Application of hederagenin polyethylene glycol derivative

A technology of helexin and polyethylene glycol is applied in the directions of medical preparations, drug combinations, steroids, etc. containing active ingredients, which can solve the problems of low solubility, improve water solubility, and reverse the resistance of excellent tumor resistance. active effect

Active Publication Date: 2020-12-15
YANTAI UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the solubility of H6 in water is low, and it needs to be prepared into lip

Method used

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  • Application of hederagenin polyethylene glycol derivative
  • Application of hederagenin polyethylene glycol derivative
  • Application of hederagenin polyethylene glycol derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 14

[0042] Example 14-(23-oxyl olean-12-en-28-acid benzyl[3,2-b]pyrazine)-4-oxo-butyric acid triethylene glycol ester (H6 -D-PEG 200 ) synthesis and characterization

[0043] The compound helexin (472.0mg, 1.0mmol) was dissolved in N,N-dimethylformamide (15.0mL), potassium carbonate (300.0mg, 2.1mmol), benzyl bromide (0.2mL, 1.3mmol) were added , Stir at 50°C for 6-10h. The reaction solution was diluted with ethyl acetate (25.0 mL), washed three times with water, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, the solvent was evaporated under reduced pressure, and silica gel column chromatography (V 石油醚 :V 乙酸乙酯 =10:1-5:1), a white solid (470.0 mg, 83.0%) was obtained.

[0044] The above compound (460.0 mg, 0.8 mmol) was dissolved in 20.0 mL of dichloromethane, 4-dimethylaminopyridine (122.0 mg, 1.0 mmol) and tert-butyldimethylsilyl chloride (360.0 mg, 2.4 mmol) were added, Stir at room temperature for 4-8h. Dichloromethane was distilled off,...

Embodiment 21

[0050] Example 21'-(23-Oloxyolean-12-ene-28-acid benzyl[3,2-b]pyrazine)-1'-propionyl-3,3'-dithiopropane Acetate triethylene glycol ester (H6-S-PEG 150 ) synthesis and characterization

[0051] H6 (100.0 mg, 0.2 mmol) was dissolved in anhydrous dichloromethane (8.0 mL), the catalyst DMAP (102.3 mg, 0.8 mmol), EDCI (160.6 mg, 0.8 mmol) and 3,3'-dithio Dipropionic acid (352.3mg, 1.7mmol) was refluxed at 40°C for 7h. After the reaction, dichloromethane was added for dilution, and the organic layer was washed once with 5% HCl solution, twice with deionized water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a white solid H6- S (121.9 mg, 92.2%).

[0052] Dissolve triethylene glycol (131.7 μL, 1.1 mmol) in anhydrous dichloromethane (8.0 mL), add H6-S (88.0 mg, 0.1 mmol), catalyst DMAP (129.4 mg, 1.1 mmol), EDCI (128.3mg, 0.7mmol), stirred at room temperature for about 10h. After the reaction finished, the solve...

Embodiment 31

[0053] Example 31'-(23-Oxylean-12-en-28-acid benzyl[3,2-b]pyrazine)-1'-acetyl-2,2'-oxoacetic acid poly Ethylene glycol (600) ester (H6-E-PEG 600 ) synthesis and characterization

[0054] Dissolve H6 (70.0mg, 0.1mmol) in anhydrous dichloromethane (8.0mL), add catalyst DMAP (71.6mg, 0.6mmol) and diglycolic anhydride (68.0mg, 0.6mmol), react at room temperature for 0.5h . After the reaction, dichloromethane was added for dilution, and the organic layer was washed once with 10% HCl solution, twice with deionized water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain white solid H6- E (78.0 mg, 93.3%).

[0055] Dissolve polyethylene glycol 600 (543.4 μL, 1.2 mmol) in anhydrous dichloromethane (8.0 mL), add H6-E (82.0 mg, 0.1 mmol), catalyst DMAP (133.5 mg, 1.1 mmol), EDCI ( 132.3mg, 0.7mmol), stirred at room temperature for about 10h. After the reaction finished, the solvent was removed by distillation under redu...

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PUM

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Abstract

The invention discloses application of a hederagenin polyethylene glycol derivative. Specifically, the invention discloses application of the hederagenin polyethylene glycol derivative in preparationof a tumor drug resistance reversal agent. The hederagenin polyethylene glycol derivative with a novel structure type provided by the invention has improved water solubility and excellent tumor drug resistance reversal activity. The hederagenin polyethylene glycol derivative and a pharmaceutically acceptable carrier are used for treating diseases or symptoms such as oral epithelial cancer, gastriccancer, lung cancer, cervical cancer, breast cancer or colon cancer together with clinically common antitumor drugs. The hederagenin polyethylene glycol derivative and the medically acceptable salt thereof are used for preparing the tumor drug resistance reversal agent and/or the pharmaceutically acceptable carrier for treating mammals, preferably human diseases or symptoms.

Description

technical field [0001] The invention relates to the fields of organic synthesis and medicinal chemistry, in particular to the application of helexin polyethylene glycol derivatives with novel structures in the preparation of tumor drug resistance reversal agents. [0002] technical background [0003] The incidence of cancer is increasing year by year. According to statistics, the number of cancer deaths worldwide in 2018 reached 9.6 million. Multidrug resistance (MDR) is one of the main reasons for the failure of cancer chemotherapy. Therefore, the research and development of new tumor drug resistance reversal agents has become the focus of attention in the field of medicinal chemistry. Natural products such as ursolic acid, glycyrrhetinic acid and other natural products and their derivatives have been proven to have MDR reversal activity, so natural products have become one of the important sources of tumor resistance reversal agents. [0004] Hederagenin (Hederagenin, H)...

Claims

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Application Information

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IPC IPC(8): A61K31/58A61K31/795A61K31/787A61P35/00C07J71/00
CPCA61K31/58A61K31/795A61K31/787A61P35/00C07J71/0047
Inventor 毕毅王洪波王炳华刘书琪黄文涛汪英杰王加丽徐斯马梦馨
Owner YANTAI UNIV
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