Brefeldin A derivatives, and preparation method and uses thereof

A Brefeldin and Fideloid technology, which can be used in drug combinations, pharmaceutical formulations, medical preparations containing active ingredients, etc., can solve problems such as poor bioavailability, neurotoxicity limitation, and low water solubility.

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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  • Brefeldin A derivatives, and preparation method and uses thereof
  • Brefeldin A derivatives, and preparation method and uses thereof
  • Brefeldin A derivatives, and preparation method and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039]

[0040] 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

[0042]

[0043] Referring to the synthetic method of Example 1. Yellow oil, yield 8.1%; 1 H-NMR (400MHz, DMSO-d 6 )δ7.73~7.99(5H,m,Ar-H),7.32(1H,dd,J=15.61Hz and 2.96Hz,C 3 -H),5.70(2H,m,C 2 ,C 11 -H),5.19(1H,d,J=5.62Hz,O H ),5.14(1H,dd,J=15.12Hz and 9.64Hz,C 10 -H),5.00(1H,m,C 7 -H),4.70(1H,m,C 15 -H),4.39~4.60(4H,t,J=4.24Hz,OC H 2 C H 2 O),4.00(1H,m,C 4 -H),2.32~2.37(4H,m,COC H 2 CH 2 C H 2 CO),0.73~2.46(17H,m,C 5 ,2C 6 ,2C 8 ,C 9 ,2C 12 ,2C 13 ,2C 14 -H,COCH 2 C H 2 CH 2 CO,C H 3 ); 13 C-NMR (400MHz, DMSO-d 6 )δ172.30,172.09,165.60,158.69,154.03,137.20,136.27,136.14,130.12,129.98,129.98,128.31,128.31,116.47,110.46,74.99,74.00,70.89,69.33,61.25,51.88,42.69,38.16,38.07,33.43 , 32.71, 32.38, 31.37, 26.38, 20.69, 19.79; HR-MS (ESI, M+Na) m / z: calcd for C 31 h 38 N 2 o 12 S: 685.2038, found 685.2039.

Embodiment 3

[0045]

[0046] Referring to the synthetic method of Example 1. Yellow oil, yield 8.6%; 1 H-NMR (400MHz, CDCl 3 )δ7.63~8.10(5H,m,Ar-H),7.34(1H,dd,J=15.69Hz and 3.09Hz,C 3 -H),5.91(1H,dd,J=15.63Hzand 1.89Hz,C 2 -H),5.71(1H,m,C 11 -H),5.21(1H,dd,J=15.22Hz and 9.65Hz,C 10 -H),5.08(1H,m,C 7 -H),4.86(1H,m,C 15 -H),4.30~4.51(4H,t,J=6.17Hz,OC H 2 CH 2 C H 2 O),4.12(1H,m,C 4 -H),2.59~2.64(4H,m,COC H 2 C H 2 CO),0.71~2.38(17H,m,C 5 ,2C 6 ,2C 8 ,C 9 ,2C 12 ,2C 13 ,2C 14 -H,OCH 2 C H 2 CH 2 O,C H 3 ); 13 C-NMR (400MHz, CDCl 3 )δ172.37,171.88,165.98,159.16,154.42,137.51,136.68,136.53,130.46,130.38,138.38,128.73,128.73,116.83,110.91,75.64,74.37,71.27,68.55,60.71,52.28,43.05,38.56,38.45,33.81 ,31.77,30.17,29.25,29.00,27.75,21.07; HR-MS(ESI,M+Na) m / z: calcd for C 31 h 38 N 2 o 12 S: 685.2038, found 685.2035.

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Abstract

The invention relates to the field of medicinal chemistry, and relates to derivatives obtained by modification on 7-site of brefeldin A. Particularly, the invention relates to 7-site furazan 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 7-position of brefeldin A. It specifically relates to a brefeldin A derivative substituted by a 7-furazan NO donor, a preparation method thereof, and an application in the preparation of an antitumor drug. Background technique [0002] Brefeldin A (brefeldin A) is isolated from Penicillium decumbens. It has a wide range of biological properties, with an average GI of 60 tumor cell lines 50 is 40nM. Although it has the potential to be developed as a tumor chemotherapy drug, its low water solubility, poor bioavailability and neurotoxicity in animal studies limit the application of brefeldin in the field of medicine. [0003] The present invention takes brefeldin A as the lead compound, selects furazan nitrogen oxide as the NO donor, connects it to the 7-position of brefeldin A through a linking group, designs and synthesizes a compound with the genera...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/12C07D313/00A61K31/4245A61P35/00
Inventor 李达翃华会明潘华奇李占林田康涛李鹤
Owner SHENYANG PHARMA UNIVERSITY
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