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STAT3 small molecular selective inhibitor and preparation method and application thereof

A molecular selectivity and inhibitor technology, applied in the field of STAT3 inhibitors and small molecule selective inhibitors of STAT3, can solve the problems of difficult medicinal use and poor bioavailability, and achieve good medical efficacy, strong practicability, and preparation. simple method effect

Inactive Publication Date: 2012-04-18
NANJING UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, because peptides are easy to metabolize, have poor bioavailability, and are difficult to use as medicine, there is an urgent need to develop organic small molecule inhibitors with high selectivity and strong activity.

Method used

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  • STAT3 small molecular selective inhibitor and preparation method and application thereof
  • STAT3 small molecular selective inhibitor and preparation method and application thereof
  • STAT3 small molecular selective inhibitor and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Example 1 Virtual screening of small molecule inhibitors based on STAT3 protein structure

[0035] STAT3 organic small molecule inhibitor obtained through virtual screening. The protein crystal structure code 1BG1 was obtained from ProteinDataBank. The databases used in the virtual screening include Specs, Maybridge, these two databases include more than 400,000 organic compounds in total, these databases can be obtained from the ZINC database, and what is obtained is a three-dimensional model of the compound.

[0036] The molecular docking program Autod°k (version 4.2) and the virtual screening tool PyRx were used for virtual screening. In order to obtain a better screening structure, the chain B of the protein structure 1BG1 was removed from the structure, and processed by removing water, adding hydrogen, mixing non-polar hydrogen, and calculating GasteigerCharges. The docking area was set in the SH2 area of ​​​​the protein, and the Gridbox setting Large enough to c...

Embodiment 2

[0037] Example 2 Synthesis of 2-phenyl-6-chloroquinoline-4-carboxylic acid methyl ester

[0038] Mix 40mL of water and 90g of sodium sulfate in a 1000mL reaction flask, dissolve 9.92g of chloral in 20mL of water, and add to the reaction flask. Mix 5.51g of p-chloroaniline, 10mL of concentrated hydrochloric acid, and 70mL of water to form a uniform solution, and slowly drop it into the reaction flask. After the dropwise addition, 9.03g of hydroxylamine hydrochloride in 40mL aqueous solution was added dropwise, and the temperature was raised to 85°C for 2.5h after the dropwise addition, and then rapidly cooled to room temperature, a white solid was precipitated, suction filtered, washed with water, and dried to obtain 7.3g of the product N-(4- Synthesis of chlorophenyl)-2-oxime)acetamide 2. The reaction formula for this reaction is:

[0039]

[0040] The product is characterized, and the specific data are: 1 HNMR (300 MHz, DMSO): δ 12.19 (s, 1H), 10.29 (s, 1H), 7.75-7.66 (m,...

Embodiment 3

[0050] Example 3 Synthesis of 2-(4-bromophenyl)-6-chloroquinoline-4-carboxylic acid methyl ester

[0051] The structural formula of 2-(4-bromophenyl)-6-chloroquinoline-4-carboxylic acid methyl ester is:

[0052]

[0053] Synthetic method is with the synthetic of 2-phenyl-6-chloroquinoline-4-carboxylate methyl ester among the embodiment 2, difference is to use 4-bromoacetophenone to replace the acetophenone in the example 2, obtain 2-(4 -Bromophenyl)-6-chloroquinoline-4-carboxylic acid, 2-(4-bromophenyl)-6-chloroquinoline-4-carboxylic acid reacts with methanol to obtain 2-(4-bromophenyl)- Methyl 6-chloroquinoline-4-carboxylate.

[0054] The product is characterized, and the specific data are: 1 HNMR (300MHz, DMSO): δ8.60(s, 1H), 8.47(s, 1H), 8.23(s, 2H), 8.10(s, 1H), 7.83(s, 1H), 7.46-1.62(m, 3H), 4.00(s, 3H); 13 CNMR (125MHz, DMSO): δ168.89, 157.95, 143.08, 138.15, 136.15, 132.46, 131.8, 131.72, 130.59, 130.22, 129.77, 125.43, 124.81, 123.11, 52.08; + .

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Abstract

The invention discloses an STAT3 small molecular selective inhibitor and a preparation method and applications thereof, and the STAT3 small molecular selective inhibitor comprises four structure general formulae as shown in formula I, formula II, formula III and formula IV. The preparation comprises the following steps: allowing 2-phenyl substituted quinoline-4-carboxylic acid thionyl chloride or oxalyl chloride to react to generate substituted acyl chloride, reacting with substituted arylamine to generate substituted quinoline-4-amide derivatives. The applications comprise an application in the preparation of medicaments for treating cancers related to abnormally-activated STAT3 pathway, and an application in the preparation of antitumor medicaments where the STAT3 small molecular selective inhibitor is used as an inhibitor of the STAT3 signal pathway. The STAT3 inhibitor of the invention is a small molecular selective inhibitor; based on results obtained by detecting its effect on cancer cells and evaluating its activity, the small molecular STAT3 selective inhibitor of the invention is applicable to the development of related cancer-treatment medicaments, has quite wide applications, and has very good medicine curative effect. The small molecular STAT3 selective inhibitor of the invention has various types, easily available raw materials, a simple preparation method, high product purity, high yield, and strong practicality.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and relates to STAT3 inhibitors, in particular to a small molecule selective inhibitor of STAT3 and its preparation method and application. Background technique [0002] The onset of tumors is usually hidden, and the early diagnosis rate is low. With the in-depth discovery and research of oncogenes, tumor suppressor genes and other related genes, tumors are considered to be a disease of polygenic abnormalities, and abnormal protein functions in signal transduction pathways play an important role in the development of tumors. Therefore, the study of important tumor-related signal transduction pathways can not only clarify the mechanism of tumor occurrence and development, but also provide targets for new treatment options and develop anti-tumor drugs. [0003] STAT3 is a member of the STAT protein family of cell signal transduction and activation factors. In normal cells, the activation of STAT3...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/52A61K31/47A61K31/4709A61P35/00A61P35/02
Inventor 李建新史志兵
Owner NANJING UNIV
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