Brefeldin A ester derivatives, and preparation and application thereof

A Brefeldin and Brefeldin technology, applied in drug combinations, antidote, antitumor drugs, etc., can solve the problems of low targeting, low bioavailability, poor water solubility, etc., and achieve good inhibitory activity. , the effect of broad application prospects

Active Publication Date: 2015-12-16
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, because brefeldin A has problems such as poor water solubility, short half-life, low targeting and low bioavailability, its application in many aspects is limited, so the structural mod

Method used

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  • Brefeldin A ester derivatives, and preparation and application thereof
  • Brefeldin A ester derivatives, and preparation and application thereof
  • Brefeldin A ester derivatives, and preparation and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Example 1: Preparation of 4'7-2-(3-(trifluoromethyl)phenoxy)-brefeldin A diester acetate (I-1)

[0033] The reaction formula is as follows:

[0034]

[0035] Weigh brefeldin A (Ⅱ) (1eq, 0.3mmol, 84mg), dissolve in 20mL of anhydrous dichloromethane to make (Ⅱ) solution, take 2-(3-(trifluoromethyl)phenoxy ) Acetic acid (Ⅲ-1) (4eq, 1.2mmol, 0.264g) was dissolved in 20ml of anhydrous dichloromethane to prepare (Ⅲ-1) solution, and (Ⅲ-1) solution was slowly added to (Ⅱ) solution Add EDC·HCl (4eq, 1.2mmol, 0.230g) and DMAP (3.3eq, 1mmol, 0.122g) in sequence, and nitrogen gas, microwave-assisted reaction at 44°C for 6.5h, the microwave power is 150W, the reaction process Whether the reaction was complete was detected by thin layer chromatography (ethyl acetate:petroleum ether=1:2, v / v). After the reaction, add 20ml of water to quench, then add 2×30ml of dichloromethane for extraction, wash the organic layer 2×50ml with water, and wash 2×50ml with saturated NaCl aqueous sol...

Embodiment 2

[0038] Example 2: Preparation of 7-2-furan-brefeldin A formic acid monoester (I-2) and 4' 7-2-furan-brefeldin A formic acid diester (I-3)

[0039] The reaction formula is as follows:

[0040]

[0041] Weigh brefeldin A (Ⅱ) (1eq, 0.3mmol, 84mg), dissolve in 20mL of anhydrous dichloromethane to make (Ⅱ) solution, take 2-furanoic acid (Ⅲ-2) (4eq, 1.2mmol , 0.135g) was dissolved in 20ml of anhydrous dichloromethane to make (Ⅲ-2) solution, and (Ⅲ-2) solution was slowly added to (Ⅱ) solution, and then EDC·HCl (4eq, 1.2 mmol, 0.230g) and DMAP (3.3eq, 1mmol, 0.122g), nitrogen flow, microwave reaction 7h under the condition of 44 ℃, microwave power is 150W, detects whether the reaction is complete with thin-layer chromatography in the reaction process (ethyl acetate : Petroleum ether=1:2, v / v). After the reaction was completed, 20ml of water was added to the reaction liquid to quench, and then 2×30ml of dichloromethane was added for extraction, the organic layer was washed with wa...

Embodiment 3

[0044] Example 3: 7-6-chloro-2-(2,6-difluorophenyl) quinoline-4-brefeldin A formic acid monoester (I-4) and 4'7-6-chloro- Preparation of 2-(2,6-difluorophenyl)quinoline-4-brefeldin A formic acid diester (Ⅰ-5)

[0045] The reaction formula is as follows:

[0046]

[0047] Weigh brefeldin A (II) (1eq, 0.3mmol, 84mg), dissolve it in 20mL of anhydrous dichloromethane to make a solution of formula (II), take 6-chloro-2-(2,6-difluoro Phenyl) quinoline-4-carboxylic acid (Ⅲ-3) (4eq, 1.2mmol, 0.3834g) was dissolved in 20ml of anhydrous dichloromethane to prepare formula (Ⅲ-3) solution, and formula (Ⅲ-3) The solution was slowly added to the solution of formula (II), and then EDC·HCl (4eq, 1.2mmol, 0.230g) and DMAP (3.3eq, 1mmol, 0.122g) were added in sequence, nitrogen gas was applied, and microwave reaction was carried out at 44°C for 7h. The power was 150W, and the completion of the reaction was detected by thin-layer chromatography during the reaction (ethyl acetate:petroleum et...

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Abstract

The invention discloses brefeldin A ester derivatives, and preparation and application thereof. The brefeldin A ester derivative compounds have antioxidation activity and antitumor activity, wherein the brefeldin A ester derivative compound disclosed as Formula (I-1), (I-3), (I-5) or (I-7) has favorable antioxidation effect and can remove DPPH, ABTS and super oxygen free radical (O2<->), and the compound (I-7) has better removal effect on DPPH, ABTS and super oxygen free radical (O2<->) than vitamin E; and the compound disclosed as Formula (I-1), (I-3), (I-5) or (I-7) has favorable inhibition activity for human lung cancer cells A549. Therefore, the result shows that the derivatives have wide application prospects in the drug development system, provide a new and broader idea for synthesizing and screening BFA (brefeldin A) derivative drugs and provide a more efficient way for treating related diseases.

Description

(1) Technical field [0001] The invention relates to the preparation and application of brefeldin A ester derivative compounds. (2) Background technology [0002] Brefeldin A ((+)-BrefeldinA, referred to as BFA), is a new type of antibiotic, a secondary metabolite produced by a macrolide fungus, also known as clinomycin or Ascosporine has a variety of biological activities, including antifungal, antiviral, antinematode, antimitotic, and can also be used as a molecular tool in the study of mammalian signal transduction pathways. However, because brefeldin A has problems such as poor water solubility, short half-life, low targeting and low bioavailability, its application in many aspects is limited, so the structural modification of BFA is carried out to overcome its own limitations. Adverse factors, so that it can be applied to clinical research as soon as possible has become a new scientific research hotspot. The present invention obtains BFA derivatives by chemically modif...

Claims

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Application Information

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IPC IPC(8): C07D407/12C07D407/14C07D405/12C07D405/14C07D313/00A61P39/06A61P35/00
CPCC07D313/00C07D405/12C07D405/14C07D407/12C07D407/14
Inventor 王宇光叶秋娟郑裕国王亚军
Owner ZHEJIANG UNIV OF TECH
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