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Application of small molecular compound WB460 in preparation of medicine for treating pancreatic cancer

A small molecule compound, pancreatic cancer technology, applied in the field of medicine and its preparation and application, can solve the problems of poor permeability, low anti-cancer activity, limitation and the like

Inactive Publication Date: 2018-07-24
EAST CHINA NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the unstable metabolism and poor permeability of STAT3 polypeptide inhibitors, their application in vivo is limited; due to the rapid degradation of nucleases, oligonucleotide inhibitors have poor bioavailability, poor pharmacokinetics and short half-life , so the clinical use is limited; STA-21, Cryptotanshinone, Stattic, BBI608 and JMC-9 among the small molecule compound inhibitors all contain quinone or quinone-like structures, which show greater toxicity and anti-cancer clinically less active
Despite some promising studies, no direct STAT3 inhibitors have been approved for clinical use

Method used

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  • Application of small molecular compound WB460 in preparation of medicine for treating pancreatic cancer
  • Application of small molecular compound WB460 in preparation of medicine for treating pancreatic cancer
  • Application of small molecular compound WB460 in preparation of medicine for treating pancreatic cancer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] Example 1: Preparation of WB460.

[0056] Weigh N-BOC-4-piperidone, malononitrile, sulfur and L-proline, dissolve them in DMF, stir and react at 60°C for 10 h; after cooling, slowly add the reaction solution dropwise to the stirred water, and The precipitated solid was filtered, dried, and purified by column chromatography to obtain an intermediate 2-amino-3-cyanopiperidothiophene derivative. The intermediate 2-amino-3-cyanopiperidothiophene derivative, 1-methylpyrazole-4-carboxylic acid, 2-chloro-1-methylpyridinium iodide and DMAP were dissolved in 10 mL of dichloromethane, While stirring, triethylamine was slowly added dropwise and heated to reflux for 4h. After column chromatography, the intermediate 2-(1-methyl-4-pyrazole)-carboxamido-3-cyano-6-tert-butoxycarbonyl was obtained -4,5,6,7-Tetrahydro[2,3-c]piperidothiophene. The intermediate 2-(1-methyl-4-pyrazole)-carboxamido-3-cyano-6-tert-butoxycarbonyl-4,5,6,7-tetrahydro[2,3-c] Piperidothiophene was dissolved in ...

Embodiment 2

[0058] Example 2: Formula (I) WB460 strongly inhibits the proliferation of pancreatic cancer cells highly expressing STAT3 (Y-705) phosphorylated protein and the protein level of STAT3 in pancreatic cancer cells.

[0059] Technical method

[0060] (1) Cell culture

[0061] Pancreatic cancer cells PANC-1, BxPC-3, MIAPaCa-2, SW1990, AsPC-1, Capan-2, and CFPAC-1 cells used in the present invention were all purchased from the Shanghai Cell Bank of the Chinese Academy of Sciences, and the cells were placed in a 37°C constant temperature incubator .

[0062] Pancreatic cancer PANC-1 cells were cultured in DMEM containing 10% fetal bovine serum and 1% sodium pyruvate, MIAPaCa-2 cells were cultured in DMEM containing 10% fetal bovine serum, 1% sodium pyruvate and 2.5% horse serum Among them, AsPC-1, BxPC-3 and Capan-2 cells were cultured in 1640 containing 10% fetal bovine serum and 1% sodium pyruvate, CFPAC-1 cells were cultured in 10% fetal bovine serum in IMEM, SW1990 Cells were...

Embodiment 3

[0069] Example 3: Formula (I) WB460 down-regulates phosphorylation of STAT3 (Y705).

[0070] Technical method

[0071] (1) Western Blot

[0072] method as above

[0073] Experimental results such as figure 2 As shown, it can be seen from Figure (A) that formula (I) WB460 concentration gradient significantly down-regulates the phosphorylation of STAT3 (Y705) in PANC-1 and BxPC-3 cells, while for STAT3 protein and STAT3 (S-727) The phosphorylation level has no effect; Figure (B) shows that the formula (I) WB460 concentration gradient down-regulates the phosphorylation level of STAT3 (Y705) in other pancreatic cancer cells.

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Abstract

The invention discloses application of a small molecular compound WB460 shown in a formula (I).in preparation of a medicine for treating pancreatic cancer In vitro, the compound can inhibit proliferation, migration, invasion and colon of pancreatic cancer cells, and can induce pancreatic cancer cells to generate apoptosis and cell cycle arrest; in vivo, WB460 inhibits growth and transferring of pancreatic cancers. The WB460 has good application prospect.

Description

technical field [0001] The invention belongs to the technical field of medicine and its preparation and application, and in particular relates to the application of small molecular compound WB460 in the preparation of drugs for treating pancreatic tumors. Background technique [0002] Pancreatic cancer is a highly malignant tumor of the digestive tract. Early patients have no obvious symptoms and no sensitive and specific labeling proteins. Prevention or early diagnosis is relatively difficult. The prognosis of patients is poor, and the 5-year survival rate is less than 7%. "King of Cancer". In recent years, the morbidity and mortality of pancreatic cancer have increased significantly, ranking fourth in the mortality rate of pancreatic cancer in developed countries, and it is predicted that it will become the second leading cause of death in the next ten years. [0003] At present, according to different stages of development, the treatment of pancreatic cancer includes sur...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4365A61P35/00A61P35/02A61P35/04
CPCA61K31/4365
Inventor 易正芳郝运周文波陈煌廖园洪陈益华刘明耀
Owner EAST CHINA NORMAL UNIV
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