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Three-stage amide microtubulin polymerization inhibitors as well as preparation method and application thereof

A technology of polymerization inhibitor and tubulin, applied in the field of anti-tumor medicinal chemistry, can solve problems such as high toxicity, and achieve the effects of high yield and simple and efficient synthesis method

Inactive Publication Date: 2019-01-15
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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  • Three-stage amide microtubulin polymerization inhibitors as well as preparation method and application thereof
  • Three-stage amide microtubulin polymerization inhibitors as well as preparation method and application thereof
  • Three-stage amide microtubulin polymerization inhibitors as well as preparation method and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] The preparation of embodiment 1 general formula (II)

[0019] (1) The preparation method of compound (I):

[0020] In an ethanol solvent, at a temperature of 60-120°C, the aryl-substituted methylene chloride compound and different substituted anilines were stirred and reacted under a bar of sodium hydroxide to obtain compound I.

[0021] (2) The preparation method of compound (II):

[0022] Compound (I) (5 mmol) and different substituted acetyl chloride compounds (5 mmol) were added into 15 mL of acetone to dissolve, and the reaction was stirred at 80 degrees Celsius. TLC monitors the reaction process. After the reaction is over, add distilled water to the system, then extract 3 times with dichloroethane, then back-extract the dichloroethane phase with saturated brine for 2 times, each 20mL, and finally the organic phase is extracted with dichloroethane. Dry over magnesium sulfate, filter out the magnesium sulfate, and distill the filtrate under reduced pressure to re...

Embodiment 2

[0059] The antitumor activity determination of the above-mentioned compound of embodiment 2:

[0060] The compounds used in the screening are all synthesized and purified by the present invention; sample stock solution: weigh 1-2 mg of the sample and place it in a 2mLEP tube, then make 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 even...

Embodiment 3

[0066] The determination of the Tubulin polymerization inhibitory activity of embodiment 3 compound IIe:

[0067] The extracted tubulin was resuspended in ice-cold G-PEM buffer (80mM PIPES pH 5.9, 5mM MgCl 2 , 1mMEGTA, 1mM ATP, 5% (v / v) glycerol), take 100ul and add it to a 96-well plate containing 100ul compound IIId, the final concentration of tubulin is 5.6g / L, and the drug concentration is set to 0uM, 1uM, 2uM, Four gradients of 4uM, the sample is fully mixed, the aggregation of tubulin is detected by spectrophotometer, the interval is 5min, the total is 60min, IC 50 Values ​​were calculated at 30 minutes using GraphPad software. Conclusion: The enzymatic activity of compound IIId on microtubules is less than 3uM.

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Abstract

The invention discloses novel three-stage amide microtubulin polymerization inhibitors, a preparation method of the novel three-stage amide microtubulin polymerization inhibitors and application thereof to medicine for treating gastric cancer, prostatic cancer, breast cancer and the like, and belongs to the field of anti-tumor medicine chemistry. A kind of novel microtubulin polymerization inhibitors are synthesized in an efficient green and environment-friendly way. The inhibitors have the following structure general formula shown in the description. The in vitro anticancer activity experiments prove that the inhibitors have certain inhibition effects on various tumor cells PC3, MCF7 and MGC803; meanwhile, the obvious inhibition effects are achieved on microtubulin. The activity of compounds (IId, IIe, IIg, IIi, IIm, IIo, IIp, IIq and IIr) on three kinds of cancer cells is better than that of anti-tumor medicine 5-fluorouracil. The inhibitors can be applied to anti-tumor medicine preparation through being used as candidate or lead compounds for further development.

Description

technical field [0001] The invention relates to the field of antitumor medicinal chemistry, in particular to a class of novel tertiary amide tubulin polymerization inhibitors, 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, and are closely related to life activities such as intracellular material transportation, cell movement, cell differentiation and development, and cell division and reproduction. 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. At present, it is urgent to develop new anti-tumor target drugs. Contents of the invention [0003] The purpose of the present invention is to provide a novel tertiary ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D333/24C07D333/60C07D409/12C07C231/02C07C233/29C07C235/38A61P35/00
CPCA61P35/00C07C233/29C07C235/38C07D333/24C07D333/60C07D409/12
Inventor 付冬君张赛扬张雁冰
Owner ZHENGZHOU UNIV
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