Hederagenin polyethylene glycol derivative and preparation method thereof

A technology of helexin and polyethylene glycol is applied in the directions of drug combinations, pharmaceutical formulations, steroids, etc., which can solve problems such as low solubility, and achieve the effects of improved water solubility and excellent tumor resistance reversal activity.

Active Publication Date: 2021-01-05
YANTAI UNIV
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  • Summary
  • 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 liposomes for in vivo administration, which limits its application to a certain extent.

Method used

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  • Hederagenin polyethylene glycol derivative and preparation method thereof
  • Hederagenin polyethylene glycol derivative and preparation method thereof
  • Hederagenin polyethylene glycol derivative and preparation method thereof

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 relates to the field of organic synthesis and medicinal chemistry, in particular to a hederagenin polyethylene glycol derivative with a novel structure and a preparation method of the hederagenin polyethylene glycol derivative. The compound disclosed by the invention is novel in structural type, improved in water solubility and excellent in tumor drug resistance reversion activity. The invention further provides a pharmaceutical composition for treating oral epithelial cancer, gastric cancer, lung cancer, cervical cancer, breast cancer or colon cancer and the like by being combined with clinically common anti-tumor drugs.

Description

technical field [0001] The invention relates to the fields of organic synthesis and medicinal chemistry, in particular to a helexin polyethylene glycol derivative with a novel structure and a preparation method thereof. [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) is derived from Araliaceae Hedera plant Hed...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J71/00C08G65/333A61P35/00A61K31/58A61K31/787
CPCA61P35/00C07J71/0047C08G65/33396Y02P20/55
Inventor 王洪波毕毅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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