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VHL ligand-based tubulin degradation agent and application thereof

A technology of tubulin and degrading agent, applied in the field of tubulin degrading agent, can solve the problems of inability to solve the defects of acquired drug resistance, and achieve the effect of delaying drug resistance

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 to bind and occupy the active site of tubulin for a long time to inhibit its activity, so it still cannot solve the inherent problem of tubulin inhibitors. resistance deficiency

Method used

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  • VHL ligand-based tubulin degradation agent and application thereof
  • VHL ligand-based tubulin degradation agent and application thereof
  • VHL ligand-based tubulin degradation agent and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] The synthesis of embodiment 1 Azo-H

[0058]

[0059] 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.

[0060] 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.

[0061] 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

[0065] Synthesis of Example 2 Azo-Me

[0066]

[0067] 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 overnight at room temperature. 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

[0068] The synthesis of embodiment 3 Azo-Pr

[0069]

[0070] 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 a tubulin degradation agent based on a VHL ligand and application of the tubulin degradation agent. Azo small molecules with a tubulin inhibiting effect are used as raw materials and are connected with a VHL ligand to obtain the tubulin degrading agent. The preparation method disclosed by the invention has the characteristics of low cost, simplicity in operation, mild conditions and the like. The tubulin degrading agent disclosed by the invention does not show pharmacological activity in a dark environment, and tubulin degradation can be promoted when illumination with a specific wavelength is given to a tumor part, so that the whole-body distribution defect of a micromolecule tubulin inhibitor is overcome.

Description

technical field [0001] The present invention relates to a tubulin degrading agent, in particular to a tubulin degrading agent based on the photoisomerization performance of azo compounds, its pharmaceutically available salt, its synthesis method and its ability to selectively degrade microtubule Pharmaceutical applications of tubulin. 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 finall...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/062A61K38/05A61P35/00A61P35/02A61P25/28A61P21/00A61P25/00A61P27/12A61P25/16A61P25/14A61P19/06A61P19/02A61P29/00A61P31/04A61P1/16
Inventor 王尊元黄文海马臻沈正荣章迟啸梁美好曾申昕潘有禄
Owner ZHEJIANG MEDICAL COLLEGE