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15-methylene-14-deoxy-11,12-dehydroandrographolide derivatives and their medicinal uses

A technology of andrographolide and methylene, applied in the field of medicine, can solve problems such as unsatisfactory drug effects, achieve the effect of improving myocardial fibrosis, good application and development prospects, and expanding the range of options

Active Publication Date: 2022-04-08
ZHENGZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] At present, although there are some drugs for the treatment of the above-mentioned fibrotic diseases clinically, the effect of the drugs is not satisfactory.

Method used

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  • 15-methylene-14-deoxy-11,12-dehydroandrographolide derivatives and their medicinal uses
  • 15-methylene-14-deoxy-11,12-dehydroandrographolide derivatives and their medicinal uses
  • 15-methylene-14-deoxy-11,12-dehydroandrographolide derivatives and their medicinal uses

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] Example 1 Compounds of the present invention inhibit the migration of human hepatic stellate cells LX-2

[0061] 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. 1) Cell culture and test compound

[0062] 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 Jinxin Bio...

Embodiment 2

[0071] Example 2 Compounds of the present invention inhibit mesenchymal transition of human type II alveolar epithelial cells A549

[0072] 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.

[0073] 1) Cell culture

[0074] A549 cells were cultured in RPMI1640 medium containing 10% (V / V) fetal bovine serum, 100 μg / mL strepto...

Embodiment 3

[0084] Example 3 Compounds of the present invention inhibit TGF-β1-induced mesenchymal transition of human renal cortex proximal tubule epithelial cells HK-2

[0085] 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.

[0086] 1) Cell culture

[0087] 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 medicine and relates to 15-methylene-14-deoxy-11,12-dehydro-andrographolide derivatives. It has been proved by experiments that this type of compound significantly inhibits the migration and activation of hepatic stellate cells; significantly inhibits TGF‑β1-induced mesenchymal transition of human alveolar type II epithelial cells A549; significantly inhibits human renal cortical proximal tubule epithelial cells HK‑2 mesenchymal transition; significantly inhibits angiotensin Ⅱ (AngⅡ)-induced migration of primary human cardiac fibroblasts HCFB. Using this type of compound as an active ingredient to prepare anti-fibrosis drugs has high efficiency and low toxicity, and provides a new drug approach for the treatment and prevention of fibrosis-related diseases, thereby expanding the optional range of clinical drugs and having good application development prospect.

Description

technical field [0001] The invention relates to andrographolide derivatives and their application as anti-fibrosis drugs, in particular to 15-methylene-14-deoxy-11,12-dehydroandrographolide derivatives, belonging to the technical field of medicine. Background technique [0002] Fibrosis can occur in a variety of organs, such as liver, lung, kidney, etc. The main pathological changes are the increase of fibrous connective tissue in the organ tissue and the decrease of parenchymal cells. Continuous progress can lead to organ structural damage, functional decline, and even failure. Serious threat to human health and life. The process of fibrosis is closely related to transforming growth factor-β (TGF-β), which can promote the proliferation of fibroblasts and activate the transformation of fibroblasts into myofibroblasts (Denney, L., et al., Immunity , 2015.43(5):945-958), and at the same time inhibit the degradation of ECM by regulating the gene expression of extracellular mat...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D405/06C07D307/58C07D417/06A61K31/443A61K31/427A61K31/4178A61K31/4155A61K31/4025A61K31/404A61K31/365A61P1/16A61P11/00A61P13/12A61P9/00
Inventor 戴桂馥徐海伟王伟宸尚宁吴健王亚铭黄俊
Owner ZHENGZHOU UNIV
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