The Design, Synthesis And Anti-tumor Activity Of Triazoloquinazolinones Substituted With 4-position Aryl

SHP2 is a protein tyrosine phosphatase.It can be used as a key regulator in cell signal transduction and can participate in cell growth and differentiation.At present,some studies have reported that SHP2 can be used as a new antitumor drug research target and it is an ideal target for cancer intervention.SHP2 is closely related to the incidence of Noonan syndrome,lung cancer and breast cancer.In recent years,although scientists have continuously discovered some new SHP2 inhibitors.In recent years,although scientists have continuously discovered some new SHP2 inhibitors.According to the different sites of action,they are generally divided into two categories:catalytic site inhibitors and allosteric site inhibitors.Previously,most of the scientists’research focused on catalytic site inhibitors,but these compounds usually have low efficacy and poor selectivity,which greatly increases the complexity of drug discovery and slows down the development of the field of phosphatase.Most of the catalytic site inhibitors have the advantages of better biological activity and higher specificity.Therefore,scientists have shifted the focus of research to allosteric inhibitors and there have been small molecule allosteric inhibitors that have successfully overcome the problems of druggability and entered phase clinical research.Unfortunately,there has been no one can enter the clinical researches and be marketed so far.Therefore,it is of great significance to research and develop novel SHP2 inhibitors.In this project,SHP244 is used as lead compound to design and synthesize 23novel 4-position aryl substituted triazoloquinazolinone derivatives that have not been reported in the literature.The computer virtual molecular docking study was carried out between the 23 compounds designed and the SHP2 target protein.The results of the study show that 23 compounds can be well docked with the SHP2 target protein.It is speculated that the target compound may be a potential SHP2 inhibitor,which provides certain theoretical guidance for further research on SHP2 inhibitors.In addition,this subject uses isatoic anhydride as the starting material to synthesize target compounds.All compounds were characterized by ¹H NMR and MS.Enzyme activity test was performed on the target compound and the test results showed that 23target compounds synthesized at a concentration of 50μM had poorer activity against SHP2 protease,but compounds 6 showed better activity than SHP244 at a concentration of 10μM.In addition,human liver cancer cells（SMMC7721）were used to perform MTT experiments on the target compound.The experiment found that that most B series compounds have better activity than A series compounds and compound B6 has significant biological activity,with an IC₅₀0 value of 395μmol/L,which is better than other target compounds.