Targeting STAT3 inhibitor and application thereof

A technology of targeting activity and thiophene, applied in the field of medicine, can solve the problems of less research, low bioavailability, complex structure of STAT3 inhibitors, etc., and achieve the effect of good anti-tumor activity and good physicochemical properties

Pending Publication Date: 2015-08-19
SUZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

STAT3 inhibitors include natural products, peptides and peptidomimetics, and small molecule inhibitors; natural product STAT3 inhibitors have complex structures and few studies; peptides and peptidomimetics have good activity, but due to low bioavailability in vivo, It is still very difficult to develop into clinical drugs; small molecule i

Method used

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  • Targeting STAT3 inhibitor and application thereof
  • Targeting STAT3 inhibitor and application thereof
  • Targeting STAT3 inhibitor and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0071] Embodiment 1 Preparation of benzothiophene 1,1-dioxy derivatives E1-E44

[0072] Synthetic routes of benzothiophene 1,1-dioxo derivatives E1-E44 (see figure 1 , figure 2 ):

[0073] (1) Preparation of Intermediate B1-B7:

[0074] Compound A1-A7 (9.90mmol) was dissolved in 20mL of DMF, adding K 2 CO 3 (5.47g, 39.6mmol), methyl thioglycolate (10.9mmol, 0.97mL), the reaction system was placed in an oil bath at 60°C and stirred for about 3h. After the reaction was completed, 50 mL of ice water was added to the reaction system, and a white solid was precipitated immediately, filtered under reduced pressure, and the filter cake was dried under an infrared lamp to obtain white solids B1-B7, yield: 67%-85%.

[0075] (2) Preparation of intermediate C1-C7:

[0076] Compounds B1-B7 (1.1 mmol) were suspended in 10 mL of aqueous methanol (80%), potassium hydroxide (0.300 g, 5.4 mmol) was added to the reaction system, and stirred at room temperature for about 16 h. After the ...

Embodiment 2

[0263] Example 2 Antitumor Activity Experiment of Benzothiophene 1,1-Dioxy Derivatives E1-E44

[0264] Example 1 provides the synthesis route of benzothiophene 1,1-dioxy derivatives E1-E44, and the following biological tests are carried out after the H NMR and C NMR structures are confirmed to be correct. The following are p-benzothiophene 1,1-dioxy derivatives E1-E44 in breast cancer cells (MDA-MB-231, MDA-MB-435S, MCF-7), prostate cancer cells (Du145), pancreatic cancer cells ( PANC-1), non-small cell lung cancer cells (A549) to evaluate the anti-proliferation effect (ie MTT test):

[0265] (1) Cytotoxicity test (MTT) of benzothiophene 1,1-dioxy derivatives E1-E44 on breast cancer cells (MDA-MB-231) and prostate cancer cells (DU145)

[0266] MTT test: With Stattic as a positive control, the MTT method was used to determine the in vitro cytotoxicity test of the compound on breast cancer cells (MDA-MB-231) and prostate cancer cells (DU145). The compound was made into a mothe...

Embodiment 3

[0278] Example 3 Effect of Benzothiophene 1,1-Dioxy Derivatives E1-E44 on Phosphorylation of STAT3 in Breast Cancer Cells

[0279] Western blot: breast cancer cells MDA-MB-231 and MDA-MB-435S growing in the logarithmic phase were respectively mixed with 1.5×10 6 The density of the dish is spread at 10cm 2 in the petri dish. After 12 hours of wall attachment, compounds E1, E15, E16, E27, E28, E29, E30, E31, E33, and E34 were added at a concentration of 4 μM, and Stattic was used as a positive control. After 12 hours of drug treatment, the cells were collected in a 1.5mL EP tube, an appropriate amount of cell lysate was added, and lysed on ice for 30 minutes, followed by 1.48×10 4 Centrifuge at r / min, take the supernatant, and measure the protein concentration. Calculate the protein concentration of the sample according to the standard protein concentration, add the corresponding 5×SDS protein loading buffer, and cook the protein at 100°C for 5 minutes. Prepare SDS-PAGE gel ...

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Abstract

The invention discloses a benzothiazine-1,1-dioxides having a structure of Formula I as a new type of highly efficient STAT3 small molecule inhibitor, which is used for developing antineoplastic drugs.

Description

technical field [0001] The invention relates to the field of medical technology, in particular to benzothiophene 1,1-dioxide as a novel high-efficiency STAT3 small molecule inhibitor for the development of antitumor drugs. Background technique [0002] Cancer is a general term for a large class of malignant tumors. Cancer cells are characterized by unlimited and endless proliferation, which consumes a large amount of nutrients in the patient's body; cancer cells release a variety of toxins, causing a series of symptoms in the human body; cancer cells can also be transferred to grow and multiply throughout the body, Lead to body weight loss, weakness, anemia, loss of appetite, fever, and severe damage to organ function. [0003] Chemotherapy is an important clinical method for treating cancer, and the development of antineoplastic drugs focuses on the research of targeted drugs. In the process of tumor development, transcription factors play an important role in regulating ...

Claims

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Application Information

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IPC IPC(8): C07D333/70C07D409/06A61P35/00
CPCC07D333/70C07D409/06
Inventor 乔春华季鹏
Owner SUZHOU UNIV
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