新型硝酮类化合物的化学合成与构效关系研究

项目名称： 新型硝酮类化合物的化学合成与构效关系研究

项目编号： No.81502908

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 孙业伟

作者单位： 暨南大学

项目金额： 17.9万元

中文摘要： 缺血性脑中风的治疗急需有效药物。曾经做过5000多人III 期临床试验的治疗缺血性脑中风药物NXY-059在体外及动物实验中具有强大的自由基清除能力和神经保护作用，但因临床试验疗效不佳，最终失败。失败的最主要原因是其难以通过血脑屏障。本课题组前期初步研究结果发现，在硝酮化合物结构中引入川芎嗪结构，可显著提高化合物通过血脑屏障的能力。同时川芎嗪的引入可赋予硝酮类化合物钙离子抑制作用，增强化合物的活性。研究还发现，增加硝酮基团的数目可以提高化合物的活性，但同时也降低了通过血脑屏障的能力。本项目拟在前期研究的基础上，设计合成一系列新型硝酮类化合物，尤其是多川芎嗪多硝酮化合物，重点解决硝酮类化合物难以通过血脑屏障这一关键科学问题。同时通过川芎嗪的引入，赋予化合物多重作用功能。通过化学合成和活性研究，探讨化合物的构效关系，为后续药物设计提供理论指导。

中文关键词： 硝酮；血脑屏障；构效关系；化学合成；多功能药物

英文摘要： There is an urgent need for effective drugs for the treatment of ischemic stroke. NXY-059, whose phase III clinical trials enrolled 5000 patients, demonstrated strong free radical scavenging effects and neuroprotective effects. Unfortunately, NXY-059 ultimately failed. The main reason for the failing of clinical trial is its difficulty to pass the blood brain barrier (BBB). Our previous studies suggested that introduction of tetramethylpyrazine (TMP) skeleton into a nitrone can significantly improve the nitrone’s ability to pass the BBB. Meanwhile, introduction of TMP endowed the compound with calcium inhibitory activity. Our previous study also suggested that although the free radical scavenging effects were improved by adding the number of ntrone groups, the abilities to pass BBB were reduced. Based on previous findings, in this project, we will design and synthesize series of novel nitrone compounds, particularly multinitrones armed with multiple TMP moieties. The key scientific issues of this project are to solve the problems of multinitrones to pass BBB. In addition, we anticipate that the introduction of TMP moieties will endow these novel compounds with multifunctions. The multifunctional activities and SAR are investigated in this project. This work will provide guidance for future anti-stroke drug design.

英文关键词： nitrone;blood brain barrier;SAR;chemical synthesis;multifunctional drug