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Brefeldin A glycosylated derivative and preparation and application thereof

A technology of brefeldin and brefeldin bacteria, applied in the field of preparation of brefeldin A glycosylated derivatives, can solve normal somatic cell toxicity, short half-life, brefeldin A water solubility Low-level problems, to achieve the effect of retaining tumor suppressor activity and enhancing water solubility

Inactive Publication Date: 2014-04-23
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] However, in terms of druggability, brefeldin A still has some shortcomings: ① Brefeldin A has low water solubility; ② The intracellular half-life of brefeldin A is short. Bruening et al. In cells, A will quickly combine with glutathione under the action of glutathione transsulfase and then be transferred out of cells; ③ Brefeldin A lacks specificity of action and is toxic to normal somatic cells side effect
[0006] At present, there are few reports on brefeldin A glycosylation methods

Method used

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  • Brefeldin A glycosylated derivative and preparation and application thereof
  • Brefeldin A glycosylated derivative and preparation and application thereof
  • Brefeldin A glycosylated derivative and preparation and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Example 1: 7-O-(D-α-glucose)-brefeldin A

[0028] (1) 7-O-(2,3,4,6-tetraacetyl-D-α-glucose)-brefeldin A

[0029]

[0030] Weigh 0.8 g of trichloroacetimidate-2,3,4,6-tetraacetyl-D-α-glucoside and 0.2 g of brefeldin A solid powder, dissolve in 30 ml of anhydrous di Chloromethane, add 0.5 g activated 4 Molecular sieves, stirred magnetically at room temperature (25°C) for 30 minutes to remove water, cooled methanol to reflux to -30°C, then added 40 microliters of boron trifluoride ether and 0.5 g of activated 4 Molecular sieves were reacted with magnetic stirring for 4 hours. After the reaction, the reaction solution was filtered to obtain filtrate c and filter cake, the filter cake was rinsed with 30 ml of dichloromethane, the washing liquid and filtrate c were combined, washed 3 times with saturated saline, and dried over anhydrous magnesium sulfate , filtered to obtain the filtrate d, the filtrate d was concentrated under reduced pressure, and the concentrate was...

Embodiment 2

[0038] Example 2: 7-O-(D-α-mannose)-brefeldin A

[0039] (1) 7-O-(2,3,4,6-tetra-O-acetyl-D-α-mannopyranose)-brefeldin A

[0040]

[0041] Weigh 0.5 g of 1-trichloroacetimidate-2,3,4,6-tetraacetyl-D-α-mannose, dissolve it in 30 ml of anhydrous dichloromethane, add 0.50 g of activated 4 Molecular sieves and 0.2 g of brefeldin A powder were magnetically stirred at room temperature (25°C) for 30 minutes, cooled and refluxed to -30°C with methanol, and then 40 μl of boron trifluoride ether and 0.5 g of activated 4 Molecular sieves, stirred and reacted at -30°C for 4 hours. Other operations were the same as in Example 1 to obtain 127 mg of light yellow powder.

[0042] Compound Characterization:

[0043] 1 H NMR (500MHz, CDCl 3 )δ7.28(m,1H),5.92(d,J=15.6Hz,1H),5.82–5.57(m,1H),5.12(dd,J=8.7,4.5Hz,1H),4.85(dd,J =10.4,5.7Hz,1H),4.11(d,J=8.7Hz,1H),2.49–2.05(m,4H),2.20,2.07,2.09,2.29(12H),2.03(d,J=27.9Hz, 1H),1.93–1.78(m,3H),1.77–1.69(m,1H),1.67–1.57(m,1H),1.69–1.58(m,1H),1.5...

Embodiment 3

[0049] Example 3: 7-O-(D-α-glucosamine)-brefeldin A

[0050] (1) 7-O-(3,4,6-Triacetyl-2-deoxy-D-α-glucosamine)-brefeldin A

[0051]

[0052] Weigh 0.5 g of trichloroacetimidate glucosamine and 0.2 g of brefeldin A, dissolve in 30 ml of anhydrous dichloromethane, add 0.5 g of activated 4 Molecular sieves, stirred at 0°C for 30 minutes. Use methanol to cool and reflux to -30°C, then add 40 microliters of boron trifluoride ether and 0.5 grams of activated 4 Molecular sieves, react at -30°C for 4 hours. Other operations were the same as in Example 1 to obtain 84 mg of light yellow solid.

[0053] Compound Characterization:

[0054] 1 H NMR (500MHz, CDCl 3 )δ7.28(m,1H),5.92(d,J=15.6Hz,1H),5.82–5.57(m,1H),5.12(dd,J=8.7,4.5Hz,1H),4.85(dd,J =10.4,5.7Hz,1H),4.11(d,J=8.7Hz,1H),2.49–2.05(m,4H),2.20,2.07,2.09,2.29(12H),2.03(d,J=27.9Hz, 1H),1.93–1.78(m,3H),1.77–1.69(m,1H),1.67–1.57(m,1H),1.69–1.58(m,1H),1.57–1.45(m,1H),1.26( t,J=6.2Hz,3H),0.92(dd,J=19.6,12.7Hz,1H). 13 C NMR ...

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Abstract

The invention discloses a brefeldin A glycosylated derivative shown in a formula (I) and a preparation method and application thereof. The invention provides a novel brefeldin A glycosylated derivative; the water solubility of the brefeldin A glycosylated derivative is enhanced; the tumor inhibiting activity of the brefeldin A is retained; in-vitro detection shows that the effective inhibition rate to cancer cells such as a human esophagus cancer and the like can be up to 80%; the preparation method of the preferred brefeldin A glycosylated derivative is obtained by optimizing the conditions of a compound (II), (img file='DDA0000451154560000011.TIF' wi='776' he='307' / ), in the formula (I), R is pentose, hexose, amino hexose or hexose acid.

Description

(1) Technical field [0001] The invention relates to a synthesis technology of brefeldin A derivatives, in particular to the preparation and application of a class of brefeldin A glycosylated derivatives. (2) Background technology [0002] Brefeldin A ((+)-Brefeldin A, BFA) is a macrolide antibiotic synthesized by filamentous fungi, also known as clinomycin and ascodioxin. The molecular structure of brefeldin A contains five chiral centers and one 13-membered macrolide structure, and the structure is shown in formula (I). In 1958, Singleton et al isolated brefeldin A for the first time from the fermentation broth of Penicillium decumben. A large number of studies have reported that brefeldin A induces the breakdown of the Golgi apparatus, inhibits the forward transport of proteins from the endoplasmic reticulum to the Golgi apparatus, and has biological activities such as antifungal, antiviral, antimitotic and antinematode. Research by the National Cancer Institute (NCI) fo...

Claims

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Application Information

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IPC IPC(8): C07H17/08C07H1/00A61K31/7048A61P35/00
Inventor 郑裕国王亚军吴植献薛锋沈寅初
Owner ZHEJIANG UNIV OF TECH
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