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Glycosylated derivatives of bufolin and its preparation method and application in the preparation of antitumor drugs

An anti-tumor drug, bufalin technology, applied in the direction of anti-tumor drugs, drug combinations, steroids, etc., can solve the problems of poor selectivity, poor water solubility, etc., and achieve low toxic and side effects, reduce toxic and side effects, and high yield Effect

Active Publication Date: 2015-09-09
GUANGXI WUZHOU PHARMA GRP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In order to overcome the defects of poor selectivity of bufalin (equal toxicity to tumor cells and normal cells) and poor water solubility, the primary purpose of the present invention is to introduce a substituted sugar group at the 3-position of bufalin to provide a drug with antitumor activity. glycosylated derivatives of bufolin

Method used

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  • Glycosylated derivatives of bufolin and its preparation method and application in the preparation of antitumor drugs
  • Glycosylated derivatives of bufolin and its preparation method and application in the preparation of antitumor drugs
  • Glycosylated derivatives of bufolin and its preparation method and application in the preparation of antitumor drugs

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] The synthesis of bufolin-3-N-D-glucoside comprises the following steps:

[0036] (1) Put bufalin (4.13g, 0.0107mol) in a 50ml round bottom flask, add CH 2 Cl 2 (35ml) was stirred until completely dissolved, slowly added PCC (pyridinium chlorochromate hydrochloride) (4.60g, 0.0214mol), and stirred at a constant speed at room temperature for 2.5h. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The reaction product Bufalinone (3.9 g, 0.0102 mol, yield 95%) was obtained by silica gel column chromatography (cyclohexane / ethyl acetate mixture at a volume ratio of 1:1).

[0037] Structural analysis of the product obtained in step (1).

[0038] Physical and chemical properties: white powder (TLC R f =0.35 cyclohexane / ethyl acetate 1:1).

[0039] Spectral information: ESI-MS m / z: 385.5[M+H] + , 407.4[M+Na] + , 791.4[2M+H] + , 823.3[2M+Na] + . 1 H NMR (CDCl 3 , 300MHz) δ7.83 (1H, dd, J=9.7, 2.6Hz, H-22), 7.22 (1H, d, J=2.6Hz, H-21), ...

Embodiment 2

[0094] The synthesis of bufolin-L-glucoside comprises the following steps:

[0095] (1)-(3) The method for preparing aglycon is the same as that in Example 1.

[0096] (4) Add aglycon III (46mg, 0.108mmol) and L-glucose (39.0mg, 0.217mmol) into a reaction tube, dissolve in DMF / AcOH3:1 (1204μl), and stir at a constant speed at 40°C for 48h. After the reaction, the mixture was concentrated and dried under reduced pressure to remove the reaction solvent, and the sample was dissolved in methanol, and the sample was separated and purified by a preparative high-performance liquid chromatography column (waters, C18, 5 μm, 20×250 mm), with a flow rate of 8 ml / min and a detection wavelength of 296 nm. Use 45% acetonitrile / water solution as mobile phase, retention time t R =16.02min, the glycosylated product glycoside 2a (26mg, 0.045mmol, yield 42%) was obtained.

[0097] The structure of the glycosylation product 2a obtained in (4) was identified.

[0098] Physical and chemical prop...

Embodiment 3

[0114] The synthesis of bufolin-D-fucoside comprises the following steps:

[0115] (1)-(3) are the same as the steps in Example 1.

[0116] (4) Add aglycon III (42mg, 0.101mmol) and D-fucose (33.6mg, 0.205mmol) into a reaction tube, dissolve in DMF / AcOH 3:1 (1122μl), and stir at a constant speed at 40°C for 48h. After the reaction, the mixture was concentrated and dried under reduced pressure to remove the reaction solvent, and the sample was dissolved in methanol, and the sample was separated and purified by a preparative high-performance liquid chromatography column (waters, C18, 5 μm, 20×250 mm), with a flow rate of 8 ml / min and a detection wavelength of 296 nm. Use 45% acetonitrile / water solution as mobile phase, retention time t R =11.57min, the glycosylated product glycoside 3a (22mg, 0.039mmol, yield 39%) was obtained.

[0117] The structure of the glycosylation product 3a obtained in (4) was identified.

[0118] Physical and chemical properties: white powder (TLC R ...

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Abstract

The invention discloses a bufalin glycosylation derivative and a preparation method and application thereof in preparation of anti-tumour medicaments. The structure of the bufalin glycosylation derivative is shown in a formula I or formula II. The synthesis method of the bufalin glycosylation derivative comprises the following steps of: oxidizing bufalin into a ketone-form derivative by pyridinium chloropyridine hydrochloride; then performing a nucleophilic addition reaction with methoxyamine hydrochloride; removing monomolecular water to generate an oxime-form intermediate; enabling the oxime-form intermediate to react with a tert-butylamine borane hydrochloride compound to generate alpha-configuration aglycone and beta-configuration aglycone; and finally enabling the aglycones of two configurations to react with reducing sugar respectively to generate the bufalin glycosylation derivative. According to the method disclosed by the invention, bufalin is modified to be the glycosylation derivative thereof, and the water solubility can be improved while the anti-tumour activity is kept and enhanced; and moreover, in-vivo experiments prove that the toxic and side effects of the bufalin glycosylation derivative disclosed by the invention on normal cells are reduced compared with those of a parent compound of bufalin.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and specifically relates to bufalin glycosylated derivatives, a preparation method thereof and an application in the preparation of antitumor drugs. Background technique [0002] Malignant tumors have always been a major disease that endangers human health. According to WHO statistics, there are about 10 million new cases of malignant tumors in the world every year, and about 8 million deaths. In my country, malignant tumors gradually account for the first place in the death rate of urban residents. At present, the main treatment methods for malignant tumors include surgery, radiotherapy and chemotherapy. Among them, chemotherapy still plays an important role, but most of the chemotherapeutic drugs used clinically have the disadvantages of high toxicity, low safety and easy drug resistance. The study of anti-tumor drugs with high efficiency and low toxicity has always been a hot spot in the ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J41/00A61P35/00
Inventor 江仁望唐红进田海妍曹威叶文才
Owner GUANGXI WUZHOU PHARMA GRP
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