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Application of 14-deoxy-11, 12-dehydrogenation-7, 8-ene-andrographolide and 15-subunit substituted derivative

A technology of andrographolide and its derivatives, which is applied in the field of medicine, and can solve the problems of prolonging the survival period of patients, ineffective organ improvement, large toxic and side effects, and easy drug resistance.

Active Publication Date: 2019-05-21
ZHENGZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Most of the existing clinical drugs can only play an auxiliary effect, and have no obvious effect on prolonging the survival period of patients and improving organs, and there are problems such as large toxic side effects and easy drug resistance.

Method used

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  • Application of 14-deoxy-11, 12-dehydrogenation-7, 8-ene-andrographolide and 15-subunit substituted derivative
  • Application of 14-deoxy-11, 12-dehydrogenation-7, 8-ene-andrographolide and 15-subunit substituted derivative
  • Application of 14-deoxy-11, 12-dehydrogenation-7, 8-ene-andrographolide and 15-subunit substituted derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0074] Example 1 Compounds of the present invention inhibit the migration of human hepatic stellate cells LX-2

[0075] Under the stimulation of various inflammatory mediators, growth factors and other cytokines, hepatic stellate cells migrate to the inflammatory site of the damaged liver tissue, and then proliferate, activate, and synthesize ECM components such as collagen, which is the key to the development of liver fibrosis. Therefore, compared with andrographolide, human hepatic stellate cells LX-2 (provided by Beijing Beina Chuanglian Biotechnology Research Institute) were used to study the anti-hepatic fibrosis effect of the compound of the present invention in vitro by scratch method.

[0076] 1) Cell culture

[0077] LX-2 cells were cultured in RPMI1640 medium containing 10% (V / V) fetal bovine serum, 100 μg / mL streptomycin, and 100 IU / mL penicillin in 5% CO 2 Cultivate in an incubator at saturated humidity at 37°C. Andrographolide was produced by Sichuan Shifang Jin...

Embodiment 2

[0084] Example 2 Compounds of the present invention inhibit mesenchymal transition of human type II alveolar epithelial cells A549

[0085] The type II alveolar epithelial cells present in the alveoli are stimulated by cytokines such as inflammatory mediators and growth factors, and the cell shape changes from pebble-like to spindle-like, completing the epithelial-mesenchymal transition (EMT) and possessing the function of mesenchymal cells , and then synthesize collagen fibers, a large amount of collagen fiber deposition can aggravate the course of pulmonary interstitial fibrosis. Therefore, compared with andrographolide, human type II alveolar epithelial cells A549 were used to evaluate the anti-pulmonary fibrosis effect of the compound of the present invention in vitro by morphological observation and cell scratch (migration) experiments.

[0086] 1) Cell culture

[0087] A549 cells were cultured in RPMI1640 medium containing 10% (V / V) fetal bovine serum, 100 μg / mL strepto...

Embodiment 3

[0097] Example 3 Compounds of the present invention inhibit TGF-β1-induced mesenchymal transition of human renal cortex proximal tubule epithelial cells HK-2

[0098] Early studies have found that renal tubular epithelial cells can transdifferentiate into fibroblasts and express their marker protein fibroblast-specific protein 1 (FSP1, fibroblast-specific protein 1), renal tubular epithelial cells-mesenchymal cell transdifferentiation is the key factor for renal interstitial fibers One of the important pathogenesis of cancer. Therefore, compare with andrographolide AD, utilize human renal cortex proximal tubule epithelial cell HK-2 (provided by China Center for Type Culture Collection), adopt TGF-β1 stimulated morphological observation method and scratch experiment to study the compound of the present invention In vitro anti-renal fibrosis effect.

[0099] 1) Cell culture

[0100] HK-2 cells were cultured in DMEM / F12 medium containing 10% fetal bovine serum (V / V), 100 μg / mL ...

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Abstract

The invention belongs to the technical field of medicines, and discloses an application of an andrographolide derivative in the preparation of medicaments for preventing and treating various fibrosis.The invention relates to an application of 14-deoxy-11, 12-dehydrogenation-7, 8-ene-andrographolide and a 15-subunit substituted derivative. Experiments prove that the compound obviously inhibits themigration and activation of hepatic stellate cells; significantly inhibits TGF-beta1 induced mesenchymal transformation of human alveolar type II epithelial cells A549; significantly inhibits TGFbeta1 induced HK-2 mesenchymal transformation of human renal cortical proximal tubular epithelial cells; inhibits the migration of HCFB in primary human cardiac fibroblasts induced by angiotensin II (AngII). In a model of common bile duct ligation in mice, a model of pulmonary fibrosis induced by silica in mice and a model of unilateral ureteral ligation in mice, the compound shows good anti-fibrosisactivity in vivo. The compound is used as an active ingredient for preparing the anti-fibrosis medicament, has high efficiency and low toxicity, and has a good prospect of developing various anti-fibrosis medicaments.

Description

technical field [0001] The present invention relates to the application of andrographolide derivatives as anti-fibrosis drugs, in particular to 14-deoxy-11,12-dehydro-7,8-ene-andrographolide (ADC) and its 15-subunit substituted derivatives , belongs to the field of medical technology. Background technique [0002] Tissue (organ) fibrosis is one of many chronic diseases faced by human beings, which seriously threatens human health. It is manifested by the increase of fibrous connective tissue in organ tissues, the substantial reduction of parenchymal cells, and the excessive deposition of extracellular matrix, which in turn leads to the destruction of organ structure and functional decline, and even life-threatening failure. Tissue fibrosis occurs in various vital organs of the body, such as the heart, liver, lungs, kidneys, etc., and even the eyeballs. [0003] Liver fibrosis is a repair response of the liver to internal and external damage, but continuous damage will lead...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/365A61K31/5377A61P1/16A61P11/00A61P13/12A61P9/10C07D307/58
Inventor 戴桂馥关珍贞朱家贞徐海伟吴笛闫光明
Owner ZHENGZHOU UNIV
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