Application of brefeldin A ester derivative in antitumor drug

A technology of feldspar and ester compounds, 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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  • Application of brefeldin A ester derivative in antitumor drug
  • Application of brefeldin A ester derivative in antitumor drug
  • Application of brefeldin A ester derivative in antitumor drug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0160] Example 1: 4-O-Nicotinyl BFA (Compound 1)

[0161]

[0162] 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, then added the DCM solution of niacin (2eq) to continue the reaction After 2 hours, after the reaction was detected by TLC, water was added for extraction, the organic phase was concentrated under reduced pressure, and the crude extract was separated and purified to obtain a white solid with a yield of 40%. 1 H NMR (400 MHz, Chloroform-d) δ= 9.23 (dd, J=2.2, 0.9, 1H), 8.78 (dd, J=4.9, 1.7, 1H), 8.30 (dt, J=8.0, 2.0,1H) , 7.40 (ddd, J=7.9, 4.9, 0.9, 1H), 7.32 (dd, J=15.7, 3.4, 1H), 5.79 – 5.66(m, 2H), 5.51 (ddd, J=10.5, 3.4, 1.9, 1H), 5.33 (dd, J=15.2, 9.5, 1H), 4.83(dqd, J=10.9, 6.2, 1.8, 1H), 4.32 (tt, J=5.3, 2.5, 1H), 2.48 (qd, J= 9.2, 6.7,1H), 2.35 (tt, J=10.5, 8.2, 1H), 2.23 (ddd, J=14.1, 9.3, 5.1, 1H), 2.12 (d, J=3.1, 1H), 2.05 – 1.94 ( m, 2H), 1.90 – 1.7...

Embodiment 2

[0163] Example 2: 4-O-(2-pyridinecarboxylic acid) acyl BFA (Compound 2)

[0164]

[0165] The preparation method of Reference Example 1 obtained a white solid with a yield of 45%. 1 H NMR (400 MHz, Chloroform-d)δ = 8.82 – 8.74 (m, 1H), 8.17 – 8.08 (d, J=7.8, 1H), 7.90 – 7.80 (td, J=7.8,1.7, 1H), 7.53 – 7.45 (dd, J=7.7, 4.8, 1H), 7.39 – 7.28 (dd, J=15.7, 3.3,1H), 5.86 – 5.77 (dt, J=15.7, 1.7, 1H), 5.77 – 5.67 (ddd, J=14.9, 10.1, 4.5,1H), 5.64 – 5.55 (ddd, J=10.3, 3.4, 1.7, 1H), 5.38 – 5.26 (dd, J=15.2, 9.2,1H), 4.88 – 4.77 (m, 1H ), 4.37 – 4.27 (p, J=4.6, 1H), 2.55 – 2.35 (ddd, J=31.1, 13.8, 8.4, 2H), 2.28 – 2.17 (ddd, J=14.1, 9.0, 5.2, 1H), 2.07 – 1.99(m, 2H), 1.89 – 1.82 (dd, J=11.4, 4.5, 2H), 1.77 – 1.66 (dt, J=13.3, 8.4,2H), 1.59 – 1.47 (m, 2H), 1.25 – 1.21 (d, J=6.3, 3H), 1.00 – 0.87 (ddt, J=17.8, 10.2, 4.6, 1H). 13 C NMR (100 MHz, Chloroform-d) δ 165.7, 164.0, 150.2, 147.5, 146.9, 137.2, 136.5, 130.8, 127.3, 125.4, 118.6, 77.9, 72.4, 72.0, 41, 4.25, 3.9 , 26.7, 20...

Embodiment 3

[0166] Example 3: 4-O-(4-pyridinecarboxylic acid) acyl BFA (Compound 3)

[0167]

[0168] The preparation method of Reference Example 1 obtained a white solid with a yield of 47%. 1 H NMR (400 MHz, Chloroform-d)δ = 8.86 – 8.69 (d, J=5.0, 2H), 7.93 – 7.82 (m, 2H), 7.36 – 7.28 (dd, J=15.7,3.4, 1H), 5.80 – 5.66 (m, 2H), 5.57 – 5.48 (ddd, J=10.5, 3.4, 1.8, 1H), 5.40– 5.28 (dd, J=15.2, 9.5, 1H), 4.90 – 4.78 (dqd, J=12.5, ( ddd, J=14.3, 9.4, 5.2, 1H), 2.07 – 1.94 (m, 2H), 1.93 –1.80 (m, 3H), 1.79 – 1.61 (dddd, J=28.3, 14.0, 9.2, 3.5, 2H), 1.59 – 1.46 (m,2H), 1.29 – 1.20 (d, J=6.3, 3H), 1.00 – 0.87 (m, 1H). 13 C NMR (100 MHz, Chloroform-d) δ 165.6, 164.1, 150.8, 146.5, 136.9, 136.4, 131.0, 123.0, 118.7, 78.0, 72.4, 72.2, 49.8, 44.5, 43.3, 41.2, 20.2, 34. .HRESIMS m / z 386.1957 [M+H] + (calcd. for [C 22 h 28 o 5 N] + , 386.1962).

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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 the aspect of inhibiting tumor proliferation activity; the brefeldin A ester derivative can be used for preventing or treating hyperproliferative diseases, and the structure of the brefeldin A ester derivative is represented by a formula (I). Hyperproliferative diseases comprise 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, so that the brefeldin A ester derivative has the potential of being developed into a novel antitumor drug.

Description

technical field [0001] The invention belongs to the field of pharmaceutical technology, and in particular relates to a class of brefeldin A ester derivatives, compositions and uses thereof, wherein the compounds or compositions have the function of inhibiting tumor proliferation and can be used for prevention or treatment hyperproliferative 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), and was determined by Weber et al. through single crystal, CD, asymmetric synthesis in 1971 Its absolute configuration (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,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/12A61K31/4427A61K31/4709A61K31/4725A61K31/4545A61P35/00
CPCC07D405/12A61P35/00C07B2200/07
Inventor 邵长伦王长云魏美燕姜瑶瑶刘明王翠芳
Owner OCEAN UNIV OF CHINA
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