Synthesis And Biological Evaluation Of Novel Leonurine Derivatives As Cardioprotective Agents

Leonurine (LEO,3,5-dimethoxy-4-hydroxy-benzoic acid4-guanidino-butyl ester)is a natural alkaloid isolated from Leonurus artemisia which has long been used inchinese traditional medicine. The reports show that it has cardioprotective effect dueto its anti-oxidation and anti-apoptosis properties both in vivo and in vitro, which hasbeen considered as a good drug candidate for treatment of ischemic heart disease andmyocardial infarction. But high-dosage using implicates its low potency, which mayhinder clinical trials in future. To improve the pharmacological effects of LEO andgain more potent drug candidates, we designed and synthesized a series of LEOderivatives in this study, and all the structures were confirmed by HRMS, MS,H1-NMR and C13-NMR.The cardioprotective effects were evaluated in cultured rat cardiac H9c2cells bypretreatment with all compounds for8h before oxidative stress injury by H2O2.Biological activity study of the compounds synthesized indicated that compound8apossessed the most effective protection against hypoxia-induced H9c2cells damage atlower molar concentration (10-fold less than Leonurine).Clinical observations suggested that the accumulation of intracellular reactiveoxygen species (ROS) and imbalance between anti-apoptotic protein Bcl-2andpro-apoptotic protein Bax played major roles in regulating apoptosis. Inhibition ofcardiomyocyte apoptosis was the key of MI disease treatment and myocardial tissueprotection.Compound3a increased the activity of the anti-oxidant enzymes SOD and CAT,as well as reduced the LDH leakage rate and the generation of lipid peroxidativeproduct MDA of biological membrane. In addition, compound3a prevented cellular apoptosis by up-regulating the expression of Bcl-2and down-regulating theexpression of Bax, and decreased the release of inflammatory cytokines.Further mechanism studies showed that compound3a possessed higherbiological activity than the parent drugs, and played a protective role throughanti-oxidant, anti-apoptosis and anti-inflammatory.