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Phenyl allylidene cyclohexenone derivatives as well as preparation method and application

A technology of phenylallylidene cyclohexenone and base allylidene cyclohexenone is applied in the preparation of carbon-based compounds, the preparation of organic compounds, the preparation of carboxylic acid nitrile, etc. Limiting clinical applications, expensive metal catalysts, etc., to achieve the effect of inhibiting TrxR enzyme activity, inducing tumor cell apoptosis, and increasing ROS levels

Active Publication Date: 2019-07-12
NANTONG UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] It is true that it has been found that perylene amide has good antitumor activity, but it also has some shortcomings, which limit its clinical application.
First of all, the activity of peronylamide is not high enough, and the specific mechanism of action has not been fully elucidated; secondly, the raw materials of peronylamide extracted from plants are limited, and the consumption of medicinal materials required for production is quite large; The preparation process is complex, expensive metal catalysts are required, and the reaction yield is low

Method used

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  • Phenyl allylidene cyclohexenone derivatives as well as preparation method and application
  • Phenyl allylidene cyclohexenone derivatives as well as preparation method and application
  • Phenyl allylidene cyclohexenone derivatives as well as preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Embodiment 1 (E)-6-((E)-3-phenylallyl) cyclohex-2-enone (I 1 ) preparation

[0051]

[0052] Dissolve cyclohexen-2-one (0.48g, 5.0mmol) and triphenylphosphine (1.31g, 5.0mmol) in 50ml of anhydrous dichloromethane, and then add 5ml of 1mol / L TiCl at -50°C 4 After 15 minutes, use a constant pressure funnel to slowly add 30ml of cinnamaldehyde (1.32g, 10.0mmol) solution dissolved in dichloromethane dropwise. After half an hour, the reaction returns to room temperature, and the reaction continues for about 12h. TLC Monitor, after the reaction is complete, add an appropriate amount of 10% K 2 CO 3 After the solution continued to stir for about 5 minutes, the pH of the reaction solution was adjusted to 9, and then extracted with dichloromethane (50ml×2), and the extracted dichloromethane layer was washed with saturated brine (50mL), and the dichloromethane layer was collected. Dry over sodium sulfate, concentrate, and purify by column chromatography (EA:PE=1:3 as eluent...

Embodiment 2

[0091] Embodiment 2 MTT method is used to measure the inhibition rate of tumor cells and normal cell proliferation of the compounds of the present invention

[0092] The anti-proliferation activity of the compound of the present invention on 4 kinds of human cancer cell lines was evaluated by tetramethylazolidine blue colorimetric method (MTT) in vitro anti-tumor test. Perimine (PL) was used as the positive control drug. Human cancer cell lines: liver cancer cell SMMC7721, colon cancer cell HCT116, gastric cancer cell HGC-27, human cervical cancer cell Hela, normal human cells: human gastric mucosal epithelial cell GES-1.

[0093] The experimental method is as follows: take a bottle of cells in a good state in the exponential growth phase, add 0.25% trypsin to digest, make the adherent cells fall off, and make each ml contain 2×10 4 ~4×10 4 suspension of cells. The cell suspension was inoculated on a 96-well plate, 180 μL per well, and placed in constant temperature CO 2 I...

Embodiment 3

[0100] Example 3 Intracellular ROS Level Determination

[0101] ROS-Glo hydrogen peroxide assay (Promega, Southampton, UK) directly detects H in cells 2 o 2 Levels measure ROS changes. Cells were seeded into 96-well cell culture plates and incubated with test drugs (0.01-12.5 μM) for 24 hours. Hydrogen peroxide substrate solution was added to each well and kept at constant temperature CO 2 Incubate in an incubator at 37°C for 6 hours. After the incubation, add ROS-Glo detection solution to each well and incubate at room temperature for 20 minutes. Fluorescence was detected by a BioTek Synergy HT multimode microplate reader.

[0102] Select I in the compound of general formula I of the present invention 4 ~I 8 , I 11 ~I 15 , I 18 , I 19 As a representative, its ROS level in tumor cells was tested. DCFH-DA was used as a fluorescent probe to measure the changes of ROS in human cervical cancer Hela cells after drug treatment, and the changes of fluorescence intensity c...

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Abstract

The invention discloses phenyl allylidene cyclohexenone derivatives with the structure shown in general formula I. In combination with structural characteristics and structure-activity relationship ofpiplartine, amino bonds are replaced with double bonds, meanwhile, active groups are reserved, aromatic substituent groups are changed, novel phenyl allylidene cyclohexenone derivatives targeting TrxR (thioredoxin reductase) for tumor tissue overexpression are designed, the defects of multiple piplartine synthesis steps and requirement for expensive metal catalysts are overcome, and the anti-tumor activity of the compounds is improved. Research results indicate that the compounds have strong inhabitation effects on proliferation of multiple tumor cells and can significantly increase the ROS level in the tumor cells and enhance the anti-tumor effect.

Description

technical field [0001] The present invention relates to the field of biomedicine, in particular to a class of phenylallylidene cyclohexenone derivatives and their preparation methods, pharmaceutical compositions containing these derivatives and pharmaceuticals with TrxR inhibitory activity, especially in the preparation of application in antineoplastic drugs. Background technique [0002] According to the report of the World Health Organization (WHO), malignant tumors have long been one of the major global diseases, and are rapidly becoming the number one "killer disease" in the world, seriously threatening human health and life. According to WHO statistics, in the past 30 years, the incidence of cancer in the world has been increasing at an average annual rate of 3-5%. It is estimated that by 2020, the incidence of cancer in the world will increase by 50% compared with 2008, that is, there will be 15 million new cancer patients every year. . Not only that, the number of d...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C49/683C07C49/697C07C45/74C07C205/45C07C201/12C07C49/747C07C49/753C07C225/22C07C221/00C07C69/157C07C67/293C07C255/40C07C253/30A61P35/00
CPCA61P35/00C07C49/683C07C49/697C07C49/747C07C49/753C07C69/157C07C205/45C07C225/22C07C255/40C07C2601/16
Inventor 凌勇杨圣菊张延安刘季凌长春李洋阳刘思群贾启新明古旭吴红梅
Owner NANTONG UNIVERSITY
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