Application of dihydroartemisinin derivatives in preparation of medicine for treating non-autoimmune synovitis

A technology of dihydroartemisinin and autoimmunity, which is applied in the field of chemical medicine, can solve the problem of not outstanding anti-inflammatory effect, and achieve the effect of increasing anti-inflammatory activity

Pending Publication Date: 2019-01-04
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, its anti-inflammatory effect is not outstanding compared with existing non-steroidal anti-inflammatory drugs. Therefore, structural modification of artemisinin compounds for the purpose of synergistic effects will promote the development of anti-synovitis drugs

Method used

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  • Application of dihydroartemisinin derivatives in preparation of medicine for treating non-autoimmune synovitis
  • Application of dihydroartemisinin derivatives in preparation of medicine for treating non-autoimmune synovitis
  • Application of dihydroartemisinin derivatives in preparation of medicine for treating non-autoimmune synovitis

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] The synthesis and identification of the four derivatives refer to the report of this laboratory 30 . A brief description is as follows:

[0044] Preparation of 9α, 12α-di-(p-methylcinnosilicate)dihydroartemisinin (DC24)

[0045] Dissolve 0.5mmol 9α-hydroxydihydroartemisinin and 1.3mmol p-methylcinnamic acid in 10mL of anhydrous dichloromethane, add 1.3mmol DMAP and 1.5mmol EDCI into a three-neck round bottom flask under nitrogen protection and ice bath , the temperature is natural, stirred and reacted for 12h, after the reaction is detected by TLC, spin-dried, dissolved in ethyl acetate, washed with water, washed with saturated sodium chloride, dried over anhydrous magnesium sulfate, spin-dried, and the residue was obtained by column chromatography. White powder, product Rate: 54%.

[0046] 1 H NMR (400MHz, Chloroform-d) δ = 7.79 (d, J = 16.0, 1H), 7.71 (d, J = 16.0, 1H), 7.57–7.53 (m, 4H), 7.42–7.38 (m, 6H) ,6.49(d,J=16.0,1H),6.44(d,J=16.0,1H),5.94(d,J=9.8,1H),5.6...

Embodiment 2

[0056] Example 2, Four derivatives (DC24, 32, 37, 38) compared with artemisinin, artemether, artether, dihydroartemisinin and artesunate anti-inflammatory activity

[0057] Anti-NO release: Take the RAW264.7 cells with a confluence of 80-90%, count them after blowing and blowing the suspension, inoculate in a 96-well plate, 10 cells per well 4 cell. Administration in the logarithmic growth phase, four derivatives (DC24,32,37,38) and artemisinin, artemether, artether, dihydroartemisinin and artesunate (1μM) pretreated cells for 1h After that, LPS (1 μg / mL) was added to the model group and each administration group. After 24 hours, the NO content was measured by Griess method, and the absorbance at 540 nm was measured using a microplate reader. NO release inhibition rate = (A 模型 -A 给药 ) / (A 模型 -A 对照 )×100%.

[0058] Chondrocyte protection experiment: culture chondrocytes, adjust the cell density to 4×10 with DMEM medium containing 10% fetal bovine serum 4 / mL, pipette 100 ...

Embodiment 3

[0060] Example 3. Research on the anti-synovitis mechanism of four derivatives (DC24, 32, 37, 38)

[0061] Experimental method: 1. Rat synovial fibroblast primary extraction

[0062] (1) Rats were sacrificed by cervical dislocation and soaked in 75% alcohol for 2 minutes. Disinfect the knee joint with alcohol, cut the skin longitudinally in the middle of the knee joint, separate the muscles, expose the kneecap and continue to separate downwards, and you can see the smooth and bright synovial tissue. Then use surgical scissors to separate the synovial layer and fibrous layer of the joint capsule, and remove the synovial layer tissue. The synovial tissue of the other knee joint was collected by the above method.

[0063] (2) Rinse the separated synovium tissue with PBS and put it into a petri dish. Cut the synovial tissue into small pieces with ophthalmic scissors, and put them into a Φ3cm petri dish. Add 2mL type II collagenase. Digest on a shaker at 37°C 80rpm for 3h.

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Abstract

The invention discloses an application of four dihydroartemisinin derivatives (DC24, 32, 37, 38) in treating non-autoimmune synovitis and its effect mechanism. The four dihydroartemisinin derivativesshowed superior anti-inflammatory and chondroprotective activity in anti-LPS-induced RAW264.7 cell NO production and cartilage injury, anti-osteoarthritis synovitis, anti-motility synovitis and anti-acute traumatic synovitis. The four dihydroartemisinin derivatives have good therapeutic effect on various non-autoimmune synovitis. The possible anti-inflammatory effect mechanism is that four dihydroartemisinin can inhibit the activation of NF-k beta signal pathway, down-regulate the levels of TNF-alpha and IL-1 beta to exert anti-inflammatory effects.

Description

technical field [0001] The invention belongs to the field of chemical medicine. Specifically, it relates to the application of novel dihydroartemisinin derivatives in the treatment of non-autoimmune synovitis. Background technique [0002] Synovitis refers to the tissue with synovium due to mechanical, biological, chemical and other stimuli, resulting in inflammatory reactions, causing synovial tissue hyperemia, edema, increased vascular permeability, excessive secretion of synovial fluid, decreased absorption, A joint disease that leads to joint swelling, pain, joint effusion, and limited mobility. The pathological changes are synovial cell proliferation, angiogenesis and inflammatory cell infiltration 1-3 . [0003] The knee joint is the joint with the most synovium in the joints of the whole body, so synovitis is more common in the knee joint. There are many reasons for the formation of knee joint synovitis, clinically, it is mostly due to aseptic inflammation of the ...

Claims

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Application Information

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IPC IPC(8): C07D493/20A61K31/357A61P19/02A61P19/04A61P29/00
CPCA61K31/357A61P19/02A61P19/04A61P29/00C07B2200/07C07D493/20
Inventor 刘吉华余伯阳樊梦霖
Owner CHINA PHARM UNIV
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