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Compound CYD19 or pharmaceutically acceptable salt thereof as Snail inhibitor, and preparation method, pharmaceutical composition and application of compound CYD19 or pharmaceutically acceptable salt thereof

A technology of inhibitors and compounds, applied in drug combinations, active ingredients of heterocyclic compounds, organic chemistry, etc., can solve the problems of uncertain mechanism research, limited compound development, no obvious inhibitory effect, etc., to reduce the level of acetylation , accelerated degradation, significant anti-tumor effect

Active Publication Date: 2020-05-22
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] However, small molecule inhibitors that directly target Snail protein have not been reported, and can only inhibit the expression of Snail through some indirect means
At present, Park et al. have reported a new type of natural product GN25, which can mainly block the combination of Snail and p53 in HCT-116 cells, and induce the expression of p53 in cancer cells in a K-Ras-dependent manner. There is no obvious inhibitory effect in vivo, which limits the further development of this type of compound
In addition, an irreversible Snail-binding Co(III)-DNA complex has been shown to be able to selectively inhibit Snail transcription and regulate the migration process of MCF-7 cells induced by Heregulinb1 (HRG), showing a certain anti-tumor metastasis potential , but the mechanism is still uncertain

Method used

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  • Compound CYD19 or pharmaceutically acceptable salt thereof as Snail inhibitor, and preparation method, pharmaceutical composition and application of compound CYD19 or pharmaceutically acceptable salt thereof
  • Compound CYD19 or pharmaceutically acceptable salt thereof as Snail inhibitor, and preparation method, pharmaceutical composition and application of compound CYD19 or pharmaceutically acceptable salt thereof
  • Compound CYD19 or pharmaceutically acceptable salt thereof as Snail inhibitor, and preparation method, pharmaceutical composition and application of compound CYD19 or pharmaceutically acceptable salt thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Embodiment 1: The preparation method of the compound CYD19 or its pharmaceutically acceptable salt as a Snail inhibitor in this embodiment, the preparation steps are as follows:

[0038]4-[[[4-[(5-methyl-1H-pyrazol-3-yl)amino]pyrrolo[2,1-f][1,2,4]triazin-2-yl]sulfur ]Methyl]benzoic acid is completely dissolved in N,N-dimethylformamide, then add TBTU and N,N-diisopropylethylamine, stir at room temperature and then add p-fluoro-o-phenylenediamine, continue stirring at room temperature , the reaction solution was evaporated to dryness under reduced pressure to obtain the evaporated product, the mixture of the evaporated product and silica gel was added to ethyl acetate solvent, and then evaporated to dryness at a temperature of 40°C to 50°C to obtain the evaporated product, and the evaporated product was added to the upper layer of the silica gel column , and then use petroleum ether and ethyl acetate to elute, the collected eluate is evaporated to dryness under reduced pr...

Embodiment 2

[0039] Example 2: Biolayer interferometry detects the affinity of compound CYD19 to Snail protein.

[0040] Dissolve the recombinant Snail protein in PBS and place it in a 100uL tube. Incubate EZ-Link NHS-biotin and Snail recombinant protein at room temperature for 60 minutes (the molar ratio of protein to biotin is 1:3). Desalting is used to remove excess biotin. The biotinylated proteins were immobilized on Super Streptavidin biosensors for further measurements. Blank recombinant protein was used as a control. CYD19 with different concentrations (0.5, 0.25, 0.125, 0.063, 0.031 μM) was used as a non-specific control. Binding of CYD19 to Snail-protein was determined using an Octet red 96 instrument (ForteBio), the intensity of the light deviation was recorded, and the association and dissociation rates were calculated using a 1:1 binding model. The results showed that CYD19 had a higher affinity with Snail protein (K d = 180nM), figure 1 .

Embodiment 3

[0041] Example 3: Detection of the effect of CYD19 on the expression of Snail protein by Western Blot.

[0042] The cells were seeded in a six-well plate, and after the cells adhered to the wall for 12-24 hours, they were treated with different concentrations of CYD19 (25, 50, 75, 100 nM) for 24 and 48 hours. After the protein was extracted and the concentration was determined, according to the molecular weight of the protein, Prepare 10% SDS polyacrylamide gel without concentration gradient, 90V stacking gel, 120V separating gel electrophoresis, 2.5-3h. Transfer the membrane through the full wet transfer method, and cut the appropriate size filter paper and nitrocellulose membrane according to the size, glue it on the negative electrode, and the film on the positive electrode, with a constant current of 250mA, and adjust the transfer time according to the required protein Kd number . Immerse the protein-transferred nitrocellulose membrane in Ponceau staining for 5 minutes, t...

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Abstract

The invention discloses a compound CYD19 which has a structure as shown a formula (I) which is described in the specification and is used as a Snail inhibitor or a pharmaceutically acceptable salt thereof, and a preparation method, a pharmaceutical composition and application of the compound CYD19 or the pharmaceutically acceptable salt thereof. The invention also discloses application of the compound in preparation of drugs for preventing or treating diseases with abnormal Snail expression. The invention especially relates to an application of the compound in preparation of antitumor and cardiovascular drugs. Pharmacological results show that the compound is highly compatible with Snail protein, and has good in-vitro anti-tumor cell proliferation effect, cell apoptosis promotion effect and tumor metastasis inhibition effect. The compound shows obvious in-vivo anti-tumor proliferation and metastasis activity in HCT-116 subcutaneous xenograft tumor nude mice and in-vivo liver metastasismodels of spleen injection, and is a potential drug clinically applicable to treatment of tumors.

Description

technical field [0001] The present invention relates to a Snail inhibitor or its pharmaceutically acceptable preparation method, pharmaceutical composition and use thereof, in particular to a compound CYD19 as a Snail inhibitor or a pharmaceutically acceptable salt thereof and its preparation method, pharmaceutical composition and use . Background technique [0002] Malignant tumor is a major disease that seriously threatens human life and health. It has the characteristics of fast growth, strong invasion and infiltration ability, and often distant metastasis. The biological characteristics of tumor cells, such as abnormal proliferation, apoptosis resistance, invasion and metastasis, pose serious challenges to tumor treatment. Among them, tumor metastasis is one of the key factors that make tumors difficult to treat, and its most obvious feature is the occurrence of epithelial-mesenchymal transition (EMT). For tumor cells, EMT not only endows tumor cells with the ability t...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61K31/53A61P35/00
CPCA61P35/00C07D487/04
Inventor 吴照球陆涛陈亚东朱雍傅蓉李红玫崔昊李阳
Owner CHINA PHARM UNIV
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