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Compound cyd19 or pharmaceutically acceptable salt as snail inhibitor and its preparation method, pharmaceutical composition and use

A technology of inhibitors and compounds, applied in drug combinations, active ingredients of heterocyclic compounds, organic chemistry, etc., can solve problems such as uncertain mechanism research, limited compound development, and no obvious inhibitory effect, so as to reduce the level of acetylation , Improve the effect of tumor treatment, accelerate the effect of degradation

Active Publication Date: 2021-08-17
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 as snail inhibitor and its preparation method, pharmaceutical composition and use
  • Compound cyd19 or pharmaceutically acceptable salt as snail inhibitor and its preparation method, pharmaceutical composition and use
  • Compound cyd19 or pharmaceutically acceptable salt as snail inhibitor and its preparation method, pharmaceutical composition and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Example 1: The preparation steps of the compound CYD19 or the pharmaceutically acceptable salt thereof of the present embodiment, the preparation steps are as follows:

[0038]4 - [[4 - [(5-methyl-1H-pyrazole-3-yl) amino group] pyrrole [2, 1-f] [1, 2, 4] triazine-2-yl] sulfur ] Methyl] benzoic acid is completely dissolved in N, N-dimethylformamide, then add TBTU and N, N-diisopropylethylamine, and then add to fluorinestorethysine after stirring, continuing normal temperature and stir The reaction solution was evaporated to dryness, and the evaporation and the silica gel mixture were added to the ethyl acetate solvent, and then evaporated to dryness at a temperature of 40 ° C to 50 ° C, and the evaporation was added to the silica gel column upper layer. The oil ether was eluted with EtOAc EtOAc (EtOAc) EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc (EtOAc) -4-fluorophenyl) -4 - [[[4 - [(5-methyl-1H-pyrazole-3-yl) amino] pyrrole [2, 1-f] [1, 2, 4] three Naz...

Embodiment 2

[0039] Example 2: Biolayer Interferometry Detection Compound CYD19 on Snail Protein affinity.

[0040] The recombinant Snail protein was dissolved in PBS and placed in a 100 ul Tube tube. EZ-LINK NHS-biotin was incubated with Snail recombinant proteins for 60 minutes at room temperature (protein and biotin molar ratio of 1: 3). Salting is used to remove excess biotin. Fixed biotinylated proteins on the Super Streptavidin biosensor for further measurement. Blank recombinant proteins were used as a control. CYD19 of different concentrations (0.5, 0.25, 0.125, 0.063, 0.031 μm) was used as a non-specific control. The combination of CYD19 and Snail-protein was measured using an OCTET RED 96 instrument (FortebiO), and the deviation strength of the light was measured using a 1: 1 binding model. The results show that CYD19 and SNAIL protein have high affinity (k d = 180 nm), figure 1 .

Embodiment 3

[0041] Example 3: WesternBlot detects the effect of CYD19 on the expression of Snail protein.

[0042] The cells were seeded in the hexagon plate, and after the cells were attached to the cells, different concentrations CYD19 (25, 50, 75, 100 nm) were treated for 24, 48 hours, extracted by the protein and determined the concentration, according to the size of the protein molecular weight, The 10% SDS polyacrylamide gel, 90V concentrated glue, 120 V separation glue electrophoresis were prepared without the concentration gradient, 2.5-3 h. The film is carried out by a full wet film transfer method, and according to the size of the suitable size, the nitrocellulose film is cut, the glue is on the negative electrode, the film is on the positive electrode, and the constant current is 250mA, the film time is adjusted according to the desired protein Kd. . The nitric acid fiber membrane transferred to the protein was immersed in Lichunhong after 5 minutes, washed with distilled water, ob...

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Abstract

The invention discloses a compound CYD19 having a structure of formula (I) as a Snail inhibitor or a pharmaceutically acceptable salt thereof, a preparation method, a pharmaceutical composition and an application thereof. Application of the compound in the preparation of medicines for preventing or treating diseases related to abnormal expression of Snail. It particularly relates to the application of the compound in the preparation of antitumor and cardiovascular drugs. Pharmacological results show that the compound has a high affinity with Snail protein, has good anti-tumor cell proliferation in vitro, promotes cell apoptosis, and inhibits tumor metastasis. Moreover, the compound exhibited obvious in vivo anti-tumor proliferation and metastasis activity in HCT-116 subcutaneous xenograft tumor nude mice and in vivo liver metastasis models injected with spleen, and is a potential drug that can be used clinically to prepare 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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Patent Type & Authority Patents(China)
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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