Macrolide brefeldin A ester derivative and application thereof

A kind of technology of feldsparin and derivatives, applied in the field of medicine

Active Publication Date: 2021-05-28
OCEAN UNIV OF CHINA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But so far, many reported BFA derivatives can only maintain anti-tumor effects in vitro (CN103788053A; CN103772342A; CN105153136A; CN106928213A), and there is no BFA that can effectively improve pharmacokinetic properties, and others such as increasing solubility and reducing toxicity Derivative reports

Method used

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  • Macrolide brefeldin A ester derivative and application thereof
  • Macrolide brefeldin A ester derivative and application thereof
  • Macrolide brefeldin A ester derivative and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0222] 7-O-(3-fluorocinnamic acid) acyl BFA (compound 1a) 4-O-(3-fluorocinnamic acid) acyl BFA (compound 1b)

[0223] 4,7-O-bis(3-fluorocinnamic acid)yl BFA (compound 1c)

[0224]

[0225] Under the protection of nitrogen, BFA (40mg, 1eq), DMAP (1eq) and EDC·HCl (4eq) were dissolved in 8ml of anhydrous DCM, stirred at 40°C for 10 min, and then the DCM solution of 3-fluorocinnamic acid (2eq) was added , continue to react for 2h, after the reaction is detected by TLC, water is added for extraction, the organic phase is concentrated under reduced pressure, the crude extract is separated and purified to obtain white solids 1a, 1b, and 1c, and the yields are 20%, 40%, and 30% in turn.

[0226] Structural Characterization: 1a: 1 H NMR (600 MHz, Chloroform- d ) δ = 7.59 (d, J =16.0, 1H),7.39 – 7.31 (m, 2H), 7.29 (s, 1H), 7.21 (dt, J =9.6, 2.0, 1H), 7.07 (td, J =8.3, 2.5, 1H), 6.39 (d, J =15.9, 1H), 5.93 (dd, J =15.6, 1.9, 1H), 5.73 (ddd, J =15.0, 10.2, 4.6, 1H), 5.32 – 5.1...

Embodiment 2

[0230] 7-O-(2-fluorocinnamic acid) acyl BFA (compound 2a) 4-O-(2-fluorocinnamic acid) acyl BFA (compound 2b)

[0231] 4,7-O-bis(2-fluorocinnamic acid)yl BFA (compound 2c)

[0232]

[0233] Referring to the preparation method of Example 1, white solids 2a, 2b, 2c were obtained. The yields were 20%, 45%, and 30%, respectively.

[0234] Structural Characterization: 2a: 1 H NMR (600 MHz, Chloroform- d ) δ = 7.78 (d, J =16.2, 1H),7.53 (td, J =7.6, 1.7, 1H), 7.39 – 7.32 (m, 2H), 7.16 (td, J =7.5, 1.1, 1H),7.10 (ddd, J =10.8, 8.2, 1.1, 1H), 6.50 (d, J =16.2, 1H), 5.93 (dd, J =15.7,2.0, 1H), 5.73 (ddd, J =15.0, 10.3, 4.6, 1H), 5.31 – 5.22 (m, 2H), 4.86 (dqd, J =12.6, 6.3, 1.7, 1H), 4.15 (dt, J =9.6, 2.5, 1H), 2.47 – 2.26 (m, 3H), 2.06 –1.81 (m, 5H), 1.78 – 1.64 (m, 2H), 1.58 – 1.48 (m, 1H), 1.26 (d, J =6.2, 3H),0.99 – 0.90 (m, 1H). 13 C NMR (150 MHz, Chloroform- d ) Δ = 166.6, 162.3, 160.6,151.6, 137.5, 136.1, 131.9, 131.1, 129.2, 124.6, 121.0, 117.9, 116.4,76.0, 71.9...

Embodiment 3

[0238] 7-O-(4-fluorocinnamic acid) acyl BFA (compound 3a) 4-O-(4-fluorocinnamic acid) acyl BFA (compound 3b)

[0239] 4,7-O-bis(4-fluorocinnamic acid)yl BFA (compound 3c)

[0240]

[0241] Referring to the preparation method of Example 1, white solids 3a, 3b, 3c were obtained. The yields were 20%, 33%, and 43%, respectively.

[0242] Structural characterization: Compound 3a: 1 H NMR (600 MHz, Chloroform- d ) δ = 7.61 (d, J =16.0,1H), 7.54 – 7.48 (m, 2H), 7.36 (dd, J =15.7, 3.1, 1H), 7.10 – 7.04 (m, 2H),6.32 (d, J =16.0, 1H), 5.93 (dd, J =15.6, 1.9, 1H), 5.73 (ddd, J =15.0, 10.2,4.6, 1H), 5.32 – 5.20 (m, 2H), 4.86 (dqd, J =12.5, 6.2, 1.8, 1H), 4.15 (dt, J =9.7, 2.3, 1H), 2.42 (qd, J =9.1, 7.0, 1H), 2.40 – 2.33 (m, 1H), 2.29 (dddd, J =12.9, 7.3, 3.3, 1.5, 1H), 2.02 (dddd, J =10.5, 8.3, 5.0, 2.7, 1H), 1.98 – 1.91(m, 1H), 1.91 – 1.82 (m, 2H), 1.78 – 1.71 (m, 1H), 1.72 – 1.62 (m, 2H), 1.53( dddd, J =14.5, 10.9, 7.3, 2.3, 1H), 1.26 (d, J =6.2, 3H), 0.99 – 0.89 (m, ...

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Abstract

The invention relates to the field of medicinal chemistry, and in particular, relates to an application of a brefeldin A ester derivative in inhibiting tumor proliferation activity, wherein the structure of the brefeldin A ester derivative is represented by a formula (I). The novel compound has outstanding effects in preventing or treating hyperproliferative diseases including liver cancer, leukemia, breast cancer, colonic adenocarcinoma, gastric cancer, lung cancer, Bartter's esophagus cancer, cervical cancer, pancreatic cancer, endometrial cancer, bone cancer, lymph cancer, kidney cancer, brain cancer, nerve cancer, nasopharynx cancer, oral cancer and colorectal cancer, and has the potential of being developed into a novel antitumor drug.

Description

technical field [0001] The present invention belongs to the field of pharmaceutical technology, and specifically relates to a brefeldin A ester derivative, composition and application, wherein the compound or composition has the function of inhibiting tumor proliferation, and can be used to prevent or treat excessive proliferative disease. Background technique [0002] Brefeldin A (English name: Brefeldin A, referred to as BFA) is a class of macrolide fungal metabolites. It was isolated from Penicillium decumbens by Singleton et al. in 1958 (Singleton, V.L. et, al .Nature , 1958, 181, 1072-1073), its absolute configuration was determined in 1971 by Weber et al. through single crystal, CD, asymmetric synthesis (Weber, H. P. et, al. Helv. Chim. Acta , 1971, 54 , 2763-2766). BFA has a wide range of biological activities, including anti-virus, anti-fungal, anti-nematode, anti-mitosis and anti-tumor, etc. (Tamura, G, et, al. J. Antibiot. 1968, 21, 160-161; Takatsuki, A , e...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D313/00C07D407/14C07D407/12C07D405/12C07D405/14A61P35/00A61P35/04A61K31/365A61K31/443A61K31/444A61K31/4709
CPCC07D313/00C07D407/14C07D407/12C07D405/12C07D405/14A61P35/00A61P35/04C07B2200/07A61K31/365A61K31/443A61K31/444A61K31/4709
Inventor 邵长伦姜瑶瑶刘明王长云魏美燕王翠芳
Owner OCEAN UNIV OF CHINA
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