Design,Synthesis And Antitumor Activity Of Natural Products Piperlongumine And Chalcone Analogues

Piperlongumine is a natural alkaloid,and chalcone is a kind of analogue of piperlongumine.They are often used as drug lead compounds because of their unique pharmacological activities.Previously,our group synthesized piperlongumine derivative PL11and chalcone derivative ZM198,which have excellent activity.In order to further explore the structure-activity relationship,investigate the effect of lactam ring extension or ring shrinkage on the activity of piperlongumine derivatives,and improve the stability of ZM198,this paper optimized the structure of piperlongumine and chalcone,respectively.1.In this paper,C2-C3 and C7-C8,the key active sites of piperlongumine receptor,were reserved,and the lactam ring was modified by ring extension or ring reduction.15 saturated or unsaturated piperlongumine derivatives were synthesized,and the antitumor activity of four tumor cell lines,which are Panc-1?human pancreatic cancer cells?,miacapa-2?human pancreatic cancer cells?,PC3?human prostate cancer cells?,Bel7404?human liver cancer cells?,were tested antitumor activity in vitro.The results showed that the activities of unsaturated lactam derivatives?PL1?PL2?PL3?PL4?PL5?PL6?PL7?PL8?PL9?were superior to piperlongumine in four tumor cell lines?Miacapa2,PC3,Bel7404,Panc1?;the activities of saturated lactam derivatives?PL1?PL2?PL3?PL4?PL5?PL6?PL7?PL8?PL9?showed no significant inhibitory activity to the four tumor cell lines.Among them,the unsaturated heptatomic ring lactam derivatives showed the best activity,2-53 times higher than piperlongumine,the activity of hexatomic ring increased by 2-12 times and that of unsaturated octatomic ring increased by 1-20 times.Chlorine substitution was superior to that of bromine in the C2 position of hexatomic and heptatomic ring derivatives.Bromine substitution was superior to that of chlorine in the C2position of octatomic ring derivatives.The loss of activity of saturated lactam derivatives confirmed that C2-C3 was the key pharmacophor of anti-tumor activity of these structures.In addition,the derivatives of unsaturated piperlongumine are sensitive to miacapa-2?human pancreatic cancer cells?and less sensitive to Bel7404?human liver cancer cells?.2.The of ZM198 was optimized and six deuterium-nitroindole chalcone derivatives were synthesized.The results of anti-tumor activity test in vitro showed that they had excellent activity against HCT116?Human colon cancer cell?,and their IC₅₀ values were all less than 1?M,especially compounds FC141(IC₅₀=12.5 nM)and FC144(IC₅₀=13.4 nM)showed better activity than ZM198(IC₅₀=23.9 nM).