Design,synthesis and the mechanism of anti-atherosclerosis of The novel Tetramethylpyrazine derivatives
会议名称：《华东六省一市生物化学与分子生物学会2008年学术交流会》
会议日期：2008年
学科分类：0710[理学-生物学] 071010[理学-生物化学与分子生物学] 07[理学]
关 键 词：Tetramethylpyrazine（TMP） TMP derivatives atherosclerosis endothelial cells oxyradical calcium overload
摘 要：Tetramethylpyrazine(TMP),the active ingredients of Chinese traditional medicine Chuanxiong with effect promoting blood flow,has been widely used in clinical for treatment of atherosclerosis.However,pharmacokinetics study show that TMP has low bioavailability,rapid metabolism and short half-life(T=2.89 h).The accumulated toxicity often appeared in the patients for keep an effective plasma concentration by the frequent administration. Structure-activity relationship studies indicated that pyrazine ring in the molecule of TMP might largely be the determinant of its pharmacodynamies,while the 4 substituted groups might primarily govern its pharmaookinetics and toxicity.Therefore,it is significance to design and synthesize the new TMP derivatives with high potency and high bioavailability. The endothelial cells injury is not only the initiating factor of atherosclerosis,but also has an important role in the development of atherosclerosis-related diseases.So the protection of vascular endothelial cells injury is a necessary means for the treatment of atherosclerosis.It’s generally believed that the free radicals production and calcium overload of endothelial cells is positively related to the cell injury.In order to obtain the agents which have the effects on eliminating free radicals and reducing intraoellular calcium load,we designed,synthesized some TMP derivatives such as double esters,Sehiff bases,lactam,in which active groups and pharmacophores were introduced to the methyl groups of TMP.Anti-atherosclerotic activities and mechanisms of these new compounds were further studied and found some compounds exhibit better pharmacological activities than TMP by the tests of eliminating free radicals and reducing intracellular calcium load.The results provide good information for further investigation and development of the new generation of TMP drugs.