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Small molecular compound for inhibiting activity of AKT and STAT3 and application of small molecular compound

A small molecule compound, active technology, applied in the direction of organic active ingredients, organic chemistry, drug combination, etc., to achieve the effect of inhibiting tumor cell proliferation and eliminating tumor stem cells

Active Publication Date: 2020-09-15
XUZHOU MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Its clinical trials in glioblastoma are ongoing, and no results have been reported

Method used

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  • Small molecular compound for inhibiting activity of AKT and STAT3 and application of small molecular compound
  • Small molecular compound for inhibiting activity of AKT and STAT3 and application of small molecular compound
  • Small molecular compound for inhibiting activity of AKT and STAT3 and application of small molecular compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] Example 1, (E)-1-(3-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5,6-dihydropyridine-2(1H) preparation of

[0023] Step 1: Synthesis of 5-bromo-1-toluene-1H-pyrrolo[2,3-b]pyridine (f-1)

[0024]

[0025] 1.5 g of sodium hydride (60 mmol) was dissolved in 250 ml of tetrahydrofuran containing 10 g of 5-bromo-1H-pyrrolo[2,3-b]pyridine (50 mmol) at -50°C. Stir at -50 °C for 30 min, then add 12 g of p-toluenesulfonyl chloride (60 mmol) dissolved in 50 ml of tetrahydrofuran, and continue stirring at -50 °C for 1.5 h; extract and combine organic layers, concentrate in vacuo, and dry over sodium sulfate , purified by column chromatography to obtain 5-bromo-1-toluene-1H-pyrrolo[2,3-b]pyridine (ie compound f-1), 15 g of white solid, and the yield was 80%.

[0026] Step 2: Synthesis of (E)- ethyl 3-(1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acrylate (f-2)

[0027]

[0028] 5 g of compound f-1, 1.56 g of ethyl acrylate, 4.16 g of palladium acetate, and 4.32 g of tris(o-to...

Embodiment 2

[0038] Example 2, CCK-8 method to detect the activity of compound f-5 on glioblastoma cells

[0039] experimental method:

[0040]Glioblastoma cells were plated in triplicate on 96-well plates (3000 cells per well). After overnight culture, 0.1% DMSO was added to the control group, and 0.375 μM, 0.75 μM, 1.5 μM, 3 μM, 6 μM and 12 μM of compound f-5 were incubated for 72 hours. 10 μL of CCK-8 solution was added to each well, and after incubation for 2 hours, the absorbance at a wavelength of 450 nm was detected with a microplate reader.

[0041] Experimental results such as figure 1 It was shown that compound f-5 had growth inhibitory effects on the four glioblastoma cell lines in a concentration-dependent manner, and the IC50 values ​​of the four cell lines ranged from 0.5 to 5.0 μM.

Embodiment 3

[0042] Embodiment 3, EdU incorporation test detects the inhibitory effect of compound f-5 on the proliferation of glioblastoma cells

[0043] experimental method:

[0044] Cell proliferation was detected with the Cell-LightTM EdU Cell Proliferation Detection Kit according to the instructions. U87 cells were seeded in 96-well plates, and after the cells adhered to the wall, the cells were treated with 0.1% DMSO or 0.5 and 1.0 μM of compound f-5. After 24 hours, incubation was continued for 4 hours with 50 μM EdU, followed by fixation with 4% paraformaldehyde for 15 minutes and treatment with 0.5% Triton X-100 for 20 minutes. Cells were incubated with 1 × Apollo® reaction cocktail for 30 minutes and then stained with DPAI for 15 minutes. After washing with PBS three times, photographs were taken under a fluorescent inverted microscope, and the experiment was repeated three times.

[0045] Values ​​represent relative percentages of EdU-positive cells in cells treated with diff...

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Abstract

The invention provides a small molecular compound for inhibiting the activity of AKT and STAT3 and an application of the small molecular compound. The structure of the small molecular compound is shown as a compound f-5. The small molecular compound f-5 provided by the invention can inhibit the activities of AKT and STAT3 at the same time, can effectively inhibit the growth and proliferation of various glioblastoma cell strains, and prolongs the survival time of tumor-bearing mice. The compound provided by the invention has a clinical treatment value on glioblastoma and tumors depending on AKTand STAT3 pathways.

Description

technical field [0001] The invention belongs to the field of medicine, and specifically, the invention provides a small molecular compound for inhibiting the activity of AKT and STAT3 and application thereof. Background technique [0002] Glioblastoma is the most malignant adult primary malignant brain tumor in the central nervous system. The current surgical methods cannot completely remove the tumor, which has the characteristics of high recurrence rate and high mortality rate. The prognosis of patients with glioblastoma is very poor, and the median survival time of patients is only 12-15 months. At present, the main treatment drug is temozolomide, but its therapeutic effect has not greatly improved the survival period of patients with glioblastoma. There is a lack of other effective therapeutic drugs, especially small molecule drugs for targeted therapy. Finding new therapeutic drugs or methods for glioblastoma to prolong the survival of patients is an urgent problem t...

Claims

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Application Information

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IPC IPC(8): C07D471/04A61K31/444A61P35/00
CPCC07D471/04A61P35/00
Inventor 刘雪娇牛铭山于如同张旭刘关政
Owner XUZHOU MEDICAL UNIV
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