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Azo compound for degrading tubulin as well as synthesis method and application of azo compound

A technology of tubulin and compounds, applied in the application field of medicine, can solve the problems such as the defects of acquired drug resistance of tubulin inhibitors

Pending Publication Date: 2022-04-15
ZHEJIANG MEDICAL COLLEGE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, because it still exerts pharmacological effects by inhibiting tubulin, it needs a certain dose of binding and needs to occupy the active site of tubulin for a long time to inhibit its activity, so it still cannot solve the inherent problems of tubulin inhibitors. acquired resistance deficiency

Method used

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  • Azo compound for degrading tubulin as well as synthesis method and application of azo compound
  • Azo compound for degrading tubulin as well as synthesis method and application of azo compound
  • Azo compound for degrading tubulin as well as synthesis method and application of azo compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] The synthesis of embodiment 1 Azo-H

[0038]

[0039] Select a 100ml three-necked flask, add a magnetic rotor, put a thermometer and a constant pressure dropping funnel on it, and place it on a magnetic stirrer. Weigh 1.83g (10mmol) of 3,4,5-trimethoxyaniline, add 5ml of 95% ethanol solution, cool to -10°C with -20°C glycerol, turn on the magnetic stirrer, stir and dissolve, the reaction solution is Bright yellow.

[0040] Measure 2ml of 37% concentrated hydrochloric acid and add it dropwise to the above reaction solution. During the dropwise addition, replace the cooling liquid regularly to ensure that the temperature of the reaction solution is lower than 0°C, and the reaction solution turns into a beige turbid liquid.

[0041] Weigh 1.39g (20mmol) of sodium nitrite, prepare 5ml of aqueous solution, and also place it in cooling liquid to cool. After the hydrochloric acid was added dropwise, the sodium nitrite solution was added dropwise, and the temperature was a...

Embodiment 2

[0045] Synthesis of Example 2 Azo-Me

[0046]

[0047] 0.55 g of Azo-H prepared in Example 1, 0.3 g of potassium carbonate and excess methyl iodide were added to 2 mL of DMF, and the reaction was stirred at room temperature 25° C. overnight. After the reaction was completed, water was added and extracted with ethyl acetate to obtain a brown-yellow solid. 1 H-NMR (CDCl 3 ,ppm):7.66(1H,dd,Ph),7.63(1H,d,Ph),7.23(2H,s,Ph),7.02(1H,d,CH),4.87(2H,f,CH2),3.97 (9H,s,3×OCH3),3.93(3H,s,OCH3).

Embodiment 3

[0048] The synthesis of embodiment 3 Azo-Pr

[0049]

[0050] According to the method described in Example 2, bromopropane was used instead of methyl iodide to obtain Azo-Pr. MS(ESI)m / z:[M+H] + =384.

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Abstract

The invention discloses an azo compound for degrading tubulin as well as a synthesis method and application of the azo compound. According to the invention, azo small molecules with tubulin inhibition effect are used as raw materials, and further reaction is carried out to obtain the azo compound for degrading tubulin. The preparation method of the azo compound for degrading tubulin has the characteristics of low cost, simplicity in operation, mild conditions and the like. The azo compound for degrading the tubulin does not show pharmacological activity in a dark environment, but shows affinity to the tubulin under illumination of a specific wavelength due to the specific photoisomerization performance, and further promotes the tubulin to degrade, so that the effect of degrading the tubulin is achieved. The method can be applied to preparation of drugs for preventing or treating diseases caused by excessive growth of microtubulin.

Description

technical field [0001] The present invention relates to an azo compound, in particular to an azo compound (based on CRBN ligand) capable of degrading tubulin and its pharmaceutically available salt, its synthesis method and its role in selectively degrading tubulin application in medicine. Background technique [0002] Microtubules are dimers formed by α and β two types of tubulin, which are distributed in a network or bundle in the cell and participate in the formation of the cytoskeleton, maintenance of cell shape, cell contraction, and intracellular material transport and cell division. Therefore, by inhibiting the polymerization of tubulin into microtubules in the process of cell division, or inhibiting the depolymerization of microtubules into tubulin, mitosis will be unable to proceed or stagnate, and the interruption of cell mitosis process will have a greater impact on cells , so that its growth is inhibited, and finally induces the occurrence of apoptosis, so as t...

Claims

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Application Information

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IPC IPC(8): C07D401/14A61P35/00A61P35/02A61P25/28A61P21/00A61P27/12A61P25/16A61P25/14A61P19/06A61P19/02A61P29/00A61P1/16A61K31/655
CPCC07D401/14A61P35/00A61P35/02A61P25/28A61P21/00A61P27/12A61P25/16A61P25/14A61P19/06A61P19/02A61P29/00A61P1/16
Inventor 王尊元马臻黄文海沈正荣梁美好章迟啸曾申昕潘有禄
Owner ZHEJIANG MEDICAL COLLEGE
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