Total Synthesis And Antitumor Structure-activity Relationship Study Of Marine Natural Product Calciamide

Cancer is an important killer threatening human health in modern society.The application of reasonable and effective drugs provides an effective means for the treatment of malignant tumors and is expected to be an important way to solve the difficult problems of cancer treatment in the future.In recent years,with the continuous upgrading of new tumor theories and the emergence of clinical drug problems such as tumor drug resistance,the research and development of innovative anticancer drugs has always been the focus and focus of cancer research.Among them,natural products have become the top priority in the research and development of anticancer drugs due to their clear anti-cancer effectiveness and the abundance of candidate resources.Calcicamide A,a Marine natural product isolated from the Irish sponge S.Calcicola,contains novel chiral bisindole structure and is a potential antitumor lead compound.In this study,the chiral Fouck-alkylation reaction developed by our research group was used as the key step to realize the total synthesis of Marine natural product Calcicamide A through a 9-step reaction.The total synthesis of this natural product has not been reported so far.Through rational design and synthesis,the analogues of Calcicamide A were constructed.The best compound CA-25 was determined by screening the antitumor activity in vitro.Biological evaluation showed that CA-25 can inhibit the proliferation and migration of breast cancer cells,cause the cycle arrest of breast cancer cells,and promote the apoptosis of breast cancer cells.Microsphere experiments showed that CA-25 could inhibit the dryness of breast cancer cells,suggesting that CA-25 has the potential of anti-breast cancer resistance application.Further studies have shown that CA-25 inhibits the activation of the IL-6/STAT3 pathway by inhibiting the expression of IL-6 receptor(gp130)and inhibiting STAT3 phosphorylation and nuclear translocation in breast cancer cells.The in vivo model of4T1 mouse transplantation tumor showed that CA-25 significantly inhibited the growth of 4T1 breast cancer in mice,and the tumor inhibition effect of CA-25 in combination with cisplatin was better than that of the cisplatin alone group,showing the greater antibreast cancer resistance potential of CA-25.In conclusion,we have successfully achieved the asymmetric total synthesis of the Marine natural product Calcicamide A,which has not been reported so far.A series of Calcicamide A derivatives were designed and synthesized,and their structure-activity relationship and action mechanism were studied through biological activity test.CA-25,a derivative of Calcicamide A,can combat breast cancer resistance by inhibiting activation of the IL-6/STAT3 pathway and targeting tumor stem cells.