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Application of piperidone-containing single-carbonyl curcumin compound in preparation of anti-inflammatory drug

A compound and drug technology, applied in the field of medicinal chemistry, can solve the problems of limited application, low absorption, fast metabolism and low bioavailability

Inactive Publication Date: 2013-07-03
WENZHOU MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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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 better stability only when PH<6.5

Method used

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  • Application of piperidone-containing single-carbonyl curcumin compound in preparation of anti-inflammatory drug
  • Application of piperidone-containing single-carbonyl curcumin compound in preparation of anti-inflammatory drug
  • Application of piperidone-containing single-carbonyl curcumin compound in preparation of anti-inflammatory drug

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] The synthesis of embodiment 1 compound

[0024] Dissolve 2 mmol of the corresponding ketone and 4 mmol of the corresponding substituted benzaldehyde in absolute ethanol: water (10:1), add 5-10 drops of 40% NaOH solution at 5-8°C (if the benzaldehyde contains hydroxyl groups, use HCl gas as a catalyst), after reacting at 5-8°C for 5-24h, the progress of the reaction was detected by TLC. After the reaction, 1-2 times the volume of the reaction liquid was added to precipitate a precipitate, which was suction filtered and vacuum-dried overnight to obtain a powder product, which was purified by silica gel column chromatography to obtain compounds with a purity greater than 98%. Representative compounds and their physicochemical properties are described below:

[0025] Comparative compound F1: (2E,5E)-2,5-bis(3,4-dihydroxybenzylidene)cyclopentanone (F1).13.7% yield, mp260.7℃. 1 H-NMR (DMSO-d 6 ), δ: 9.563 (brs, 2H, OH-4), 9.211 (brs, 2H, OH-3), 7.238 (s, 2H, Ar-CH=C×2), 7....

Embodiment 2

[0059] Inhibition of the compound of Example 2 on the release of inflammatory factors from macrophages stimulated by LPS

[0060] The preliminary anti-inflammatory activity of the compound in vitro was tested by using the compound to inhibit the release of inflammatory factors (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 average va...

Embodiment 3

[0061] Example 3 The dose-effect relationship of the active compound inhibiting the release of inflammatory factors from macrophages stimulated by LPS

[0062] The dose-effect relationship of active compounds inhibiting the release of IL-6 from RAW264.7 macrophages stimulated by LPS was further tested. The method was the same as in Example 2. For experimental data, see figure 2 . The inhibitory activity of the compounds on IL-6 has a good dose-effect relationship, the IC of F8, F29, F33, F35, F36 on the inhibitory activity of IL-6 50 They are 2.04, 2.73, 4.19, <1.0, and 2.68 μM, respectively, which shows that these compounds all have medicinal prospects.

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Abstract

The invention belongs to the field of pharmaceutical chemistry and in particular relates to an application of a specific piperidone-containing single-carbonyl curcumin compound in preparation of an anti-inflammatory drug and medicines used for treating related inflammation diseases. The curcumin compound can inhibit expression and release of an inflammation-suppressing factor IL-6, obviously reverse degradation of I kappa B related to regulation of inflammation and inhibit phosphorylation of inflammation signal channels such as ERK and JNK; and in vivo experiments show the curcumin compound can obviously improve survival rate of mice which are about to die owning to induction by virtue of LPS (lean process solution).

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): A61K31/45A61P29/00A61P19/02A61P19/06A61P31/00A61P3/10A61P9/10A61P13/12
Inventor 梁广吴建章姜鑫张亚利陈高帜王哲
Owner WENZHOU MEDICAL UNIV
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