Design, Synthesis And Anticancer Activity Of Natural Product Piperlongum Amide Derivative

Piperlongumine is a natural product from piper Longum L,has a variety of biological activities,including anti-inflammation,anti-insect,hypoglycemic,anti-liver fibrosis,neuroprotection,anti-tumor,etc.Among them,anti-tumor is a hot research direction,so benzene research adopts the principle of integrating key pharmacophore,retains the key Michael receptor unit structure of piperamide,and combines with urea,a dominant fragment in drug molecular design,to design and synthesize 34 novel piperamide derivatives containing biarylurea structure.The structures of all the target compounds were characterized and confirmed by ¹H NMR,¹³C NMR and HRMS.The antiproliferative activities of all compounds against human non-small cell lung cancer cell line A549,human prostate cancer cell line PC-3 and human chronic myeloid leukemia cell line K562 were evaluated by MTT method,and the toxicity of some target compounds to normal human embryonic kidney cell line HEK293 was also evaluated.The results showed that the antiproliferative activity of most of the compounds against the three tumor cells was better than that of piperlongumine,a positive control drug.For PC-3 cells,the IC₅₀ value of compound C11 reached 0.37μM,about 16 folds that of the positive control drug piperlongumine,for K562 cells,compound C5 reached 0.11μM,about 29 folds that of the positive control drug piperlongumine,and for A549 cells,compound C10 reached 0.74μM,about 10 folds that of the positive control drug piperlongumine.Moreover,C5 exhibited better selectivity than pieprlongumine.Structure-activity relationship analysis based on the bioactivity data showed that the introduction of an electrophilic group at the C2 site increased the overall activity of the compounds,while saturation of the C2-C3 double bond resulted in a significant decrease in activity.In addition,this serise of compounds generally has better antitumor effects on K562 cells,so C5,which has the best IC₅₀ value for K562 cells,was selected for a preliminary investigation of its anti-K562 cell line mechanism of action.The results showed that C5 was able to induce apoptosis in K562 cells and induced tumor cell apoptosis by inhibiting PI3K/Akt/m TOR signaling pathway,as well as another downstream signal of Akt,MDM2/p53,while C5 also inhibited brc-abl fusion protein,a classical target of chronic myeloid leukemia,which led to cell death.