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One-pot On-DNA Suzuki reaction method

A Suzuki reaction and on-DNA technology, applied in the field of encoded compound libraries, can solve problems such as difficult separation and purification, inability to introduce DNA-encoded compound libraries, and limiting the diversity of DNA-encoded compound libraries.

Pending Publication Date: 2021-05-25
HITGEN INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the commonly used Suzuki reaction requires boronic acid or boronic acid ester compounds as raw materials, and the number of boronic acid or boronic acid ester compounds currently available on the market is limited, which limits the diversity of DNA-encoded compound libraries constructed during its application.
And some boronic acid / boronic acid ester compounds are not easy to separate and purify, and cannot be introduced into the DNA-encoded compound library by traditional methods

Method used

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  • One-pot On-DNA Suzuki reaction method
  • One-pot On-DNA Suzuki reaction method
  • One-pot On-DNA Suzuki reaction method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] The synthesis of embodiment 1, 7 kinds of On-DNA aryl halide compounds

[0056]

[0057] DNA-NH 2 Dissolve in 250mM, pH=9.4 boric acid buffer solution, prepare 1mM concentration solution (20μL, 20nmol), acid aromatic halide (1μmol, 50 equivalent, 200mM DMA solution), HATU (1μmol, 50 equivalent, 400mM DMA solution), DIPEA (1 μmol, 50 equivalents, 400 mM DMA solution) was placed in a -20°C refrigerator for 5 minutes and then mixed. The mixture was thoroughly mixed by vortexing, and then placed in a 4°C refrigerator for 5 minutes; the above mixture Add to the solution of DNA raw materials, mix well, and leave overnight at room temperature.

[0058] Ethanol precipitation standard operating post-processing. Standard operation of ethanol precipitation: add a total volume of 10% 5M sodium chloride solution to the solution, and then continue to add 3 times the total volume of absolute ethanol. After shaking evenly, place the reaction in dry ice to freeze for 2 hours, and t...

Embodiment 2

[0059] Embodiment 2, the synthesis of On-DNA biaryl compound 4

[0060]

[0061] Dissolve B2pin2 in ACN to prepare a 1.2M concentration solution (0.11 μmol, 11 equivalents, 0.092 μL), and add BPO (0.002 μmol, 0.2 equivalents, 0.01 μL, 0.2M ACN solution), aromatic amine (0.1 μmol, 10 equivalents, 0.08 μL, 1.25M ACN solution), t-BuONO (0.15 μmol, 15 equivalents, 0.12 μL, 1.25M ACN solution), mixed in a 1.5mL centrifuge tube, shake evenly, and react at 25°C for 16 hours , for the next reaction.

[0062] The On-DNA aryl halogen raw material was dissolved in deionized water to prepare a 1mM concentration solution (10nmol, 1 equivalent, 10 μL), and the above mixed solution (100nmol, 10 equivalent, 0.302μL, 331mM ACN solution), KOH (1500 nmol, 150 equiv, 1.5 μL, 1M aqueous solution), POPd (6.7 nmol, 0.67 equiv, 0.335 μL, 20 mM DMA solution) and ligand (13.3 nmol, 1.33 equiv, 0.665 μL, 20 mM DMA solution) were mixed at 1.5 mL centrifuge tube, mix evenly, add to the aforementioned...

Embodiment 3

[0064] Embodiment 3, the synthesis of On-DNA biaryl compound 7

[0065]

[0066] Dissolve B2pin2 in ACN to prepare a 1.2M concentration solution (0.11 μmol, 11 equivalents, 0.092 μL), and add BPO (0.002 μmol, 0.2 equivalents, 0.01 μL, 0.2M ACN solution), aromatic amine (0.1 μmol, 10 equivalents, 0.08 μL, 1.25M ACN solution), t-BuONO (0.15 μmol, 15 equivalents, 0.12 μL, 1.25M ACN solution), mixed in a 1.5mL centrifuge tube, shake evenly, and react at 25°C for 16 hours , for the next reaction.

[0067] Dissolve the On-DNA aryl halogen raw material in deionized water to prepare a 1mM concentration solution (10nmol, 1 equivalent, 10μL), and add the above mixed solution (100nmol, 10 equivalent, 0.302μL, 331mM ACN solution), KOH (1500nmol, 150 equivalents, 1.5μL, 1M aqueous solution), POPd (6.7nmol, 0.67 equivalents, 0.335μL, 20mM DMA solution) and ligand (13.3nmol, 1.33 equivalents, 0.665μL, 20mM DMA solution) were mixed in 1.5mL In a centrifuge tube, mix evenly, add to the af...

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Abstract

The invention relates to a one-pot On-DNA Suzuki reaction method, which comprises the following steps: in the presence of boric acid ester, nitrite ester and a free radical initiator, converting an amino compound into a boric acid ester compound, and then carrying out one-pot method on the boric acid ester compound and an On-DNA aryl halogenated compound in the presence of a palladium catalyst to obtain an On-DNA product. The method disclosed by the invention is high in yield and mild in reaction condition, can be introduced into a boric acid synthesis module in a large scale through an amino compound, especially a boric acid module which is difficult to separate and purify, and is suitable for synthesizing a DNA coding compound library by using a porous plate.

Description

technical field [0001] The invention belongs to the technical field of encoded compound libraries, and specifically relates to a method for obtaining On-DNA products from On-DNA aryl halogenated compounds through "one-pot" Suzuki carbon-carbon coupling reaction in the construction of DNA encoded compound libraries. Background technique [0002] In drug development, especially new drug development, high-throughput screening for biological targets is one of the main means to quickly obtain lead compounds. However, the traditional high-throughput screening based on a single molecule requires a long time, huge investment in equipment, limited number of library compounds (millions), and the construction of a compound library requires decades of accumulation, which limits the efficiency and efficiency of lead compound discovery. possibility. The DNA-encoded compound library technology (WO2005058479, WO2018166532, CN103882532) that has emerged in recent years combines combinatoria...

Claims

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Application Information

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IPC IPC(8): C40B50/10C40B40/06
CPCC40B50/10C40B40/06
Inventor 李进谭平叶雨松陈柳罗华东刘观赛马慧勇万金桥
Owner HITGEN INC
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