Study On Anticancer Effects Of Novel Diamino Ester Compounds And Their Underlying Mechanisms

Malignant neoplasms are a major disease that currently threaten to human health and life quality.There is no way to completely cure.Thus discovery of new compounds having antitumor activity has become the key to this development of anticancer drugs.In this study,CCK8 method was used to screen the compound library of Hu Wenhao's group.It was found that the new DAM series had good antitumor effect.Compared with the existing anti-tumor compounds,we have a completely different structure.We initially studied the mechanism of DAM154058 on the proliferation of colon cancer cells HCT116,and found that the compound can effectively induce apoptosis of tumor cells,the cell cycle arrest in the S phase,and P53 pathway-related protein is not involved in the process of apoptosis regulation.We then screened the anti-tumor activity of LR series compound,which was-optimized after the DAM154058 structure.The results showed that compound LR4 had stronger antitumor activity in vitro and was able to inhibit the proliferation of various tumor cells.The inhibitory effect of SJSA-1 on human osteosarcoma cells was the strongest,and the half inhibitory concentration(IC50)reached 8.12nM.Therefore,we mainly use LR4 and SJSA-1 cells as the research object,the effects of this compound on the apoptosis,cell cycle distribution,mitochondrial membrane potential and ATP production level of SJSA-1 cells were analyzed,the anti-tumor mechanism was discussed with anti-tumor signaling pathway method and western blotting.The results showed that LR4 induced the apoptosis of SJSA-1 cells,no obvious cell cycle arrest was caused,decreased mitochondrial membrane potential,reduced ATP levels of the cell.In addition;LR4 treatment also inhibited the activation of NF-?B pathway and the activation of Akt protein,the expression of p53-related protein.Bcl-2,Bax protein and Caspase-3 and p38 protein were not affected.Probably LR4-induced apoptosis did not depend on the way of Caspase,the anti-tumor effect may be related to NF-?B pathway and Akt-PI3K,its specific mechanism needs further study.This study was found a novel class diamino-based compound having excellent antitumor activity.Further optimization and in-depth pharmacological efficacy analysis of these compounds were conducted,expecting to find a new anti-tumor lead compounds,as well as providing new ideas for anti-tumor drug research and development.