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4,7-site difurazan NO donor substituted derivatives of brefeldin A, and preparation method and uses thereof

A technology of brefeldin and feldspar, which is applied to the derivatives modified at the 4 and 7 positions of brefeldin A, to prepare anti-tumor drugs, which can solve the problems of poor bioavailability, low water solubility, Issues such as neurotoxicity limitations

Active Publication Date: 2017-07-07
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although it has the potential to be developed as a tumor chemotherapy drug, the low water solubility, poor bioavailability and neurotoxicity in animal studies have limited the application of brefeldin in the field of medicine

Method used

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  • 4,7-site difurazan NO donor substituted derivatives of brefeldin A, and preparation method and uses thereof
  • 4,7-site difurazan NO donor substituted derivatives of brefeldin A, and preparation method and uses thereof
  • 4,7-site difurazan NO donor substituted derivatives of brefeldin A, and preparation method and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033]

[0034] 60g NaOH and 480mL H 2 The solution prepared by O was poured into a reaction flask, thiophenol (75mL, 0.63mol) was taken, and then chloroacetic acid (78g, 0.825mol) was added, and a large amount of white precipitates were precipitated in the reaction solution. 6N HCl was added to obtain phenylthioacetic acid (3) as a white solid. Dissolve 3 (20g, 0.12mol) in 90mL glacial acetic acid, add 24.3mL 30% H 2 o 2 , stirring at room temperature. After the reaction is complete, add fuming HNO 3 48mL. Heating reaction, after 4 hours, white needle-like crystals precipitated, filtered and dried to obtain 3,4-diphenylsulfonylfurazan nitrogen oxide (5). Ethylene glycol (0.56mL, 10mmol) and 5 (1g, 2.7mmol) were dissolved in 10mL THF, and 30% NaOH aqueous solution (0.5mL, 3mmol) was added dropwise to react for 2h. Pour into 20mL H 2 O, extracted with EtOAc (3×20 mL), the organic layers were combined, washed once with saturated brine, dried over anhydrous sodium sulf...

Embodiment 2

[0036]

[0037] Referring to the synthetic method of Example 1. Yellow oil, yield 13.4%; 1 H-NMR (400MHz, DMSO-d 6 )δ7.72~8.02(10H,m,Ar-H),7.23(1H,dd,J=15.70Hz and 3.29Hz,C 3 -H),5.73(1H,m,C 11 -H),5.60(1H,dd,J=15.80Hz and 1.69Hz,C 2 -H),5.28(1H,m,C 10 -H),5.16(1H,dd,J=15.14Hz and 9.75Hz,C 4 -H),5.01(1H,m,C 7 -H),4.73(1H,m,C 15 -H),4.43~4.62(8H,m,2OC H 2 C H 2 O),2.39~2.63(8H,m,2COC H 2 CH 2 C H 2 CO),0.73~2.34(19H,m,C 5 ,2C 6 ,2C 8 ,C 9 ,2C 12 ,2C 13 ,2C 14 -H,2COCH 2 C H 2 CH 2 CO,C H 3 ); 13 C-NMR (400MHz, DMSO-d 6 )δ172.83,172.29,172.05,171.56,164.86,158.69,158.69,148.34,137.21,136.13,136.13,136.10,135.78,130.68,129.97,129.97,129.97,129.97,128.31,128.31,128.31,128.31,117.13,110.46,110.46 ,75.76,74.74,71.26,69.33,69.33,61.28,61.24,51.28,42.43,42.40,37.43,33.40,32.71,32.66,32.40,32.28,31.27,26.26,20.57,19.82,19.7 HR-ES ( +Na)m / z: calcd for C 46 h 52 N 4 o 20 S 2 :1067.2509, found 1067.2510.

Embodiment 3

[0039]

[0040] Referring to the synthetic method of Example 1. Yellow oil, yield 8.7%; 1 H-NMR (400MHz, DMSO-d 6 )δ7.71~8.01(10H,m,Ar-H),7.22(1H,dd,J=15.86Hz and 3.25Hz,C 3 -H),5.74(1H,m,C 11 -H),5.63(1H,dd,J=15.80Hz and 1.67Hz,C 2 -H),5.25(1H,m,C 10 -H),5.18(1H,dd,J=15.04Hzand 9.74Hz,C 4 -H),4.94(1H,m,C 7 -H),4.71(1H,m,C 15 -H),4.15~4.45(8H,t,J=6.13Hz,2OC H 2 CH 2 C H 2 O),2.52~2.70(8H,m,2COC H 2 C H 2 CO),0.72~2.52(19H,m,C 5 ,2C 6 ,2C 8 ,C 9 ,2C 12 ,2C 13 ,2C 14 -H,2OCH 2 C H 2 CH 2 O,C H 3 ); 13 C-NMR (400MHz, DMSO-d 6 )δ172.36,172.36,171.83,171.40,165.26,159.15,159.15,148.45,137.53,137.50,136.50,136.50,136.16,131.03,130.37,130.37,130.37,130.37,128.72,128.72,128.72,128.72,117.60,110.88,110.88 HR-ES +Na)m / z: calcd for C 46 h 52 N 4 o 20 S 2 :1067.2509, found 1067.2456.

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Abstract

The invention relates to the field of medicinal chemistry, and relates to derivatives obtained by simultaneous modification on 4-site and 7-site of brefeldin A. Particularly, the invention relates to 4,7-site difurazan NO donor substituted brefeldin A derivatives, and a preparation method of the derivatives and uses of the derivatives in preparing antineoplastic drugs. The brefeldin A derivatives are as shown by a general formula I or II, shown in the description, wherein m and n are respectively integers within the range of 1 to 8.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, and relates to derivatives modified at the 4 and 7 positions of brefeldin A. It specifically relates to brefeldin A derivatives substituted by 4,7-difurazan NO donors, a preparation method thereof and an application in preparation of antitumor drugs. Background technique [0002] Brefeldin A (brefeldin A) is a macrolide antibiotics, first isolated from Penicilliumdecumbens. It has a wide range of biological properties, including antitumor, antiviral, antifungal, and antimitotic activities. According to the testing data of the National Cancer Institute (NCI), the average GI of brefeldin A on 60 tumor cell lines 50 is 40nM. The mechanism of action of brefeldin A is closely related to the breakdown of the Golgi apparatus. The reversible breakdown of the Golgi apparatus leads to the interruption of protein transport, which in turn leads to the redistribution of Golgi apparatus proteins into the ...

Claims

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Application Information

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IPC IPC(8): C07D413/14C07D313/00A61K31/4245A61P35/00
Inventor 李达翃华会明潘华奇李占林田康涛李佳
Owner SHENYANG PHARMA UNIVERSITY
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