| 摘要: |
| 目的 以卡托普利为先导化合物，设计合成一类新型二硫代二丙酰胺类衍生物，并考察其血管内皮细胞保护活性。方法 保留先导物卡托普利结构上的巯基丙酰胺骨架和侧链甲基，对脯氨酸片段进行结构改造并进行二聚化，设计合成了5个二硫代二丙酰胺类衍生物。以人脐静脉内皮细胞为实验细胞株，利用400 μmol/L过氧化氢溶液刺激3 h建立氧化诱导损伤细胞模型，以卡托普利为阳性对照药测试目标化合物对血管内皮细胞的保护活性。结果 所有目标化合物结构均通过核磁共振波谱（1HNMR、13CNMR）和电喷雾电离质谱法（ESI-MS）确证。初步的血管内皮细胞保护活性测试结果表明，除化合物4c外4个目标化合物均具有不同程度的血管内皮细胞保护活性，其中化合物4e即3，3’-二硫（N-（［1，1’-联苯］-3-基甲基）-2-甲基丙酰胺）活性最优。结论 将卡托普利分子结构上的脯氨酸替换为4-甲基苄胺及4-叔丁基苄胺等相对较大的疏水性片段并进行二聚化，能显著改善其血管内皮细胞保护活性。 |
| 关键词: 卡托普利 设计合成 血管内皮细胞 保护活性 |
| DOI：10.16781/j.0258-879x.2020.04.0429 |
| 投稿时间：2019-11-06修订日期：2020-01-06 |
| 基金项目: |
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| Synthesis and vascular endothelial cell protective activity of novel dithiodipropionamide derivatives |
| DU Hong-li,WANG Lin-zhao,CHEN An-ni,XIA Jin,HU Yun-ying,ZHANG Guo-qing* |
(Department of Pharmacy, Eastern Hepatobiliary Surgery Hospital, Naval Medical University (Second Military Medical University), Shanghai 200438, China
*Corresponding author) |
| Abstract: |
| Objective To design and synthesize a series of novel dithiodipropionamide derivatives based on precursor captopril, and to investigate their vascular endothelial cell protective activities. Methods Based on the structure of captopril, we designed and synthesized five dithiodipropionamide derivatives, whose mercapto propionamide and methyl side chain were retained and the proline were modified. Human umbilical vein endothelial cells (HUVECs) were exposed to H2O2 at a concentration of 400 μmol/L for 3 h. Then in vitro endothelial cell protective activities of the target compounds were determined using captopril as the positive control drug. Results The target compounds were confirmed by nuclear magnetic resonance spectroscopy (1HNMR and 13CNMR) and electrospray ionization-mass spectrometry (ESI-MS). Preliminary results of vascular endothelial cell protective activity test showed that, except for compound 4c, all the four target derivatives exhibited cytoprotective activity to different extents. The compound 4e, namely 3,3’-disulfide (N-(［1,1’-biphenyl］-3-methyl)-2-methylpropionamide) had the best activity. Conclusion The proline structure on captopril substituted by relatively large hydrophobic fragments, such as 4-methylbenzylamine and 4-tert-butylbenzylamine, followed by dimerization, can improve protective activity of vascular endothelial cells. |
| Key words: captopril design and synthesize vascular endothelial cells protective activity |
