1,2,3-triazole tubulin polymerization inhibitor and synthesis method and application thereof

A technology of polymerization inhibitor and triazole, which is applied in the field of anti-tumor pharmaceutical chemistry, can solve the problems of high toxicity and achieve the effect of high yield and simple and efficient synthesis method

Inactive Publication Date: 2019-03-12
ZHENGZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

As a tubulin polymerization inhibitor, colchicine can inhibit cell mitosis and has anti-tumor effect, but it is highly toxic and is rarely used now

Method used

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  • 1,2,3-triazole tubulin polymerization inhibitor and synthesis method and application thereof
  • 1,2,3-triazole tubulin polymerization inhibitor and synthesis method and application thereof
  • 1,2,3-triazole tubulin polymerization inhibitor and synthesis method and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] Preparation of Embodiment 1 General Formula (6a~6l) (1) Preparation of Compound (4):

[0022] (1) In an ethanol solvent at room temperature, add 3,4,5-trimethoxyaniline (1), 4-methoxybenzyl chloride, and sodium carbonate to react, then add chloroacetyl chloride to react to obtain compound (4);

[0023] (2) Preparation of compound (5):

[0024] In the ethanol solvent, add potassium phosphate, compound (4) and sodium azide, stir and react at 60°C to obtain compound (5);

[0025] (3) Preparation of compound (6a~6l): Add compound (5) (1.93g, 5mmol) and different alkynyl compounds (6mmol) into 10mL acetone / water (5ml / 5ml) to dissolve, and finally add copper sulfate pentahydrate (1mmol ) and sodium ascorbate (0.5 mmol), stirred overnight at room temperature. TLC monitors the reaction process. After the reaction is over, add distilled water to the system, then extract 6 times with dichloroethane, then back-extract the dichloroethane phase with saturated brine for 3 times, ea...

Embodiment 2

[0038] The antitumor activity determination of the above-mentioned compound of embodiment 2:

[0039] The compounds used in the screening are all synthesized and purified by the present invention; sample stock solution: weigh 1-2mg of the sample and place it in a 2mLEP tube, then prepare a solution with DMSO, store it at 4°C, and use the culture medium according to the required concentration during the experiment dilution. Take the cells in the logarithmic growth phase, digest and count them, adjust the cell density with the medium, inoculate 4000-5000 cells / well into a 96-well plate, 150 μL per well, cultivate for 24 hours, discard the medium, and add the culture medium Base-diluted drugs (50 μg / mL, 100 μg / mL), 6 replicate wells were set up for each concentration, and a blank control group and a negative control group were also set up. After 72 hours of drug action, add 20 μL MTT to each hole, continue to cultivate for 4 hours, absorb the liquid, add 150 mL of DMSO, shake ev...

Embodiment 3

[0043] The Tubulin polymerization inhibition activity assay of embodiment 3 compound 6c:

[0044] Resuspend the extracted tubulin in ice-cold G-PEM buffer (80mM PIPES pH 5.9, 5mM MgCl 2 , 1mMEGTA, 1mMATP, 5% (v / v) glycerol), take 100ul and add it to a 96-well plate containing 100ul compound 6c, the final concentration of tubulin is 5.6g / L, and the drug concentration is set to 0uM, 1uM, 2uM, 4uM Four gradients, the samples were mixed well, the aggregation of tubulin was detected by spectrophotometer, the interval was 5min, the total was 60min, IC 50 Values ​​were calculated at 30 minutes using GraphPad software. IC of the tubulin polymerization inhibitory activity of compound 6c 50 The value is 2.17μM, indicating that compound 6c can indeed bind to tubulin and inhibit its polymerization. The results are shown in figure 1 .

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Abstract

The invention discloses 1,2,3-triazole compounds, preparation methods thereof and application thereof in tubulin polymerization inhibition, and belongs to the field of antitumor medicinal chemistry. The preparation methods are simple and efficient, and are environmentally friendly in the synthesis of the 1,2,3-triazole compounds. The compounds have the following structural formula: as shown in thespecification. An anti-cancer activity test of the compounds shows that the compounds have certain inhibition effect on various tumor cells PC3, HepG2 and MGC803 and also has a significant inhibitionaction on tubulin polymerization. The compound (6c) has the activity, superior to that of an antitumor drug colchicine and an antitumor drug 5-fluorouracil, to three cancer cells, and the compounds (6a, 6b, 6c, 6g, 6j) have the activity, superior to the antitumor drug 5-fluorouracil, to three cancer cells. The compounds can be used as candidate or pilot compounds for further development and are applied to preparation of antitumor drugs.

Description

technical field [0001] The invention relates to the field of antitumor drug chemistry, in particular to a class of novel 1,2,3-triazole compounds, their preparation method and their application as a class of new antitumor drug lead compounds. Background technique [0002] Microtubules are an important component of the cytoskeleton of most eukaryotic organisms. They play an important role in maintaining cell shape and maintaining the order of the internal structure of cells. Life activities such as division and reproduction are closely related. The important physiological role of tubulin makes it an important target in the field of tumors. As a tubulin polymerization inhibitor, colchicine can inhibit cell mitosis and has anti-tumor effect, but it is highly toxic and is rarely used now. Contents of the invention [0003] The purpose of the present invention is to provide a class of novel 1,2,3-triazole compounds with stronger antitumor activity than colchicine. [0004] A...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/12C07D249/04C07D417/12C07D413/12C07D403/12A61P35/00
CPCA61P35/00C07D249/04C07D403/12C07D405/12C07D413/12C07D417/12
Inventor 张雁冰张赛扬付冬君
Owner ZHENGZHOU UNIV
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