large scale. 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.
Definitions of terms used in connection with the present invention: the initial definitions provided herein for a group or term apply to that group or term throughout the specification unless otherwise indicated; for terms not specifically defined herein, the meanings that would be given to them by a person skilled in the art are to be given in light of the disclosure and the context.
"substituted" means that a hydrogen atom in a molecule is replaced by a different atom or molecule.
The minimum and maximum values of the carbon atom content in the hydrocarbon group are indicated by a prefix, e.g. prefix (Ca-C)b) Alkyl indicates any of those containing "a" to "b"Alkyl of carbon atoms. Thus, for example, C1～C12The alkyl group is a straight-chain or branched alkyl group having 1 to 12 carbon atoms.
Alkyl means a straight or branched hydrocarbon radical in an alkane molecule, e.g. methyl-CH3ethyl-CH2CH3methylene-CH2-; the alkyl group may also be part of another group, such as C1～C6Alkoxy radical, C1～C6An alkylamino group.
Cycloalkyl refers to a saturated or partially saturated cyclic group 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 means that the alkyl radical is linked to an oxygen atom to form a substituent, e.g. methoxy is-OCH3。
The halophenyl group means a group in which H on a phenyl group is substituted with halogen.
Alkylphenyl refers to a group formed by substituting H on a phenyl group with an alkyl group.
The 5-to 10-membered aryl group is an aromatic monocyclic or polycyclic group containing no hetero atom and consisting of C atoms.
The 5-to 10-membered aromatic heterocyclic group is a single cyclic group or a plurality of cyclic groups having aromaticity and comprising 5 to 10 atoms of C, O, S, N and the like.
Heterocyclyl is a saturated or unsaturated monocyclic or polycyclic hydrocarbon radical carrying at least one atom of 3 to 8 selected from O, S, N.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. 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 transformation rate distribution map of the 25 On-DNA1, 4-thiazepine 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.
DNA-NH in the present invention2Is formed by single-stranded or double-stranded DNA and a linker group and has-NH2DNA constructs for linkers, e.g. DNA-NH of "compound 1" in WO20050584792And (5) structure. Also for example the following DNA structure:
wherein A is adenine, T is thymine, C is cytosine, and G is guanine.
DMSO, DMSO: dimethyl sulfoxide (DMSO).
Example 1 Synthesis of On-DNA1, 4-Thiazapine Compounds
Step 1, synthesis of On-DNA alpha, beta-unsaturated carbonyl compound
The On-DNA arylethanones (1) were dissolved in a 250mM boric acid buffer at pH 9.4 to prepare a 1mM solution (20. mu.L, 20nmol), benzaldehyde (4000nmol,200 equiv., 200mM DMSO), sodium hydroxide (10000nmol, 500 equiv., 500mM double distilled water) were sequentially added to the solution, and the mixture was mixed well and reacted at 30 ℃ for 1 hour.
And (3) after the reaction is finished, carrying out ethanol precipitation: adding a 5M sodium chloride solution with the total volume of 10% into the reacted solution, 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 0.5 hour, then centrifuging for half an hour at the rotating speed of 12000rpm, pouring out supernatant, dissolving the rest precipitate with deionized water to obtain a solution of the On-DNA alpha, beta-unsaturated carbonyl compound (2), and after the quantification is carried out by an enzyme labeling instrument OD, sending LCMS to confirm that the conversion rate of the reaction is 90%.
Step 2, synthesis of On-DNA1, 4-thiazepine compound
On-DNA α, β -unsaturated carbonyl compound (2) was dissolved in 250mM phosphate buffer at pH 5.5 to prepare a 1mM concentration solution (20 μ L,20 nmol), o-mercaptoaniline (8000nmol, 400 eq, 400mM DMSO) was added to the solution and mixed well, and after 16 hours of reaction at 30 ℃, sodium cyanoborohydride (2000nmol, 100 eq, 200mM DMSO) was added to the system and mixed well, and then reacted at 60 ℃ for 1 hour.
And (3) after the reaction is finished, carrying out ethanol precipitation: adding a 5M sodium chloride solution with the total volume of 10% into the reacted solution, 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 0.5 hour, then centrifuging for half an hour at the rotating speed of 12000rpm, pouring out 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, sending LCMS to confirm that the reaction conversion rate is 87%.
Example 2 Synthesis of On-DNA1, 4-Thiazapine Compounds
25 On-DNA α, β -unsaturated carbonyl compounds were dissolved in 250mM phosphate buffer (pH 5.5) to prepare a 1mM concentration solution (20 μ L,20 nmol), o-mercaptoaniline (8000nmol, 400 equiv., 400mM DMSO) was added to the solution and mixed uniformly, and after 16 hours of reaction at 30 ℃, sodium cyanoborohydride (2000nmol, 100 equiv., 200mM DMSO) was added to the system and mixed uniformly, and the reaction was carried out at 60 ℃ for 1 hour.
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 0.5 hour, then centrifuging for half an hour at the rotating speed of 12000rpm, pouring out the 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, sending to LCMS to confirm the conversion rate of the reaction.
In conclusion, the method can obtain the On-DNA1, 4-thiazepine compound by controlling the conditions of solvent, temperature, pH and the like during the reaction and reacting the On-DNA alpha, beta-unsaturated carbonyl compound with the o-mercaptoamine compound in the presence of a reducing agent. 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 (10)
1. A method for synthesizing an On-DNA1, 4-thiazepine compound is characterized in that: the method takes an On-DNA alpha, beta-unsaturated carbonyl compound and an o-mercaptoamine compound as raw materials, and the On-DNA product is obtained by reaction in the presence of a reducing agent; wherein the structural formula of the On-DNA alpha, beta-unsaturated carbonyl compound is shown in the specification
The structural formula of the o-mercaptoamine compound is shown in the specification
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 the rest part in the compound through one or more chemical bonds or groups;
R1selected from the group consisting of groups having a molecular weight of 1000 or less which are directly attached to the DNA and carbonyl carbon atoms or are absent;
R2selected from groups having a molecular weight of 1000 or less directly bonded to an alkenyl carbon atom;
R3selected from the group consisting of groups having a molecular weight of 1000 or less directly attached to the DNA and to the alkenyl carbon atom or are absent;
R4selected from groups having a molecular weight below 1000 directly attached to the carbonyl carbon atom;
R5selected from hydrogen or a group having a molecular weight of 1000 or less directly bonded to an alkenyl carbon atom;
or R5Are each independently of R1、R2、R3Or R4Looping;
R6、R6' is selected from hydrogen or a group having a molecular weight of 1000 or less; or R6、R6' are linked to form optionally substituted cycloalkyl, heterocycle, aromatic ring, aromatic heterocycle having a molecular weight of 1000 or less.
2. The method of claim 1, wherein: said R1、R2、R3、R4Are respectively selected from alkyl, substituted alkyl, carboxyl, 5-10-membered aryl, substituted 5-10-membered aryl, 5-10-membered aromatic heterocyclic group and substituted 5-10-membered aromatic heterocyclic group; wherein the alkyl is C1～C20Alkyl or C3～C8A cycloalkyl group; the number of substituents of the substituted alkyl group is one or more; the substituent of the substituted alkyl is one or more independently selected from halogen, carboxyl, nitro, alkoxy, halogenated phenyl, alkyl phenyl and heterocyclic radical; the number of the substituent for substituting the 5-to 10-membered aryl is one or more, and the substituents for substituting the 5-to 10-membered aryl are independently selected from halogen, cyano, nitro, carboxyl, alkoxy and C1～C20One or more of alkyl and trifluoromethyl; the number of the substituent(s) for substituting the 5-to 10-membered aromatic heterocyclic group is one or more, and the substituent(s) for substituting the 5-to 10-membered aromatic heterocyclic group are independently selected from the group consisting of halogen, cyano, nitro, carboxyl, alkoxy, C1～C20One or more of alkyl and trifluoromethyl;
the R is5Selected from hydrogen, C1～C20An alkyl group; the R is6、R6' selected from C1～C20An alkyl group; orR6、R6' are linked to form an aromatic ring.
3. The method of claim 1, wherein: adding 10-1000 times of molar equivalent of o-mercaptoamine compounds into an On-DNA alpha, beta-unsaturated carbonyl compound solution with the molar equivalent of 1 and the molar concentration of 0.5-5mM, adding 10-500 times of molar equivalent of reducing agents, and reacting at 10-100 ℃ for 0.5-24 hours.
4. The method of claim 3, wherein: the reducing agent is selected from sodium borohydride, sodium cyanoborohydride or lithium aluminum hydride.
5. The method of claim 3, wherein: the reaction is carried out in a solvent, and the solvent is a water-containing mixed solvent of any one or more of water, methanol, ethanol, acetonitrile, dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide, an inorganic salt buffer solution, an organic acid buffer solution and an organic base buffer solution.
6. The method of claim 3, wherein: the feeding sequence of the reaction is that an On-DNA alpha, beta-unsaturated carbonyl compound is added firstly, an o-mercaptoamine compound is added, after 16 hours of reaction at 30 ℃, sodium cyanoborohydride is added, and the reaction is carried out for 1 hour at 60 ℃.
7. The method of claim 3, wherein: the reaction temperature of the reaction is 20 ℃, 30 ℃, 40 ℃, 50 ℃, 60 ℃, 70 ℃ or 80 ℃.
8. The method of claim 3, wherein: in the method, the molar equivalent of the On-DNA alpha, beta-unsaturated carbonyl compound is 1, and the molar equivalent of the o-mercaptoamine compound is 50 equivalents, 100 equivalents, 200 equivalents, 300 equivalents, 400 equivalents, 500 equivalents, 600 equivalents, 800 equivalents and 1000 equivalents; the molar equivalent of the reducing agent is 20 equivalents, 60 equivalents, 80 equivalents, 100 equivalents, 200 equivalents, or 400 equivalents.
9. The method according to any one of claims 1 to 8, wherein the method is used for a batch multi-well plate operation.
10. The method of any one of claims 1 to 8, wherein the method is used for the synthesis of libraries of DNA-encoding compounds for multi-well plates.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109937201A (en) * | 2016-09-15 | 2019-06-25 | 组装生物科学股份有限公司 | Hepatitis B virus regulator |
| CN110041390A (en) * | 2019-04-26 | 2019-07-23 | 上海药明康德新药开发有限公司 | The synthetic method of the 1,2,3- 3-triazole compounds of On-DNA in DNA encoding compound library |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109937201A (en) * | 2016-09-15 | 2019-06-25 | 组装生物科学股份有限公司 | Hepatitis B virus regulator |
| CN110041390A (en) * | 2019-04-26 | 2019-07-23 | 上海药明康德新药开发有限公司 | The synthetic method of the 1,2,3- 3-triazole compounds of On-DNA in DNA encoding compound library |
Non-Patent Citations (2)
| Title |
|---|
| SATZ, ALEXANDER LEE: "DNA Compatible Multistep Synthesis and Applications to DNA Encoded Libraries", 《BIOCONJUGATE CHEMISTRY》 * |
| 杨福德 等: "二氢和四氢-2-芳基-4-甲基（1.5）苯并硫氮杂（艹卓）的构象分析（Ⅱ）", 《有机化学》 * |
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