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Abietane type diterpenoid compound with blood lipid lowering activity as well as preparation method and application of abietane type diterpenoids compound

A compound and application technology, applied in the field of medicinal chemistry, can solve problems such as the high incidence of cardiovascular disease

Active Publication Date: 2017-01-04
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Statins are not effective for all patients with hyperlipidemia and high risk of atherosclerosis. Clinical studies have shown that the use of pravastatin (pravastatin) or atorvastatin (atorvastatin) intensive treatment of coronary heart disease patients after an average of 24 months , LDL cholesterol levels have been reduced to varying degrees, but there is still a high incidence of cardiovascular disease
In addition, a large proportion of patients are insensitive to statins and cannot rely on statins to prevent the development of atherosclerosis

Method used

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  • Abietane type diterpenoid compound with blood lipid lowering activity as well as preparation method and application of abietane type diterpenoids compound
  • Abietane type diterpenoid compound with blood lipid lowering activity as well as preparation method and application of abietane type diterpenoids compound
  • Abietane type diterpenoid compound with blood lipid lowering activity as well as preparation method and application of abietane type diterpenoids compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0213] Example 1 Extraction and separation method of compound LS 41-76

[0214] After 9.5Kg of cedar stem bark was dried in the shade, it was crushed, soaked in 60L of acetone at room temperature for 20 days, repeated 3 times, combined the extracts, and concentrated under reduced pressure to obtain 860g of total extract. The total extract was suspended in 5L of water, extracted with petroleum ether, dichloromethane, and ethyl acetate in sequence, and the organic solvent was evaporated under reduced pressure to obtain 500 g of petroleum ether in oil, 120 g of methylene chloride and 160 g of ethyl acetate. Take 120g of the dichloromethane part and mix it with 100-200 mesh silica gel (240g), pack it with 200-300 mesh silica gel (2kg), and use petroleum ether: acetone system 100:2, 100:5, 10:1, 5:1 , 3:1, 2:1, 1:1, eluted with acetone, and combined after TLC detection to obtain 10 fractions. Fraction 2 was subjected to silica gel column chromatography (petroleum ether: ethyl acetate...

Embodiment 2

[0423] Example 2 Discovery of rosinane-type diterpenoids for lowering blood lipid activity

[0424] The previously isolated compounds LSP-6-1 to LSP-6-6 (final concentration 5μM) were treated with HepG2 cells starved for 12 hours by defatting serum for 24 hours, and fluorescently labeled low-density lipoprotein (DiI-LDL) 20μg / ml was added Incubate at 37°C for 4 hours, wash the cells gently with phosphate buffered saline (PBS) 5 times, extract lipids with isopropanol, and measure fluorescence readings on a microplate reader (excitation light: 520nm; emission light: 570nm). Then the cells were lysed with 0.2M sodium hydroxide, the protein content was measured, and the fluorescence / protein value was calculated. The experimental results are shown in Table 1 and figure 1 , The 6 compounds can significantly increase the uptake of low-density lipoprotein LDL by HepG2 in hepatocytes at a concentration of 5μM.

[0425] Table 1. The effect of compound LSP-6-1~LSP-6-6 on the uptake of low-de...

Embodiment 3

[0433] Example 3 Compound LSP-6-6 up-regulates the expression level of low-density lipoprotein receptor (LDLR) in liver cells

[0434] Compound LSP-6-6, berberine (BBR) and ZBM30 were treated with different concentrations of liver cells for 24 hours. After the cells were lysed according to the same method as in Example 2, the total RNA of the cells was extracted with TRIzol reagent, and 3 μg RNA was used M-MLV (reverse transcriptase) was reverse transcribed into cDNA, and then real-time PCR (real-time quantitative PCR) was performed with LDLR specific primers, and GAPDH was used as an internal reference gene to compare the compound's regulatory effect on LDLR gene. See experimental results image 3 . The above results indicate that the compound LSP-6-6 significantly increased the expression of LDLR gene and increased the expression level of low-density lipoprotein receptor (LDLR) in hepatocytes, and with the increase of drug concentration, the level of LDLR protein increased. Fr...

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Abstract

The invention provides an abietane type diterpenoid compound with blood lipid lowering activity as well as a preparation method and application of the abietane type diterpenoids compound. Particularly, the compound provided by the invention has a structure shown as the formula I in the description, wherein the definition of all radicals is described in the description. The compound provided by the invention has the activity of increasing low-density lipoprotein intake in vivo or in vitro, and has the potential of being used as novel blood lipid lowering medicine.

Description

Technical field [0001] The present invention belongs to the field of medicinal chemistry. More specifically, it relates to a new class of rosinane diterpenoids with hypolipidemic activity, a preparation method thereof and use in drugs for hypolipidemic / atherosclerosis. Background technique [0002] Atherosclerosis (AS) refers to the deposition of lipids (mainly cholesterol and cholesterol lipids) in the intima and intima of the artery and its branches, accompanied by the migration of smooth muscle cells in the middle layer to the subintima. The formation of yellow or gray-yellow plaques that look like atheromas makes the arterial wall thicker and harder, loses elasticity, and the lumen becomes smaller. AS is the most common and most important disease in arteriosclerotic vascular disease, and it has been the main cause of death in western developed countries. In recent years, with the improvement of Chinese people's living standards and changes in eating habits, the disease has a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D493/08C07D311/80C07D319/14C07D317/70C07D307/77C07D303/02C07C62/32C07C62/36C07C43/23C07C49/755C07C49/747C07C39/14C07C59/52C07C69/157C07C63/49C07C49/757C07C47/57C07C47/47C07C59/54C07C50/34C07C50/38C07C43/253A61K31/366A61K31/192A61K31/085A61K31/122A61K31/05A61K31/357A61K31/222A61K31/343A61K31/11A61K31/336A61P3/06A61P1/16
CPCC07D493/08A61K31/366C07C43/23C07C62/32C07C62/36C07D303/02C07D307/77C07D311/80C07D317/70C07D319/14
Inventor 叶阳王逸平姚胜赵晶唐春萍徐文伟柯昌强席聪
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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