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Application of japonicone A in preparation of tumor necrosis factor (TNF) inhibitor drugs

A technology of tumor necrosis factor and inula lactone, which can be used in anti-tumor drugs, drug combinations, respiratory diseases, etc., can solve problems such as slow progress in applied research, and achieve the effect of great clinical application value.

Inactive Publication Date: 2012-04-11
SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, compared with biological agents such as TNF-α monoclonal antibodies, the basic and applied research on small molecule antagonists of TNF-α is progressing slowly

Method used

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  • Application of japonicone A in preparation of tumor necrosis factor (TNF) inhibitor drugs
  • Application of japonicone A in preparation of tumor necrosis factor (TNF) inhibitor drugs
  • Application of japonicone A in preparation of tumor necrosis factor (TNF) inhibitor drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Example 1 Preparation of compound bisinulalide A

[0038] Dry inula (I.japonica, grown in Bozhou, Anhui, commercially available) aerial parts including stems, leaves, flowers) 10.0kg powder, room temperature (25 ℃) with 95% ethanol extraction 3 times, each Each time 80L took 24, 12, 12 hours respectively. After diluting 408.7 g of the obtained crude extract with an appropriate amount of water 10 L, it was sequentially extracted with 40 L of petroleum ether for four times, 40 L of dichloromethane for four times, 40 L of ethyl acetate for four times, and 10 L of n-butanol for extraction. The obtained dichloromethane extract 42.3g was separated with 200-300 mesh thin-layer silica gel, and the 2 Cl 2 - MeOH (100:0, 50:1, 20:1, 10:1, 5:1, 2:1,) for gradient elution. Thin-layer chromatography detects, collects and contains diinulalide A therein, adopts Sephadex LH-20 to carry out separation again, uses CH 2 Cl 2 -MeOH (1:1) was used to elute the mixture to obtain a mixtu...

Embodiment 2

[0040] Example 2 Virtual target screening suggests that TNF-α is the target of inulalide A

[0041] Inverse molecular docking calculations were performed using the INVDOCK software package. The software package has been patented by the United States (Patent No. US6519611). In this method, the three-dimensional structure of the drug molecule is input, and the combination of the drug molecule and the protein in the protein three-dimensional structure database is simulated by a computer program, so as to predict the protein to which the drug molecule binds and the binding active site. Using the INVDOCK software package, the potential target proteins of the active ingredients of traditional Chinese medicine can be predicted.

[0042] In this application, the three-dimensional structure of inulalide A was input into the INVDOCK software package for the NF-κB (cell transcription factor) signaling pathway (NF-Kbsignaling pathway) in the Biocarta signaling pathway database, see http:...

Embodiment 3

[0043] Example 3 BIACORE (Biomacromolecule Interaction Analyzer) analysis confirms the interaction between inulalide A and TNF-α

[0044] In order to further verify the direct interaction between inula lactone A and TNF-α, the biomolecular interaction analysis equipment BIACORE 3000 developed by Amersham Bioscience based on the principle of surface plasmon resonance (SPR) was used to analyze the interaction between inula lactone A and TNF-α. Interaction between lactone A and recombinant TNF-α molecule coupled to a sensor chip. The experimental process is as follows: Firstly, recombinantly expressed TNF-α (purchased from GeneTex, Inc., USA, purity>98%) is covalently coupled to the surface of the sensor chip using the amino coupling method in Biacore 3000 control software, and TNF-α is coupled to the surface of the sensor chip. The joint volume is 4000 Response Units (Response Unit, RU) ( image 3 ); the compound was dissolved in phosphate buffer containing 1‰ dimethyl sulfoxid...

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Abstract

The invention provides an application of japonicone A (chemical structural formula I) in preparation of tumor necrosis factor (TNF) inhibitor drugs. The japonicone A is inula japonica extract. In the invention, by adopting a reverse docking technology for virtual screening, the result shows that TNF-alpha is potential binding protein of the japonicone A; by adopting a BIACORE technology, the result shows that the japonicone A can be directly combined with TNF-alpha coupled on a chip, and can inhibit the combination of the TNF-alpha and the TNF-R (receptor) coupled on a sensor chip; and furthermore, an experiment confirms that the japonicone A can be directly combined with the TNF-alpha and can inhibit the interaction of the TNF-alpha and the TNF-R, thus the japonicone A can be used for preparing TNF inhibitor drugs. The drug provided by the invention is a pharmaceutical composition prepared from a medicinal carrier and the japonicone A used as an active ingredient. The pharmaceutical composition can be used for treating TNF-related diseases such as osteoarthropathy, asthma, bronchitis, allergic rhinitis and the like, thereby providing a new way for treating the diseases and obtaining greater clinical application values.

Description

technical field [0001] The invention relates to medicines, in particular to the application of inula inula extract in pharmacy, especially the application of inulalide A in the preparation of tumor necrosis factor inhibitor medicines. Background technique [0002] In 1975, Caswell et al. first injected BCG and endotoxin into mice, and found a substance in their serum that could cause hemorrhagic necrosis of mouse tumors, called tumor necrosis factor (tumor necrosis factor). TNF is a protein produced by monocyte-macrophage system cells. It not only has cytotoxic and cytostatic effects on various tumor cells in humans and animals, but also is an important regulator of inflammation and immunity in the body. It is closely related to the occurrence of body fever, shock, cachexia, etc., so it has been paid more and more attention by people. [0003] TNF is produced by monocytes / macrophages and has a variety of biological activities related to the pathogenesis of rheumatoid arthri...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/365A61P35/00A61P19/02A61P11/06A61P11/00A61P11/02A61P37/08
Inventor 张卫东胡振林覃江江金慧子单磊苏娟沈云亨李慧梁赵静
Owner SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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