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Polyethylene glycol-brefeldin A ester derivatives and preparation and applications of the derivatives

A technology of brefeldin and brefeldin, which is applied in the field of polyethylene glycol-brefeldin A ester derivatives, can solve the problems of poor water solubility, short plasma half-life, inability to apply anti-tumor therapeutic reagents, etc. question

Active Publication Date: 2015-07-22
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, brefeldin A is not ideal because of its own pharmacokinetic properties (low bioavailability, poor water solubility, short plasma half-life, etc.), so it cannot be used as an anti-tumor therapeutic agent in clinical practice.

Method used

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  • Polyethylene glycol-brefeldin A ester derivatives and preparation and applications of the derivatives
  • Polyethylene glycol-brefeldin A ester derivatives and preparation and applications of the derivatives
  • Polyethylene glycol-brefeldin A ester derivatives and preparation and applications of the derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0100] Embodiment 1: the preparation of (II-1)

[0101]

[0102] Under nitrogen protection, polyethylene glycol 1000 diacid ester (0.12g, 0.1mM) was added to a round-bottomed flask equipped with 25ml of anhydrous dichloromethane, stirred to completely dissolve, and brefeldin A (0.056g, 0.2 mM) was heated at 40°C until completely dissolved, EDC (0.058g, 0.3mM) and DMAP (0.012g, 0.1mM) were added in sequence, and the mixture was heated to reflux for reaction. The reaction process was monitored by TLC, and concentrated sulfuric acid was used for color development. After 24h, the reaction was terminated, and 30mlH was added to the reaction solution. 2 O, with CH 2 Cl 2 Extraction (3x15ml), the combined organic phase was washed with anhydrous Na 2 SO 4 Drying, filtration, the filtrate was concentrated to remove most of the solvent, separated by silica gel column chromatography, the eluent was a mixed solvent of dichloromethane: methanol (D / M) volume ratio=15:1, and the elue...

Embodiment 2

[0105] Embodiment 2: Preparation of 4b (II-2)

[0106]

[0107] Under the protection of nitrogen, polyethylene glycol 4000 diacid ester (0.41g, 0.1mM) was added to a round-bottomed flask equipped with 25ml of anhydrous dichloromethane, stirred to completely dissolve, and brefeldin A (0.056g, 0.2 mM) was heated at 40°C until completely dissolved, EDC (0.058g, 0.3mM) and DMAP (0.012g, 0.1mM) were added in sequence, mixed and heated to reflux for reaction. The reaction process was monitored by TLC, and concentrated sulfuric acid was used for color development. After 24h, the reaction was terminated, and 30mlH was added to the reaction solution. 2 O, with CH 2 Cl 2 Extraction (3x15ml), the combined organic phase was washed with anhydrous Na 2 SO 4 Dry, filter, concentrate to remove most of the solvent, separate by silica gel column chromatography, the eluent is dichloromethane: methanol (D / M) volume ratio = 15:1 mixed solvent, collect the eluate containing the product, eva...

Embodiment 3

[0110] Embodiment 3: 4c (I-1) preparation

[0111]

[0112] Under nitrogen protection, monomethyl ether polyethylene glycol 1000-1-ester (0.11g, 0.1mM) was added to a round-bottomed flask containing 25ml of anhydrous dichloromethane, stirred to completely dissolve, and brefeldin A was added (0.056g, 0.2mM) was heated at 40°C until completely dissolved, EDC (0.058g, 0.3mM) and DMAP (0.012g, 0.1mM) were added in sequence, and the mixture was heated to reflux for reaction. The reaction process was monitored by TLC, and concentrated sulfuric acid was used for color development. After 24h, the reaction was terminated, and 30mlH was added to the reaction solution. 2 O, with CH 2 Cl 2 Extraction (3x15ml), the combined organic phase was washed with anhydrous Na 2 SO 4 Dry, filter, concentrate to remove most of the solvent, separate by silica gel column chromatography, the eluent is dichloromethane: methanol (D / M) volume ratio = 15:1 mixed solvent, collect the eluate containing...

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Abstract

Polyethylene glycol-brefeldin A ester derivatives are provided. Structures of the derivatives are shown as a formula I, a formula II, a formula III or a formula IV. Applications of the novel compounds in preparation of medicines for treating and preventing liver cancer, lung cancer, breast cancer, kidney cancer, cancer of colon and prostatic cancer are also provided.

Description

(1) Technical field [0001] The invention relates to a class of polyethylene glycol (PEG)-brefeldin A ester derivatives with antitumor activity and its preparation and application. (2) Background technology [0002] Brefeldin A ((+) Brefeldin A BFA) is a natural macrolide antibiotic and a secondary metabolite of Ascomycetes, also known as clinomycin or ascodiosporum. In 1958, Singleton et al. first isolated it from the fermentation broth of Penicillium decumbens. 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 shown in formula A below: [0003] [0004] Brefeldin A has a variety of biological activities, including antifungal, antiviral, antinematode, antimitotic, and it was found to have highly active inhibitory effect...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08G65/00A61K31/77A61P35/00
Inventor 朱勍张海峰郑裕国王亚军
Owner ZHEJIANG UNIV OF TECH
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