Design,Synthesis And Activity Of Novel Tyrosine Kinase Inhibitors Containing Quinazolinamide Structures

Traditional treatment of cancer has many drawbacks,so designing safe and efficient targeted drugs will give cancer patients new hope.The drug imatinib as the earliest small molecule targeted drug for the treatment of chronic myelogenous leukemia（CML）in China,has opened a new chapter in the treatment of such diseases.The first generation of drugs imatinib has a good effect on most CML patients and the second and third generation drugs have a better therapeutic effect than imatinib,but the side effects are larger.Therefore,it is necessary to design drugs that are safer and more efficient to treat CML.Taking the drug imatinib as the lead compound,the molecular structure of the compound is modified,and it is expected to obtain a new anti-tumor targeted drug with high activity and few adverse reactions.Through reading and analysis of the eutectic structure of the Bcr-Abl kinase protein,a series of target compounds with quinazolinamide structures as the parent nucleus were designed,and structural units such as imidazoli[1,2-b] pyridazine,1H-pyrazolith [3,4-b] pyridine and phenethylamine were introduced into the structure by computer-aided drug design.Secondly,different secondary amine substituents are introduced for structural modification and optimization,and finally 30 target compounds are prepared.All target compounds were confirmed by 1H NMR and MS.The in vitro activity test adopted MTT method to screen the anti-tumor activity of the target compounds of the HCW series by the MTT method,using human chronic myeloid leukemia cells K562,gastrointestinal stromal tumor cells GIST-882,gastrointestinal stromal tumor resistance cells GIST-1210 as the screening cell lines,and Imaginib and Ponatinib as positive control drugs.The results showed that the target compound had good inhibitory activity on K562 cells,of which 14 compounds were better active than the control drug imatinib,and the inhibitory activity of compound HCW-8 on K562 cells was the strongest comparable to Thatatinib.The inhibitory effect of HCW-14 on GIST-1210 cells was better than that of the control drug imatinib,and the inhibitory effect of HCW-10 on GIST-882 cells was better than that of the control drugs imatinib and propatinib.The preferred compound HCW-8 studies its mechanism of action,with imatinib as the control drug and K562 cells as the test cell line.Apoptosis was observed by AO-EB staining,and the results showed that HCW-8 was concentration-dependent induction of apoptosis.Cell morphology observation experiments have shown that under the action of drugs,cells appear irregular（shrinkage,rupture）,HCW-8 can inhibit the viability of K562 cells depending on concentration,and the inhibition effect is better than that of imatinib administration group at the same drug concentration.The docking of HCW-8 with the target protein（3ik3）molecule showed that the compound HCW-8 could interact with the amino acid residues of the target protein through multiple hydrogen bonds.In summary,the compounds of the HCW series have the value of in-depth research laying the foundation for the research of new tyrosine kinase inhibitors.