Application of allyl-containing monocarbonyl curcumin analogs in preparing antiinflammatory drugs

A technology of allyl phenyl and medicinal salts, applied in the field of medicinal chemistry, can solve the problems of excessive metabolism, low bioavailability, low activity of curcumin, and limited application

Active Publication Date: 2014-01-22
WENZHOU MEDICAL UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, further studies have found that curcumin has low activity in the body, less absorption in the body, fast metabolism and low bioavailability, which greatly limits its application.
However, considering its exact biological activity and relatively simple molecular structure, curcumin is still an excellent lead compound for structural modification and anti-inflammatory drug screening. The design, synthesis, evaluation and screening of curcumin analogues for sexual purposes has attracted many drug research and development institutions and drug companies
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 curcumin analogues that do not contain these two active groups In terms of research, it has also been found that monocarbonyl curcumin analogues that do not contain β-diketones sometimes show stronger activity, which raises doubts that the β-diketone group is an essential group for the activity of curcumin
Moreover, due to the existence of the β-diketone structure, the stability of curcumin is weak, and it has good stability only when PH<6.5

Method used

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  • Application of allyl-containing monocarbonyl curcumin analogs in preparing antiinflammatory drugs
  • Application of allyl-containing monocarbonyl curcumin analogs in preparing antiinflammatory drugs
  • Application of allyl-containing monocarbonyl curcumin analogs in preparing antiinflammatory drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] The synthesis of embodiment 1 compound

[0047] Preparation of intermediate 4-allyloxybenzaldehyde or 4'-(3-methyl-2-butenyloxy)benzaldehyde (7): Weigh 5 g (40.9 mmol) of p-hydroxybenzaldehyde and potassium carbonate 11.3 g (81.8mmol), it was dissolved in 20ml of acetone, stirred until dissolved, then added allyl bromide 9.9g (81.8mmol) or isopentenyl benzaldehyde 15.56g (81.8mmol), stirred at room temperature, TLC The reaction process was monitored, and the reaction was completed after about 5 hours. Spin the solvent with a vacuum pump, then extract with ethyl acetate, wash with saturated NaCl for 3 times, and wash the ethyl acetate layer with anhydrous NaCl 2 SO 4 After drying, the ethyl acetate layer was removed by rotary evaporation and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow oily liquid 7.

[0048] Preparation of intermediate α, β-unsaturated ketone analog (9): Weigh 2 g (11.3 mmol) of com...

Embodiment 2

[0071] Inhibition of the compound of Example 2 on the release of inflammatory factors from macrophages stimulated by LPS

[0072] The preliminary anti-inflammatory activity of the compound in vitro was tested by using the compound to inhibit the release of inflammatory factors (TNF-α and IL-6) from RAW264.7 macrophages stimulated by LPS. The specific method is 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 test compound (final concentration: 10 μM) was added for pretreatment for 2 hours, and then treated with 0.5 μg / mL LPS for 22 hours. hours, collect the culture fluid and use ELISA method to detect the content of TNF-α and IL-6; collect the cells to detect the total protein concentration, the ELISA results are divided by the corresponding total protein concentration, and the TNF-α and IL-6 in the LPS control group The content was calibrated to 100; each compound was tested three times, and the ...

Embodiment 3

[0073] Example 3 Toxicity of Active Compounds to Human Normal Hepatocytes HL-7702

[0074] Spread HL7702 cells into 96-well plates at a density of 5000 cells per well, and use 1640 medium containing 5% heat-inactivated serum, 100 U / ml penicillin, and 100 μg / ml streptomycin at 37 °C containing 5%CO 2cultured in an incubator for 24 h. The test compound dissolved in DMSO was added to the culture medium with a final concentration of 20 μM, and the MTT assay was carried out after 72 hours of action. Add 25 μL of MTT (5 mg / ml) dissolved in physiological saline to each well and incubate for 3 h. Then the cells were lysed with 100 μL DMSO, and the OD value was detected with a microplate reader at a wavelength of 570 nm. For experimental data, see image 3 . All tested active compounds showed no toxicity to HL7702 cells.

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Abstract

The invention provides allyl-containing monocarbonyl curcumin analogs with antiinflammatory actions. In addition, the invention also provides a pharmaceutical composition of the compounds, antiinflammatory application and the like.

Description

Technical field: [0001] The invention belongs to the field of medicinal chemistry. Specifically, the invention relates to the application of a class of curcumin structural analogs in the preparation of anti-inflammatory drugs and therapeutic drugs for inflammation-related diseases. These curcumin compounds inhibit various inflammatory factors The expression and release of the protein can achieve good anti-inflammatory effects in vitro and in vivo. Background technique: [0002] As an important pathological process, inflammation is very common in the human body, and it itself is an autoimmune response of the body to external or foreign body stimuli. And when this response is dysregulated or excessively responds to the body's self-injury, it evolves into inflammation. Therefore, most diseases are accompanied by the mediation and occurrence of inflammation, and the mediation and occurrence of inflammation aggravate the damage to the body of the disease, such as rheumatoid arth...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C49/255C07D295/112C07C205/45A61K31/12A61K31/5375A61P29/00A61P19/02A61P1/00A61P21/00A61P9/00A61P25/00A61P37/00A61P1/16A61P11/00A61P1/18A61P3/00
CPCC07C49/248C07C49/255C07C205/45C07D295/112
Inventor 梁广刘志国唐龙光蔡跃飘王怡邹鹏胡杰
Owner WENZHOU MEDICAL UNIV
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