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Application of curcumin analog S5 containing thiapyrone structure in preparation of anti-inflammation drugs

A technology of curcumin analogues and thiopyrones, which can be used in medical preparations containing active ingredients, anti-inflammatory agents, drug combinations and other directions, and can solve the problems of weak stability of curcumin and the like

Inactive Publication Date: 2014-07-16
WENZHOU MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Through a large number of documents and patents, we found that although it is generally believed that the active groups in the structure of curcumin are its phenolic hydroxyl group and β-diketone group, in the related research on curcumin analogues, it was also found that no Monocarbonyl curcumin analogues of β-diketones sometimes also exhibit strong biological activity, which also raises doubts that the β-diketone group is an essential group for the activity of curcumin
Moreover, the β-diketone skeleton is the main reason for the weaker stability of curcumin

Method used

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  • Application of curcumin analog S5 containing thiapyrone structure in preparation of anti-inflammation drugs
  • Application of curcumin analog S5 containing thiapyrone structure in preparation of anti-inflammation drugs
  • Application of curcumin analog S5 containing thiapyrone structure in preparation of anti-inflammation drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] Synthesis of Compound S5

[0023] At room temperature, 10 mmol of vanillin was dissolved in 12 mL of ethanol, and then 5 mmol of thiopyrone was added thereto. After reacting at room temperature for half an hour, HCl gas was passed into it until TLC detected that the starting point disappeared. Then the reaction mixture was poured into 25 mL of ice water, and a yellow precipitate was produced. After filtration, the residual solid was washed with water and directly carried out to the next reaction without further purification. Dissolve the residual solid in 10 mL of tetrahydrofuran, add 3 mL of triethylamine, stir for half an hour, then add corresponding 10 mmol of isobutyryl chloride to it, after the reaction is complete, concentrate, and pass through a silica gel column to obtain compound S5 with a purity greater than 98%. target compound.

[0024] [(1Z,1'Z)-(4-Oxo-2H-thiopyran-3,5(4H,6H)-diylidene)bis(methylidene)]bis(2-methoxy-4,1-phenylene)bis(2- methylpropanoate)...

Embodiment 2

[0026] Compound S5 inhibits the release of inflammatory factors (TNF-α and IL-6) from macrophages stimulated by LPS

[0027] The method of inhibiting the release of inflammatory factors by LPS-stimulated macrophages using compounds, the detailed steps are as follows: 1.2×10 6 RAW264.7 macrophages were cultured with DMEM medium at 37°C. After 24 hours, the medium was renewed, and the compound to be tested (the final concentration was 10 μM) was added for pretreatment for 2 hours, and then continued to be treated with 0.5 μg / mL LPS. After 22 hours, the culture fluid was collected, and the contents of TNF-α and IL-6 were detected by ELISA; the cells were collected to detect the total protein concentration. The -6 content was calibrated to 100; each compound was tested three times, and the average value and error value were calculated. During the test, the positive drug curcumin (cur) was used as a control. The inhibitory activities of compound S5 on the release of IL-6 and TNF-...

Embodiment 3

[0030] Toxicity of compound S5 to normal human liver cells HL-7702 and the stability test of its compound

[0031] After being treated with 10 μM compound S5 for 24 hours, the cell survival rate of human normal hepatocyte cells HL-7702 was detected by MTT (thiazolium blue), which was used to characterize the activity of the compound on hepatocyte HL-7702 ( image 3 A); Compound S5 was dissolved in DMSO to prepare a 10 μM solution. The absorbance of the compound at 0, 5, 10, 15, 20, and 25 min was detected in the wavelength range of 250-600 nm. Because the intensity of absorbance is directly proportional to the content or concentration of the compound in the solution, this parameter is used to characterize the stability of the compound ( image 3 B).

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Abstract

The invention belongs to the field of the pharmaceutical chemistry and pharmacology, and concretely relates to an application of a compound of [(1Z,1'Z)-(4-Oxo-2H-1-thiopyran-3,5(4H,6H)-diylidene)bis(methanylylidene)]bis(2-methoxy-4,1-phenylene)bis(2-methylpropanoate) (S5) in the preparation of anti-inflammation or / and anti-oxidation drugs. The above thiapyrone type curcumin analog S5 can dose-dependently inhibit the expression and release of inflammation factors comprising TNF-alpha, IL-6 and the like, and can also obviously improve the survival rate of mice death-induced by LPS. The compound has a good safety and stability, and can be exploited to inflammation or / and oxidation stress related disease treatment drugs.

Description

Technical field: [0001] The invention belongs to the field of medicinal chemistry and pharmacology, in particular to compound S5, whose chemical name is [(1Z, 1'Z)-(4-Oxo-2H-thiopyran-3, 5(4H, 6H)-diylidene)bis( Methylidene)]bis(2-methoxy-4, 1-phenylene)bis(2-methylpropanoate) in the treatment of diseases caused by inflammation or / and oxidative stress, this compound inhibits the expression and release of various inflammatory factors Therefore, they can achieve good anti-inflammatory effects in vitro and in vivo, and they also have good antioxidant activity, and have the prospect of being developed as therapeutic drugs related to inflammation or / and oxidative stress. Background technique: [0002] Current status of anti-inflammatory drugs: [0003] Inflammation is a defense response of living tissue with vascular system to damaging factors. Most diseases are accompanied by inflammation, which can aggravate the occurrence and development of diseases, and some chronic inflamm...

Claims

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Application Information

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IPC IPC(8): A61K31/382A61P29/00A61P19/02A61P9/00A61P7/10A61P21/00A61P9/10A61P25/16A61P15/00A61P1/02C07D335/02
Inventor 冯建鹏梁广李校堃姜鑫唐龙光张亚利胡杰蔡跃飘吴建章
Owner WENZHOU MEDICAL UNIV
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