Brefeldin A derivative as well as preparation method and application thereof
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A technology of feldspar and its derivatives, which is applied in the field of medicine to achieve broad research value and the effect of improving solubility
Active Publication Date: 2021-05-28
OCEAN UNIV OF CHINA
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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
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Embodiment 1
[0223] Example 1: BFA-7-(pyridin-3-ylmethyl)carbonate (Compound 1)
[0224]
[0225] Under nitrogen protection, BFA (50 mg, 1 eq) and triphosgene (50 mg, 1 eq) were dissolved in 3 ml of dry acetone, stirred at room temperature for 10 min, and then slowly added dropwise 2 ml of DMAP (100 mg, 5 eq) in acetone After stirring for 5 min, the system was transferred to an oil bath at 65 °C, continued to stir for 15 min, and slowly added dropwise 1 ml of nicotinyl alcohol (0.15 ml, 8 eq) in acetone solution, and continued stirring for 2 h after the dropwise addition. The reaction solution was concentrated under reduced pressure, and the crude extract was purified by reverse-phase silica gel column chromatography and HPLC preparation twice to obtain a colorless oily liquid. Yield 30%. 1 H NMR (600 MHz, CDC1 3 ) δ = 8.61 – 8.49 (m, 2H), 7.69 (dt, J=7.8, 2.0, 1H), 7.34 – 7.26 (m, 2H), 5.89 (dd, J=15.6, 1.9, 1H), 5.67 (ddd ,J=15.0, 10.2, 4.6, 1H), 5.18 (dd, J=15.2, 9.4, 1H), 5.10 (s...
Embodiment 2
[0226] Example 2: BFA-7-(pyridin-2-ylmethyl)carbonate (Compound 2)
[0227]
[0228] Referring to the preparation method of Example 1, a colorless oily liquid was obtained. The yield was 41%. ESIMS m / z 416.21 [M + H] + .
Embodiment 3
[0229] Example 3: BFA-7-(pyridin-4-ylmethyl)carbonate (Compound 3)
[0230]
[0231] Referring to the preparation method of Example 1, a colorless oily liquid was obtained. The yield was 38%. ESIMS m / z 416.21 [M + H] + .
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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 derivative represented by a formula (I) in the aspect of inhibiting tumor proliferation activity. 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 invention belongs to the technical field of medicine, and in particular relates to a class of Brefeldin A derivatives, compositions and preparation methods and uses thereof, wherein the compounds or compositions have the purpose of inhibiting tumor proliferation activity, and can be used for preventing or Treatment of hyperproliferative diseases. Background technique [0002] Brefeldin A (English name: Brefeldin A, BFA for short) is a class of macrolide fungal metabolites. Isolated from Penicillium decumbens by Singleton et al. in 1958 (Singleton, V.L. et, al. .Nature , 1958, 181, 1072-1073), whose absolute configuration was determined by single crystal, CD, asymmetric synthesis by Weber et al. in 1971 (Weber, H. P. et, al. Helv. Chim. Acta , 1971, 54 , 2763-2766). BFA has a wide range of biological activities, including antiviral, antifungal, antinematode, antimitotic and antitumor (Tamura, G, et, al. J. Antibiot. 1968, 21, 160-161; Takatsu...
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