Synthesis And Characterization Of Bradykinin Receptor Antagonists And Preliminary Study On Their Anticancer Effects

At present,cancer is an important problem that threatens human health.Chemotherapy is one of the main methods of clinical cancer treatment.Cisplatin,doxorubicin and paclitaxel are the three most commonly used chemotherapy drugs.However,all three drugs have different limitations,such as cisplatin can cause very serious kidney damage,doxorubicin has cardiotoxicity and bone marrow limitation,and paclitaxel is also prohibitive because of its high price.Therefore,the search for new anticancer drugs has become a hot research topic.BKM-570 is a bradykinin receptor antagonist with good anticancer effect in small cell line lung cancer(SCLC),non-small cell line lung cancer(non-SCLC),lung,prostate,colon and cervix Certain activities,especially for lung cancer and prostate cancer,are superior to cisplatin,which can effectively inhibit the migration and proliferation of breast cancer and prostate cancer.In this study,we modified and modified BKM-570 as a template,and while using its computer software for activity simulation,designed and screened three active bradykinin receptor antagonists.Named J051-71,J051-87 and J051-105.First,three compounds were synthesized by organic chemistry,and their synthetic routes were optimized.Three compounds were screened for the activity of anti-cancer cell lines.Through the MTT toxicity test on seven different cancer cells,it was found that all three compounds have good anticancer activity,especially for A549,IC50 is about 1 ?M.By comparing the expression levels of two bradykinin receptors B1 R and B2 R in seven cancer cells,it was found that both receptors have higher expression levels in A549 cells.Therefore,in the follow-up study,we selected A549 cells for related activities and mechanisms.Three kinds of bradykinin receptor antagonists can effectively inhibit the migration of cancer cell A549,but only J051-71 and J051-105 showed apoptosisinducing effects in a concentration-dependent manner,but J051-87 was not obvious.The role of inducing apoptosis.Western Blot experiments confirmed the same results,that is,as the concentration of J051-71 and J051-105 increased,the protein expression levels of CL-PARP and CL-Caspase 3 increased.By using DALBK and HOE-140,inhibitors of the bradykinin receptors B1 R and B2 R,it was found that the induction of apoptosis by J051-71 was inhibited only after the use of DALBK,but had no effect on J051-105.The use of HOE-140 had no significant effect on the induction of the two compounds.We speculate that J051-71 may act through B1 R to induce apoptosis and kill cancer cells.The mechanism of action of J051-105 and J051-87 remains to be further studied.