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Novel berberine 9-position coupled cholic acid derivative and preparation method thereof

A derivative, berberine technology, applied in the field of preparation of berberine derivatives, can solve the problems of low bioavailability, poor targeting, poor fat solubility, etc., achieve good fat solubility, maintain pharmacological activity, increase biological The effect of utilization

Inactive Publication Date: 2011-10-26
NORTHEAST FORESTRY UNIVERSITY +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The object of the present invention is to provide a class of berberine derivatives that fully maintain the antitumor pharmacological activity of berberine, improve drug targeting, and solve the problems of poor fat solubility, poor targeting, and low bioavailability

Method used

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  • Novel berberine 9-position coupled cholic acid derivative and preparation method thereof
  • Novel berberine 9-position coupled cholic acid derivative and preparation method thereof
  • Novel berberine 9-position coupled cholic acid derivative and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Embodiment 1: the synthesis of cholic acid-9-O-propionamide berberine: (A1)

[0045] (1) Synthesis of Berberine

[0046] Add 744mg (2mmol) of berberine into a 250mL round bottom flask, heat at 195-210°C for 30min at a vacuum of 20-30mmHg, the yellow solid gradually turns dark red, cool to room temperature in a vacuum desiccator, and perform silica gel column chromatography Purified to obtain a dark red powder with a yield of 73%, molecular weight: 322, and the structure as follows:

[0047]

[0048] (2) Synthesis of 9-O-3-bromo-propyl berberine

[0049] Add 161mg (0.5mmol) of berbererythrine into a 25mL round bottom flask, add 3mL of DMF to dissolve, heat at 60°C, add 500μL of 1,3-dibromopropane, the dark red solution gradually turns brownish yellow, follow the reaction by TLC, after the reaction is complete Add 10 mL of anhydrous diethyl ether, a yellow solid is precipitated, filtered under reduced pressure, and purified by silica gel column chromatography to obta...

Embodiment 2

[0060] Embodiment 2: the synthesis of dehydrocholic acid-9-O-propionamide berberine: (A2)

[0061] (1) Synthesis of Berberine

[0062] Same as (1) in Example 1.

[0063] (2) Synthesis of 9-O-3-bromopropyl berberine

[0064] Same as (2) in Example 1.

[0065] (3) Synthesis of 9-O-3-aminopropyl berberine:

[0066] Same as (3) in Example 1.

[0067] (4) Synthesis of dehydrocholic acid activated ester:

[0068] Add 201 mg (0.5 mmol) of dehydrocholic acid to a 50 mL round bottom flask, add 10 mL of dichloromethane, add 115 mg of N-hydroxysuccinimide, and add 1-ethyl-3-(3-dimethylaminopropyl Base) carbodiimide 766mg (4mmol) dichloromethane solution 10mL, follow the reaction by TLC. After the reaction was complete, 30 mL of chloroform was added to the reaction liquid, followed by 50 mL of saturated saline, 50 mL of saturated NaHCO 3 Solution extraction 3 times, anhydrous MgSO 4 Dry, filter under reduced pressure to remove MgSO 4 Concentrate under reduced pressure, separate a...

Embodiment 3

[0073] Embodiment 3: Synthesis of deoxycholic acid-9-O-propionamide berberine: (A3)

[0074] (1) Synthesis of Berberine

[0075] Same as (1) in Example 1.

[0076] (2) Synthesis of 9-O-3-bromopropyl berberine

[0077] Same as (2) in Example 1.

[0078] (3) Synthesis of 9-O-3-aminopropyl berberine:

[0079] Same as (3) in Example 1.

[0080] (4) Synthesis of deoxycholic acid activated ester:

[0081] Add 196 mg (0.5 mmol) of deoxycholic acid to a 50 mL round bottom flask, add 10 mL of dichloromethane, add 115 mg of N-hydroxysuccinimide, and add 1-ethyl-3-(3-dimethylaminopropyl ) carbodiimide 766mg (4mmol) dichloromethane solution 10mL, follow the reaction by TLC. After the reaction was complete, 30 mL of chloroform was added to the reaction liquid, followed by 50 mL of saturated saline, 50 mL of saturated NaHCO 3 Solution extraction 3 times, anhydrous MgSO 4 Dry, filter under reduced pressure to remove MgSO 4 Concentrate under reduced pressure, separate and purify by s...

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Abstract

The invention relates to a novel berberine 9-position coupled cholic acid derivative as shown in a formula (I) and a preparation method thereof as well as application of the derivative in the aspect of being a medicament, especially treating tumour. In the formula (I), R1 is hydroxyl or carbonyl; and R2 and R3 are hydrogen, hydroxyl or carbonyl.

Description

technical field [0001] The invention relates to a preparation method of a class of berberine derivatives and their application in antitumor therapy. Background technique [0002] Since M.-E. Chavalier and G. Peltin first extracted berberine from the bark of Xanthoxylonclava in 1826, pharmacologists have found that berberine has a wide antibacterial spectrum and has the functions of lowering blood fat, blood sugar, Anti-peptic ulcer and other pharmacological effects. Coptis chinensis, Cortex Phellodendron, Sangezhen, etc. are commonly used in traditional Chinese medicine as heat-clearing and detoxifying drugs, the main ingredient of which is berberine. In 1966, the Japanese Pharmacopoeia collected berberine hydrochloride and berberine tannic acid for the treatment of intestinal infections. With in-depth research, Japanese scholars in the 1970s proposed that berberine and its derivatives have anti-tumor effects. In recent years, many researchers have actively invested in th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J43/00A61K31/58A61P35/00
Inventor 李庆勇何乌娜邱伟张宝友赵腾飞高文轻邓晓秋
Owner NORTHEAST FORESTRY UNIVERSITY
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