Design And Synthesis Of Piperlongumine Derivatives And Their Radiosensitization In Pancreatic Cancer

Piperlongumine,a natural alkaloid that extracted from plant Piper longum L.has a widely variety of pharmacological activities.Piperlongumine has been widely studied as its selective anticancer activity.Our previous work identified the main active site of piperlongumine of C2=C3 and C7=C8 bond as Michael receptors.The C2=C3 bond was the key position for piperlongumine to exert its biological activity.In addition,the C7=C8 bond played an important role in maintaining the high antitumor activity of piperlongumine.The introduction of halogen atom in C2=C3 bond greatly enhanced the biological activity of the piperlongumine.However,the methoxyl group on the benzene ring is not the key structure for the biological activity,which indicated that there were more spaces for structural modification.In order to improve the physicochemical property and biological activity of the piperlongumine,we designed and synthesized 38 compounds.And 15 highly active piperlongumine derivatives were obtained.The structure-activity relationship of piperlongumine on benzene ring was concluded.Among these compounds,8c and 8d showed the best radiosensitizating activity.8c and 8d combined with radiotherapy can significantly increase ROS level,upregulate the expression of Nrf2 and p53,cause DNA damage,and arrest cells at G2/M phase.Then,cell apoptosis is observed and tumor proliferation is remarkly inhibited.