A Study Of Design,Synthesis And Bioactivity Of Novel CDK4 Inhibitors

Breast cancer is one of the most common malignancies in women,and the mammary gland epithelial cells are the culprits.Under a variety of carcinogenic factors,the occurrence of gene mutation results in cell proliferation out of control,and thus leads to tumors.With the deepening understanding of the biological behavior of breast cancer,as well as the transformation and renewal of the concept of treatment,breast cancer treatment has entered the era of comprehensive treatment.In the field of breast cancer treatment,molecular targeted therapy is one of the most active research fields in recent years.Based on known tumor mutations involved in the abnormal protein molecules or gene fragments,molecular targeted therapy is to design and development of the corresponding treatment at the cellular molecular level.Drugs into the body will be specific to combine with carcinogenic sites to play a role in the tumor cell-specific death,and will not affect the normal cells around the tumor.So,molecular targeted therapy is also known as "biological missile".In the biological target associated with breast cancer,cell cycle-dependent kinase 4(CDK4)and epidermal growth factor receptor(EGFR)are both proven and very important biological targets.The research work of this thesis is divided into two parts.The first part is about CDK4 small molecule inhibitor.A novel CDK4 inhibitor of novel skeleton was designed by means of docking technique of computer aided simulation and virtual screening software(Sybal X 1.0)by summarizing the characteristics and rules of the interaction between inhibitor structure and CDK4.Nine CDK4 small molecule inhibitors were selected to synthesize by organic chemistry method.The biological activity test results showed that the nine compounds had no inhibitory activity against CDK4 in vitro activity screening.However,in the comparative selective activity screening,compounds P4 and P5 were found to inhibit EGFR and its mutant T790M/L858R.So,we carried out the second part of the work.The second part is about EGFR small molecule inhibitor.EGFR small molecule inhibitor was designed by means of docking technique of computer aided simulation and virtual screening software(Sybal X 1.0)by summarizing the characteristics and rules of the interaction between inhibitor structure and EGFR.22 EGFR small molecule inhibitors were selected to synthesize by organic chemistry method.The biological activity test results showed that the 22 compounds showed different levels of EGFR inhibitory activity in in vitro activity screening.Among these 22 compounds,the inhibitory activity of the compounds P20,P22,P26,and P28 reaches a great improvement.The work of this paper provides exploratory experience and new research base for finding new CDK4 and EGFR small molecule inhibitors.