Design,Synthesis And Biological Evaluation Of Marine Phidianidine-inspired Derivatives Against Oxidized LDL-induced Endothelial Injury By Activating Nrf2 Anti-oxidation Pathway

Atherosclerosis(AS)is a chronic disease of arterial wall with slow onset and serious endothelial dysfunction,and it is also an important cause of various cardiovascular diseases.Vascular endothelial injury is the initial link of AS and plays an important role in the development of AS.At the cellular level,endothelial damage is mainly caused by oxidized low density lipoprotein(ox-LDL),ox-LDL can promote the production of reactive oxygen species(ROS)in endothelial cells,cause serious damage to endothelial structure and function,and promote the pathogenesis of v AScular diseases such as AS.Exploring the mechanism of ox-LDL on vascular endothelial injury will have great significance for the prevention and treatment of AS,inhibition of vascular endothelial injury induced by ox-LDL is one of the effective methods to prevent and treat cardiovascular diseases such as AS.Although clinically available drugs can alleviate the progression of cardiovascular diseases to a certain extent,these therapeutic drugs have certain side effects,such as nausea,flatulence,gastrointestinal discomfort,and so on.Therefore,the development of anti-endothelial injury drugs with high efficacy and low side effects has important research value in the treatment of cardiovascular diseases caused by AS.It is found that marine natural products,such as phidianidines,have a variety of biological activities.In this thesis,a series of novel indole-1,2,4-oxadiazole derivatives were designed and synthesized based on marine natural product phidianidine B,and their protective effects against ox-LDL induced damage to human umbilical vein endothelial cells were evaluated.The experimental results showed that compound D-6 exhibited the most effective endothelial protective activity.it was found that D-6 could significantly inhibit ox-LDL induced apoptosis of human umbilical vein endothelial cells and effectively inhibit the expression of adhesion molecules(ICAM-1,VCAM-1)in endothelial cells.The mechanism study shows that D-6 can trigger the nuclear translocation of Nrf2,and then lead to an increase in the expression of Nrf2 target gene HO-1.At the same time,D-6 can also inhibit the increase of ROS level and NF-κB nuclear translocation induced by ox-LDL.More importantly,Nrf2 knockout attenuates D-6 inhibition effect on ox-LDL induced apoptosis,ROS production and NF-κB nuclear translocation.In conclusion,our study shows that compound D-6 can protect vascular endothelial cell injury induced by ox-LDL by activating Nrf2/HO-1 antioxidant pathway.The research in this topic shows that the derivatives based on marine natural product phidianidine B have good anti-ox-LDL-induced vascular endothelial cell damage effects.These compounds can be used as candidate compounds for the treatment of AS and other vascular diseases caused by endothelial injury,which is conducive to our further research and development of new cardiovascular drugs.