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7-amide-brefeldin a derivative as well as preparation method and application of 7-amide-brefeldin a derivative

A technology of brefeldin and fideloidin, which is applied in the fields of drug combination, tripeptide composition, organic chemistry, etc., can solve the problems of short plasma half-life, inability to apply anti-tumor therapeutic reagents, and unsatisfactory problems.

Inactive Publication Date: 2015-04-22
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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  • 7-amide-brefeldin a derivative as well as preparation method and application of 7-amide-brefeldin a derivative
  • 7-amide-brefeldin a derivative as well as preparation method and application of 7-amide-brefeldin a derivative
  • 7-amide-brefeldin a derivative as well as preparation method and application of 7-amide-brefeldin a derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063] Embodiment 1: the preparation of 7-O-methylsulfonyl-BFA (formula VI)

[0064]

[0065] Under nitrogen protection, 6 mL of pyridine was added to a 50 mL round-bottomed flask with a magnetic stirrer, then BFA (500 mg, 1.79 mmol), and then triethylamine (240 mg, 2.38 mmol) was added to start stirring at -20°C; Methanesulfonyl chloride (273mg, 2.38mmol) was added dropwise to the mixture (dropwise for 10min), and after the dropwise reaction was completed, it was reacted at -20°C for 2h to terminate the reaction. After the reaction solution was concentrated, 30ml of ethyl acetate was added for dilution, washed with 5% citric acid solution (2×10ml), saturated sodium bicarbonate solution (2×10ml), saturated sodium chloride solution (2×10ml), and organic phase, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was separated by thin-layer chromatography under the condition that the developer ethyl acetate (E):petr...

Embodiment 2

[0068] Example 2: 7-N 3 - Preparation of BFA(II)

[0069]

[0070] Under nitrogen protection, add 10mL N,N-dimethylformamide to a 50mL round-bottomed flask with a magnetic stirrer, then add compound VI 7-O-methylsulfonyl-BFA (400mg, 1.12mmol), and then add Sodium azide (217mg, 3.35mmol) was stirred at reflux at 70°C for 4h to terminate the reaction. After the reaction solution was cooled and concentrated, 30ml of ethyl acetate was added to dilute, washed with 5% citric acid solution (2×10ml), saturated sodium bicarbonate solution (2×10ml), saturated sodium chloride solution (2×10ml), and combined The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was separated by thin-layer chromatography under the condition of developing solvent E / P volume ratio=1:5 to obtain compound II (Rf=0.3, yield 83.40%).

[0071] Compound Characterization:

[0072] Compound II: pale yellow solid, yield 83.4% 1 ...

Embodiment 3

[0073] Example 3: 7-NH 2 - Preparation of BFAIII

[0074]

[0075] Under the protection of helium, add 20mL tetrahydrofuran to a 50mL round bottom flask with a magnetic stirrer, then add 7-N3-BFA (305mg, 1.0mmol), triphenylphosphine (340mg, 1.3mmol) and stir at 25°C 24h to terminate the reaction. After cooling and concentrating the reaction solution, add 30ml of ethyl acetate to dilute, wash with water (2×10ml), wash with saturated sodium chloride solution (2×10ml), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain the crude product. The crude product was separated by thin layer chromatography under the condition of developer D / M (volume ratio)=5:1 to obtain compound III (Rf=0.3, yield 54.80%).

[0076] Compound Characterization:

[0077] Compound III 7-NH 2 -BFA: pale yellow solid, yield 54.8% 1 H NMR (500MHz, CDCl 3 )δ7.38(dd, J=15.6,3.0Hz,1H),5.89(dd,J=15.6,1.6Hz,1H),5.72(m,1H),5.17(dd,J=15.1,9.6Hz,1H ), ...

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PUM

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Abstract

The invention relates to a 7-amide-brefeldin A derivative with anti-tumor activity as well as a preparation method and application of the 7-amide-brefeldin A derivative. The 7-amide-brefeldin A derivative serving as a novel compound provided by the invention has a high effect on treating liver cancer, lung cancer, breast cancer, kidney cancer, colorectal cancer and prostate cancer, and has the effective inhibition ratio of 80% through in-vitro detection; and the method for obtaining 7-NH2-brefeldin A and 7-amide-brefeldin A derivatives is simple and easy to operate.

Description

(1) Technical field [0001] The invention relates to a class of 7-amide-brefeldin A derivatives with anti-tumor activity and its preparation and application. (2) Background technology [0002] Brefeldin A ((+) Brefeldin A, referred to as BFA) is a natural macrolide antibiotic and a secondary metabolite of Ascomycetes, also known as clinomycetes 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 macrocyclic lactone, the structure is shown in I below: [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 effe...

Claims

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Application Information

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IPC IPC(8): C07D313/00C07D495/04C07D405/12C07D405/14C07K5/023A61K38/06A61K31/365A61K31/405A61K31/455A61K31/4188A61P35/00
CPCC07D313/00C07D405/12C07D405/14C07D495/04C07K5/0202
Inventor 朱勍张海峰郑裕国王亚军
Owner ZHEJIANG UNIV OF TECH
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