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5-benzylidene-2-phenylthiazolone compounds and their preparation and application

A technology of phenylthiazolone and benzylidene, which is applied in the fields of medicinal chemistry and pharmacotherapeutics, can solve problems such as cell cycle arrest and genome instability, and achieve easy-to-obtain raw materials, simple and easy preparation methods, and strong tumor cell Effect of Proliferation Inhibitory Activity

Active Publication Date: 2022-03-04
UNIV OF JINAN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Misregulation of these histone demethylases often causes cell cycle arrest and may also lead to genomic instability in cancer

Method used

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  • 5-benzylidene-2-phenylthiazolone compounds and their preparation and application
  • 5-benzylidene-2-phenylthiazolone compounds and their preparation and application
  • 5-benzylidene-2-phenylthiazolone compounds and their preparation and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] The preparation of embodiment 1 general formula (I) compound

[0039] Dissolve p-toluonitrile (59 mg, 0.5 mmol), thioglycolic acid (1 equiv), triethylamine (1 equiv) and the corresponding benzaldehyde derivative (1 equiv) in 10 mL of ethanol. The mixture was heated to reflux for 12 hours, and then the solvent was removed under reduced pressure, and the residue was separated by column chromatography to obtain the target compound.

[0040]

[0041] The following products are obtained:

[0042] ( Z )-5-benzylidene-2-( p -Methylphenyl)thiazole-4(5 H )-ketone (I-1), yellow solid (46 mg, 33%), melting point 190-192 °C. 1 H NMR (600 MHz, CDCl 3 ) δ 8.12 (d, J= 7.8 Hz, 2H), 8.05 (s,1H), 7.68 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 7.8 Hz,2H), 2.48 (s, 3H). 13 C NMR (150 MHz, CDCl 3 ) δ 187.1, 183.4, 146.7, 138.1, 133.9, 131.0, 130.6, 130.0, 129.2, 129.2, 129.0, 126.6, 22.0. ESI-MS m / z :280.0 [M+H] + .

[0043] ( Z )-5-(2-Methoxybenzylid...

Embodiment 2

[0068] Example 2 The enzyme activity inhibitory activity of compounds was tested by radioisotope method.

[0069] 1. Prepare 1x assay buffer (improved Tris-HCl buffer); 2. Dilute the compound to the desired concentration in a 96-well plate; 3. Prepare protein solution, also use 1x assay buffer; 4. Dilute the substrate Add to 1x assay buffer to prepare substrate solution; 5. [ 3 H]-SAM was added to 1x assay buffer to prepare [ 3 H]-SAM solution; 6. Add SAM to 1x assay buffer to prepare a cold SAM solution; 7. Pipette 10 μL protein solution to a 96-well plate containing the compound; 8. Incubate at room temperature for 15 minutes; 9. Add 10 μL substrate solution to each well; 10. Add 10 μL [ 3 H]-SAM solution initiates the reaction; 11. Incubate at room temperature for 240 minutes. 12. Add 10 μL of cold SAM solution to each well to terminate the reaction; 13. Transfer 40 μL of the reaction mixture solution to the GF / B plate, and wash with triple-distilled water for 3 times in...

Embodiment 3

[0084] Example 3 Effects of Compounds on Cell Proliferation

[0085] 1. Test method

[0086] (1) Cell culture

[0087] The culture medium used for MV4-11, Jeko, KOPN8, RCH-ACV, REH, RS4.11, THP1, U937, NALM6 cell culture is RPMI 1640 + 10% fetal bovine serum, and in order to prevent bacterial contamination, 100 U / mL penicillin and 100 μg / mL streptomycin. The cells were cultured at 37°C and 5% CO2 saturated humidity, and the cells used in the experiment were all in the logarithmic growth phase.

[0088] (2) Detection of cell proliferation activity

[0089] Adjust cell concentration to 1 x 10 5 / mL and inoculated in a 24-well culture plate with a volume of 1 mL per well. Set up a control group and an experimental group. The control group was added with DMSO, and the experimental group was added with a small molecule inhibitor of PRMT5 activity to a final concentration of 0-100 μM. Three detection time points were set for MV4-11 cells, which were 4, 8 and 12 days respectiv...

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Abstract

The invention relates to a 5-benzylidene-2-phenylthiazolone compound and its preparation and application. Specifically, the compound of the present invention has a structure represented by general formula (I), wherein the definitions of each group and substituent are as described in the specification. The invention also discloses the preparation method of the compound and its use in preventing and / or treating cancer-related diseases. The compound of the present invention has excellent inhibitory activity of protein arginine methyltransferase 1 (PRMT1), protein arginine methyltransferase 5 (PRMT5) and histone demethylase LSD1, and can induce tumor cell apoptosis cell death and arrest tumor cells in the G1 phase, so it can be used to prepare a series of therapeutic drugs related to the abnormal activity of arginine methyltransferase 1, arginine methyltransferase 5 and histone demethylase LSD1 Medicines for diseases.

Description

technical field [0001] The present invention relates to the fields of medicinal chemistry and pharmacotherapeutics, in particular to the preparation and application of a 5-benzylidene-2-phenylthiazolone compound represented by formula I. Background technique [0002] Methylation of histone lysines and arginines is one of the more well-studied post-translational modifications. Its methylation status is balanced by two classes of enzymes: histone methyltransferases (HMTs) and histone demethylases (HDMs). And its abnormal state is associated with many human diseases. [0003] Arginine methylation involved in the protein arginine methyltransferase (PRMTs) family is a post-translational modification widely present in the nucleus and cytoplasm, which uses S-adenosyl-methionine as the methyl donor In the body, the nitrogen atom of the arginine side chain of the protein is methylated to generate S-adenosyl homocysteine ​​and methyl arginine. The substrates of PRMTs are proteins r...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D277/34A61K31/426A61P35/00A61P35/02
CPCA61P35/00A61P35/02C07D277/34
Inventor 朱孔凯江成世张华宋佳丽陶洪瑞
Owner UNIV OF JINAN