Brefeldin A ester derivatives and their preparation and application

A Brefeldin and Brefeldin technology, which is applied in the directions of drug combinations, medical preparations containing active ingredients, organic active ingredients, etc., can solve the problems of short plasma half-life, poor water solubility, and unsatisfactory, and achieve high efficiency The effect of curative effect, simple method and easy operation

Active Publication Date: 2016-05-25
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to its unsatisfactory pharmacokinetic properties (low bioavailability, poor water solubility, short plasma half-life, etc.), brefeldin A cannot be used as an anti-tumor therapeutic agent in clinical practice.

Method used

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  • Brefeldin A ester derivatives and their preparation and application
  • Brefeldin A ester derivatives and their preparation and application
  • Brefeldin A ester derivatives and their preparation and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Example 1: Preparation of 7-O-acetyl-BFA (I-1), 4,7-O-diacetyl-BFA (I-2)

[0035]

[0036] Add 10mL of anhydrous dichloromethane (10ml) to a 50mL round-bottomed flask with a magnetic stirring bar, then add BFA (100mg, 0.36mmol), and start stirring; then add acetic acid (45mg, 0.75mmol), EDC.HCl (1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride) (205mg, 108mmol), DMAP (4-dimethylaminopyridine) (22mg, 0.18mmol), at 40°C The reaction was heated for 24h to terminate the reaction. The reaction solution was diluted with 10ml of dichloromethane, washed with water (2×10ml), washed with saturated sodium chloride solution (2×10ml), the combined aqueous phase was extracted with ethyl acetate (1×30ml), the combined organic phase was anhydrous Sodium sulfate was dried, filtered, and concentrated to obtain a crude product, which was separated by thin-layer chromatography under the condition of developing solvent E / P=1:5 to obtain compound (I-1) (Rf=0.2, yield 42.50%) an...

Embodiment 2

[0040] Example 2: Preparation of 7-O-(benzoic acid) acyl-BFA (I-3), 4,7-O-di(benzoic acid) acyl-BFA (I-4)

[0041]

[0042] Add 10mL of anhydrous dichloromethane (10ml) to a 50mL round-bottomed flask with a magnetic stirring bar, then add BFA (100mg, 0.36mmol), and start stirring; then add benzoic acid (91.5mg, 0.75mmol), EDC .HCl (205mg, 108mmol), DMAP (22mg, 0.18mmol), heated at 40°C for 24h to terminate the reaction. The reaction solution was diluted with 10ml of dichloromethane, washed with water (2×10ml), washed with saturated sodium chloride solution (2×10ml), the combined aqueous phase was extracted with ethyl acetate (1×30ml), the combined organic phase was anhydrous Sodium sulfate was dried, filtered, and concentrated to obtain a crude product, which was separated by thin-layer chromatography under the condition of developing solvent E / P=1:5 to obtain compound (I-3) (Rf=0.2, yield 46.7%) and Compound (I-4) (Rf=0.8 yield, 29.6%).

[0043] Compound Characterization...

Embodiment 3

[0046] Example 3: Preparation of 7-O-(p-fluorobenzoic acid) acyl-BFA (I-5), 4,7-O-di(p-fluorobenzoic acid) acyl-BFA (I-6)

[0047]

[0048] Add 10mL of anhydrous dichloromethane (10ml) to a 50mL round bottom flask with a magnetic stirring bar, then add BFA (100mg, 0.36mmol), and start stirring; then add 4-fluorobenzoic acid (105mg, 0.75mmol) , EDC.HCl (205mg, 108mmol), DMAP (22mg, 0.18mmol), heated at 40°C for 24h to terminate the reaction. The reaction solution was diluted with 10ml of dichloromethane, washed with water (2×10ml), washed with saturated sodium chloride solution (2×10ml), the combined aqueous phase was extracted with ethyl acetate (1×30ml), the combined organic phase was anhydrous Sodium sulfate was dried, filtered, and concentrated to obtain a crude product, which was separated by thin-layer chromatography under the condition of developer E / P=1:5 to obtain compound (I-5) (Rf=0.2, yield 36.4%) and Compound (I-6) (Rf=0.8, yield 20.0%).

[0049] Compound Char...

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PUM

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Abstract

The invention provides brefeldin A ester derivatives having antitumor activity and their preparation method and use. The brefeldin A ester derivatives have structures shown in the structural general formula (I). The brefeldin A ester derivatives have high effects on esophagus cancer, lung cancer, kidney cancer, colorectal cancer and prostatic cancer and have an in-vitro detection effective inhibition rate of 80%. The preparation method of the brefeldin A ester derivatives has simple processes and can be operated easily.

Description

(1) Technical field [0001] The invention relates to a class of brefeldin A ester derivatives with antitumor activity and its preparation and application. (2) Background technology [0002] Brefeldin A ((+) Brefeldin ABFA) is a natural macrolide antibiotic and a secondary metabolite of Ascomycetes, also known as clinomycin or ascodiosporum. In 1958, Singleton et al first isolated from Penicillium decumbens fermentation broth. In 1971, the complete configuration of BFA was determined by X-ray crystal structure analysis. Brefeldin A molecular formula C 16 h 24 o 4 , molecular weight 280Da, molecular structure contains 5 chiral centers, 2 double bonds, 1 five-membered carbon ring and 1 13-membered macrolide, the structure is as follows: [0003] [0004] Brefeldin A has a variety of biological activities, including antifungal, antiviral, antinematode, antimitotic, and it has been found to have highly active inhibitory effects on various cancer cells (GI50=0.04 μM). Curr...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D313/00C07D409/12C07D409/14C07D495/04C07D405/14A61K31/365A61K31/4427A61K31/4188A61K31/625A61K31/381A61P35/00
CPCC07D313/00C07D405/14C07D409/12C07D409/14C07D495/04
Inventor 朱勍何秉踊郑裕国王亚军
Owner ZHEJIANG UNIV OF TECH
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