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Brefeldin A ester derivatives and their preparation and application

A technology of brefeldin and brefeldin, applied in drug combination, organic chemistry, antineoplastic 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: 2018-11-13
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 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

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

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

[0033] The reaction formula is as follows:

[0034]

[0035] Weigh Brefeldin A (Ⅱ) (1eq, 0.3mmol, 84mg), and dissolve it 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 make (Ⅲ-1) solution, and (Ⅲ-1) solution was slowly added to (Ⅱ) solution Then, add EDC·HCl (4eq, 1.2mmol, 0.230g) and DMAP (3.3eq, 1mmol, 0.122g) in sequence, ventilate nitrogen, microwave assisted reaction at 44℃ for 6.5h, microwave power 150W, reaction process TLC was used to detect whether the reaction was complete (ethyl acetate: petroleum ether = 1:2, v / v). After the reaction is over, add 20ml of water to quench, add 2×30ml of dichloromethane for extraction, wash the organic layer 2×50ml with water, and wash 2×50ml with saturated NaCl aqueous solution. Anhydrous Na for coll...

Embodiment 2

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

[0039] The reaction formula is as follows:

[0040]

[0041] Weigh Brefeldin A (II) (1eq, 0.3mmol, 84mg) and dissolve it in 20mL of anhydrous dichloromethane to make (II) solution, take 2-furancarboxylic 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 gas, microwave reaction at 44 ℃ for 7h, microwave power 150W, during the reaction, TLC is used to check whether the reaction is complete (ethyl acetate : Petroleum ether = 1:2, v / v). After the reaction, the reaction solution was quenched by adding 20 ml of water, and then 2×30 ml of dichloromethane was added for extraction. The organic layer was washed with 2×50 ml with water and 2×50 ml with saturated NaCl aqueous s...

Embodiment 3

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

[0045] The reaction formula is as follows:

[0046]

[0047] Weigh Brefeldin A (II) (1eq, 0.3mmol, 84mg), and dissolve it in 20mL of anhydrous dichloromethane to prepare a solution of formula (II). Phenyl) quinoline-4-carboxylic acid (Ⅲ-3) (4eq, 1.2mmol, 0.3834g) was dissolved in 20ml of anhydrous dichloromethane to prepare a solution of formula (Ⅲ-3), 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 added, and microwave reaction was performed at 44℃ for 7h. The power is 150W. During the reaction, thin layer chromatography is used to check whether the reaction is complete (ethyl acetate: petroleum ether=1: 2, v / v). After the reaction, the reaction ...

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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 derivatives. (2) Background technology [0002] Brefeldin A ((+)-Brefeldin A, referred to as BFA), is a new type of antibiotic, a secondary metabolite produced by a macrolide fungus, also called reprodin Or ascosporin has a variety of biological activities, including anti-fungal, anti-viral, anti-nematode, anti-mitosis, and can also be used as a molecular tool to study 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. Therefore, BFA is structurally modified to overcome its own existing problems. Unfavorable factors that enable it to be applied to clinical research as soon as possible have become a new scientific research focus. The present invention obtains BFA derivatives by chemically modifying the 4-OH and 7-OH ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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