Triazole active molecule-based photoaffinity probe molecule as well as preparation method and application thereof

A technology of active molecules and probe molecules, which is applied in the field of photoaffinity probe molecules based on triazole active molecules and its preparation and application, can solve the problem of probe molecules that cannot be stably combined with drug target molecules and the activity of probe molecules Reduction, poor cell permeability and other problems, to achieve the effect of improving the inability to stably bind drugs and the decrease in activity of probe molecules, simple preparation method, and high yield

Pending Publication Date: 2020-09-18
XI AN JIAOTONG UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] In the existing target confirmation technology, the probe molecule cannot stably bind to the drug target molecule, which may easily cause false positive results
Moreover, the existing technology usually needs to attach a large-volume fluorescent group to the drug molecule for analysis, which will lead to the disadvantages of reduced activity of the probe molecule, poor solubility, poor cell permeability, etc.

Method used

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  • Triazole active molecule-based photoaffinity probe molecule as well as preparation method and application thereof
  • Triazole active molecule-based photoaffinity probe molecule as well as preparation method and application thereof
  • Triazole active molecule-based photoaffinity probe molecule as well as preparation method and application thereof

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preparation example Construction

[0032] see figure 1 , a method for preparing a photoaffinity probe molecule based on a triazole active molecule, comprising the following steps:

[0033] 1) 3-(1-(4-(6-methoxypyridin-3-yl)benzyl)-1H-1,2,3-triazol-4-yl)aniline (i.e. triazole active molecule) Reaction with succinic anhydride in acetonitrile solution to obtain an intermediate product with a monocarboxylic acid;

[0034] The specific operation of the step 1) is: dissolve 1.40mmol of triazole active molecule and 2.10mmol of succinic anhydride in 10mL of acetonitrile solution, react at 60°C for 8h, after the reaction is completed, spin off the organic solvent under low pressure, add an appropriate amount of water, Extracted with ethyl acetate, the extracted organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain a crude product, which was separated by a chromatographic column to obtain an intermediate product with monocarbox...

Embodiment 1

[0042] see figure 1 , the structural formula of the photoaffinity probe molecule based on the triazole active molecule, which has the function of target confirmation, is prepared by the following steps:

[0043] Dissolve triazole active molecules and succinic anhydride in acetonitrile, react at 60°C for 8 hours to obtain an intermediate product with monocarboxylic acid; the specific process is as follows:

[0044] Dissolve 1.40mmol of triazole active molecule and 2.10mmol of succinic anhydride in 10mL of acetonitrile solution, react at 60°C for 8h, after the reaction is completed; spin off the organic solvent under low pressure, add an appropriate amount of water, extract with ethyl acetate, and extract the organic phase After washing with saturated brine and drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to obtain a crude product, which was separated by chromatography and eluted with petroleum ether / ethyl acetate (V / V=1 / 1) to obtain th...

Embodiment 2

[0051] Application of photoaffinity probe molecules based on triazole active molecules in the confirmation of target proteins.

[0052] After the photoaffinity probe based on the triazole active molecule is incubated with the cells, the ultraviolet light makes the probe form an irreversible covalent bond with its target, and the fluorescent group (azidocoumarin) is connected to the fluorescent group (azidocoumarin) through click chemistry. Soybein emits blue fluorescence, and the fluorescence localization is the action site of the probe. According to the preliminary experiment, the experimental parameters were determined as follows: the concentration ratio of fluorescein to photoaffinity probe was 1:1, and the concentration ratio of competitor to photoaffinity probe was 5:1, and the obtained results were relatively clear. For target protein confirmation experiments, select 4 μM photoaffinity probe, 4 μM azidocoumarin, 20 μM competitor, UV irradiation for 15 min and other param...

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Abstract

The invention discloses a triazole active molecule-based photoaffinity probe molecule as well as a preparation method and application thereof. The preparation method comprises the following steps thattriazole active molecules and succinic anhydride are stirred in acetonitrile to obtain an intermediate product with monocarboxylic acid; and the triazole active molecule-based photoaffinity probe molecule is prepared from a linker containing photoaffinity group diaziridine and alkynyl and the intermediate product with monocarboxylic acid under the condensation action of EDC.HCl. The preparation method of the triazole active molecule-based photoaffinity probe molecule is simple, easy to implement and high in yield. The triazole active molecule-based photoaffinity probe can be used for confirming the target protein of the triazole active molecule and verifying the feasibility of a photoaffinity labeling technology in the aspect of confirming a small molecule target.

Description

technical field [0001] The invention relates to a photoaffinity probe molecule based on a triazole active molecule, a preparation method and application thereof. Background technique [0002] Photoaffinity labeling technology (PAL) combines the advantages of modern molecular biology, cell biology, medicinal chemistry, analytical chemistry and other disciplines. It uses synthetic photoaffinity probe molecules to produce high activity under the irradiation of specific wavelength light. The intermediate can be directly irreversibly covalently cross-linked with the protein specifically bound by the drug molecule to achieve the capture of the drug target protein molecule. It is one of the core tools for studying ligand-receptor interaction at the molecular level, and it will greatly promote the elucidation of ligand-receptor interaction mechanism and the discovery of new drug targets. [0003] In recent years, this technology has been mainly used in the confirmation of drug mole...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14G01N33/532G01N33/68
CPCC07D401/14G01N33/532G01N33/68
Inventor 张杰强薇卢闻潘晓艳单媛媛王瑾司茹张晴晴
Owner XI AN JIAOTONG UNIV
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