Li Guoliang, Xu Xin, Xu Kuo, Chu Fuhao, Song Jixiang, Zhou Shen, Xu Bing, Gong Yan, Zhang Huazheng, Zhang Yuzhong, Wang Penglong, Lei Haimin
School of Chinese Pharmacy, Beijing University of Chinese Medicine, No.6 Wangjing Middle Ring South Road, Beijing, Chaoyang District China.
Department of Pathology, Beijing University of Chinese Medicine, No.11 North Third Ring Road, Beijing, Chaoyang District China.
Chem Cent J. 2015 Mar 4;9:9. doi: 10.1186/s13065-015-0084-5. eCollection 2015.
Ligustrazine has potent effects of thrombolysis, neuroprotection and vascular protection, which were important for effectively protecting the nervous system. Previous study in our laboratory reported that ligustrazine-benzoic acid derivatives have been shown to exhibit beneficial effect against CoCl2-induced neurotoxicity in differentiated PC12 cells. To further improve ligustrazine's neuroprotection, we integrated the ligustrazine and phenolic acid fragments into one molecule via an amide bond based on structural combination.
In this study, 12 novel ligustrazine-phenolic acid derivatives were synthesized and nine others were prepared by improved methods. Furthermore, these compounds were evaluated for their protective effects against CoCl2-induced neurotoxicity in differentiated PC12 cells. The amides conjunctional derivatives exhibited promising neuroprotective activities in comparison with ligustrazine. In addition, the most active congener (E)-3-(2,3,4-trimethoxyphenyl)-N-((3,5,6-trimethylpyrazin-2-yl)methyl)acrylamide (L10, EC50 = 25 μM), which is 2 times higher than that of ligustrazine, may be a potential candidate for intervention in neurological diseases. Structure-activity relationship was discussed briefly.
Results of series of ligustrazinyl amides enrich the study of ligustrazine derivatives with neuroprotective effects. Our completed work supports that the attempt to apply structure combination to discover more efficient neuroprotection lead compounds is viable. Graphical AbstractLigustrazinyl Amides L1-L21 with Neuroprotective Effects.
川芎嗪具有强大的溶栓、神经保护和血管保护作用，对有效保护神经系统具有重要意义。我们实验室之前的研究报道，川芎嗪-苯甲酸衍生物已被证明对分化的PC12细胞中CoCl2诱导的神经毒性具有有益作用。为了进一步提高川芎嗪的神经保护作用，我们基于结构组合通过酰胺键将川芎嗪和酚酸片段整合到一个分子中。
在本研究中，合成了12种新型川芎嗪-酚酸衍生物，另外9种通过改进方法制备。此外，评估了这些化合物对分化的PC12细胞中CoCl2诱导的神经毒性的保护作用。与川芎嗪相比，酰胺连接衍生物表现出有前景的神经保护活性。此外，活性最高的同系物（E）-3-（2,3,4-三甲氧基苯基）-N-（（3,5,6-三甲基吡嗪-2-基）甲基）丙烯酰胺（L10，EC50 = 25 μM），其活性是川芎嗪的2倍，可能是干预神经疾病的潜在候选物。简要讨论了构效关系。
一系列川芎嗪酰胺的结果丰富了具有神经保护作用的川芎嗪衍生物的研究。我们完成的工作支持通过结构组合发现更有效的神经保护先导化合物的尝试是可行的。图形摘要：具有神经保护作用的川芎嗪酰胺L1-L21。
