肉桂酰酪胺类似物的合成与抗血小板聚集评价

doi:10.11944/j.issn.1000-0518.2018.10.170365

摘要/Abstract

摘要：

为了探究肉桂酰酪胺的苯环上甲氧基取代、酪胺上羟基和酰胺上胺基被甲基化对衍生物抗血小板聚集活性的影响,以8种苯甲醛衍生物为原料,经过缩合反应及甲基化等反应制得肉桂酰酪胺类似物,经核磁共振波谱仪(NMR)、质谱(MS)、单晶衍射等技术手段表征了目标化合物结构。基于变温核磁,探讨了化合物4a~4h中旋转异构及酰胺C—N键双键性质对氢核磁谱的影响。采用Born比浊法对目标化合物进行活性筛选,9个类似物的活性均强于柄果花椒酰胺,特别是化合物2c、4c、4f在200 μmol/L时显示出强的抑制率,分别为50.03%、60.87%、53.33%。该类化合物的构效关系是4位甲氧基取代对化合物的抗ADP(二磷酸腺苷)诱导血小板聚集活性最为有利,甲基化B环中的羟基和结构中的酰胺氮原子时,在某种程度上可增强化合物活性。

关键词: 肉桂酰酪胺, 变温核磁, 旋转异构, 抗血小板聚集

Abstract:

In order to explore the influence of methoxy substitution in benzene ring, methylation of tyramine hydroxyl and cinnamoyl-tyramine amines, on anti-platelet aggregation activities analogues, cinnamoyl-tyramine amide analogues were synthesized via condensation and methylation with eight benzaldehyde derivatives as raw materials. The structures of synthesized compounds were characterized by nuclear magnetic resonance spectroscopy(NMR), mass spectrometry(MS) and single crystal diffraction. Based on variable-temperature NMR, rotational isomerization based on amide C—N bond was studied for compounds 4a~4h. Their anti-platelet aggregation activities were tested in vitro and assayed by Born test. The results show that nine analogues are more active than podocarpamide. Specifically, compounds 2c, 4c and 4f show inhibition rates of 50.03%, 60.87% and 53.33%, respectively, at 200 μmol/L. The preliminary structure-activity relationship studies on these compounds indicate that 4-methoxy substituent is the most favorable for anti-ADP(adenosine-diphosphate) induced platelet aggregation, and methylated hydroxyl group on ring B and the amide nitrogen also increase the activities to some extent.

Key words: thrombus, variable-temperature nuclear magnetic resonance spectroscopy, rotational isomerization, antiplatelet aggregation

李悦青,吴茜茜,宋其玲,曹雷,秦秋燕,徐艳,赵伟杰. 肉桂酰酪胺类似物的合成与抗血小板聚集评价[J]. 应用化学, 2018, 35(10): 1174-1183.

LI Yueqing,WU Qianqian,SONG Qilin,CAO Lei,QIN Qiuyan,XU Yan,ZHAO Weijie. Synthesis and Anti-platelet Aggregation Assay of Cinnamoyl-tyramine Amide Analogues[J]. Chinese Journal of Applied Chemistry, 2018, 35(10): 1174-1183.

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