Design, Synthesis And Biological Activity Determination Of Novel Quinazoline Compounds

JAK3is a janus kinase which exists only in the bone marrow and lymphocytes.JAK3medicating JAK3-STAT5signaling pathway regulats transcription of DNAwithin the nucleus, result in abnormal expression of gene, lymphocyte disorders,ultimately causing a series of immunodeficiency disease. Nowdays, approved drugs orclinical research drug of JAK3inhibitors exist a number of side effects because thatthey inhibit both JAK3receptors and other JAK kinase receptor subtypes at the sametime.The characteristics of backbone of quinazoline compounds so easy to modificate,that it been a hot spot and applied widely in medicine and pesticides research, Thispaper explores aimed at the relationship of3LXK and inhibits which has thequinazoline scaffold, and find a new drugs for regulating immune diseases.Virtual screening is an common method used in drug development incomputer-aided drug design. Virtual screening could reduce the number of screeningcompounds to hit the target quickly, while could improve efficiency of drugdiscoverty research. In virtual screening, molecular docking method is well-knownthat be used for a known target protein, there are four steps that are defining activitysite, questioning the site shape, matching the shape of the molecule, evaluationfunction to find qualified compounds. Basing on the good results which has achivedin prior research study that applyied virtual screening in quinazoline compounds. Weexpanded the scope of virtual screening which used3LXK as an target for seekingbetter immunosuppressants.The main idea as follows:1) The design of new immunosuppressive agentsThere were794473small molecules which downloaded from the BindingDatabase, Drugbank, NCI database structures have been used for virtual screening.We based on the results that was used SYBYLX1.3, Discovery Studio2.55in virtual screening, molecular docking and molecular dynamics calculation to guide thetransformation of the lead compound.2) Synthesis of novel quinazolinesWe have used2-amino-acid compounds,2-cyano-4’-methyl-biphenyl andbutylamine as starting material synthesized4-{N-Butyl-N-[(2’-[1H-tetrazol-5-yl]biphenyl-4-yl)methyl] amino}-2-R1-6-R2-7-R3‐quinazoline（R1=Me，R2=R3=H；R1=R3=H，R2=OCH3、OH；R1=H，R2=R3=OH，OCH3）.And we confirmed thepurity and structure by LC-MS and1H NMR and13C NMR.3) Measured the biological activity of novel quinazoline compoundsDetecting influence of the different concentrations of DMSO on Jurkat cellsappreciated CCK8method;Measured the growth curve of Jurkat cells in a96well cultrue cluster;Exploring vitro biological activity of different concentrations of the designeddrug to Jurkat cells appreciated CCK8method.Research results:1) Determine4-{N-Butyl-N-[(2’-[1H-tetrazol-5-yl] biphenyl-4-yl)methyl] amino}-6-hydroxy-quinazoline as a lead compound by virtual screening.2) molecular docking studies applied to design a series of quinazolines,4-{N-Butyl-N-[(2’-[1H-tetrazol-5-yl] biphenyl-4-yl)methyl] amino}-2-R1-6-R2-7-R3quinazoline（R1=Me，R2=R3=H； R1=R3=H，R2=OCH3、OH；R1=H，R2=R3=OH，OCH3）.3) we confirmed the content and structure by LC-MS and1H NMR and13C NMR.;4) and the concentration of DMSO is not affected by0.25%(V/V) of the Jurkat cellproliferation;5) Measured the growth curve of Jurkat cells in a96well cultrue cluster;6) All designed quinazoline-tetrazole compounds can inhibit proliferation in Jurkatcell. The result indicated a certain amount-effect relationship and the number ofapoptotic cells gradually increased has a positive correlation with quinazolines’concentration. And4-{N-Butyl-N-[(2’-[1H-tetrazol-5-yl] biphenyl-4-yl)methyl]amino}--6,7-dihydroxy-quinazoline showed a best effect.Conclusion: computer-aided drug design in immunosuppression can guide the designof new immunosuppressants.The novel quinazolines designed in this study caneffectively inhibit proliferate of Jurkat cell. The may lay a foundation for a profoundresearchment of JAK3inhibitors.