Method for obtaining On-DNA aromatic hydrocarbon compound by Suzuki coupling reaction in construction of DNA encoded compound library

A technology for aromatic compounds and compound libraries, applied in the field of DNA-encoded compound libraries, can solve problems such as limited substrate applicability, unstable reagents, and easy deterioration, and achieve the effects of increasing diversity, convenient operation, and good stability

Active Publication Date: 2019-10-22
上海药明康德新药开发有限公司
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  • Application Information

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Problems solved by technology

[0023] However, the above On-DNA Suzuki coupling reactions are all for aryl boronic acid or boronic acid ester, and the obtained products are mainly On-DNA biaryl ring compounds. These methods are applied to alkyl/alkenyl/alkyne

Method used

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  • Method for obtaining On-DNA aromatic hydrocarbon compound by Suzuki coupling reaction in construction of DNA encoded compound library
  • Method for obtaining On-DNA aromatic hydrocarbon compound by Suzuki coupling reaction in construction of DNA encoded compound library
  • Method for obtaining On-DNA aromatic hydrocarbon compound by Suzuki coupling reaction in construction of DNA encoded compound library

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Experimental program
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Embodiment 1

[0049] Embodiment 1, the synthesis of On-DNA aryl bromide

[0050]

[0051] DNA-NH 2 (For example, the starting head fragment mentioned in the patent CN108070009A) was dissolved in 250mM, pH=9.5 boric acid buffer solution, prepared into a 1mM concentration solution, dispensed into a 96-well plate, and mixed with the bromoaryl carboxyl binary compound (total 569) using EDCI as a condensing agent and s-NHS condensation activator to react to obtain the corresponding On-DNA aryl bromide (abbreviated as DNA-Ar-Br, reference: Nat.Chem., 2015, 7, 3, 241), After this reaction is completed, only ethanol precipitation is done, and after concentration and drying, it is directly used in the reduction reaction of the next step (see figure 1 ).

[0052]We have reacted a total of 589 different bromoaryl carboxyl binary compounds, but in order to reduce the impact of the inconsistent yield of the first condensation reaction on the calculation of the yield of the second Suzuki coupling re...

Embodiment 2

[0053] Embodiment 2, the synthesis of On-DNA aryl olefin compound

[0054]

[0055] The DNA-Ar-Br generated in situ was redissolved in ultrapure water, and prepared into a 1mM concentration solution. Two aliquots were taken out and distributed into new 96-well plates (5μL, 5nmol, 1mM aqueous solution), and vinyl Potassium trifluoroborate (1.25μL, 250nmol, 200mM dimethylacetamide solution, 50eq.), cesium carbonate solution (3.75μL, 750nmol, 200mM aqueous solution, 150eq.), centrifuge to allow the solution to sink to the bottom, vortex to mix, and again After centrifugation, nitrogen was replaced 3 times, and palladium acetate (Pd(OAc) 2 ) and a premixed solution (1.5 μL, volume ratio = 2 / 1, 10mM dimethylacetamide solution / 40mM dimethylacetamide solution, 2eq. / 4eq.), replace nitrogen 3 times again, seal the film, and react 2 hours (cover temperature: 100°C).

[0056] Palladium removal: After the reaction is completed, add sodium diethyldithiocarbamate solution (3.0 μL, 300...

Embodiment 3

[0060] Embodiment 3, the synthesis of On-DNA benzylamine compound

[0061]

[0062] DNA-Ar-Br (5 μL, 5 nmol, 1 mM aqueous solution) was added to a 96-well plate, followed by adding N-Boc-aminomethyl potassium trifluoroborate (3.75 μL, 750 nmol, 200 mM dimethylacetamide solution, 150 eq.), Potassium carbonate solution (7.5μL, 1500nmol, 200mM aqueous solution, 300eq.), centrifuged to allow the solution to sink to the bottom, vortexed to mix well, after centrifuging again, replace nitrogen 3 times, add palladium acetate (Pd(OAc) 2 ) and 4-(2,6-dimethoxyphenyl)-3-(1,1-dimethylethyl)-2,3-dihydro-1,3-benzoxaphosphapan Pre-mixed solution of rac-BI-DIME (5.0 μL, volume ratio=1 / 1, 10 mM dimethylacetamide solution / 40 mM dimethylacetamide solution, 5eq. / 20eq.), again Nitrogen was replaced 3 times, the film was sealed, and the 96-well plate was reacted at 95° C. for 2 hours in a PCR instrument (cover temperature: 105° C.).

[0063] After the reaction is complete, add sodium diethyldi...

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Abstract

The invention discloses a method for obtaining an On-DNA aromatic hydrocarbon compound by a Suzuki coupling reaction of an On-DNA aryl halide and an organic trifluoroborate reagent in the constructionof a DNA encoded compound library. The On-DNA aryl halide used as a substrate reacts with the n organic potassium trifluoroborate reagent in the presence of a Pd catalyst, a ligand and an alkali to prepare the On-DNA aromatic compound. The reaction method of the invention provides a new idea for the functional group transformation and capping method of the On-DNA aryl halide, can significantly increase the diversity of the DNA encoded compound library of On-DNA aryl halides, has the advantages of high yield, wide universality of the substrate, mild conditions, and convenience in operation, and is suitable for synthesizing the DNA encoded compound library on a perforated plate.

Description

technical field [0001] The invention belongs to the technical field of DNA-encoded compound libraries, and in particular relates to a method for obtaining On-DNA aromatic compounds through Suzuki coupling reaction of On-DNA aromatic halides and potassium trifluoroborate reagents in the construction of DNA-encoded compound libraries. Background technique [0002] Sydney Brenner and Professor Richard Lerner of the Scripps Research Institute in the United States proposed the concept of DNA Encoded Library (DNA Encoded Library, referred to as DEL) in 1992 (reference: Proc.Natl.Acad.Sci., 1992,89,5381, patent : US5573905), the method connects an organic small molecule reagent with a unique sequence of DNA at the molecular level (i.e. DNA labeling the small molecule reagent), and utilizes the "combination-splitting" strategy of combinatorial chemistry to pass two at most A large number of compound libraries can be quickly constructed in one cycle, each compound in the compound lib...

Claims

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Application Information

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IPC IPC(8): C40B50/10C40B40/06
CPCC40B50/10C40B40/06
Inventor 吴阿亮曲毅陈琳琳高红赵蒙温石阳徐艳芬陈雯婷李科蒯乐天杨洪芳彭宣嘉
Owner 上海药明康德新药开发有限公司
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