| A According to statistics,in terms of morbidity and mortality,lung cancer is among the highest in incidence.At present,the new hope of clinical medication is molecular targeted drugs.Tyrosine kinase is the target receptor site,and it has also become a key research issue at home and abroad.This project constructed a new type of targeted small molecule inhibitors with 2,4-dichloroquinazoline as the core,cyclic polyamine side chains conjugated,and aryl side chains connected via Miyaura reaction at the 2 position.Through the structural modification of macrocyclic polyamines and aryl positions,and the complexation of metal ligands,10 chemically synthesized target compounds were obtained.By introducing the ATP capture group-cyclic polyamine into the inhibitor structure,while competitively binding to ATP sites,it reduces the level of ATP in the tumor microenvironment and synergistically inhibits kinase activity to achieve effective regulation of tumor cell proliferation and apoptosis.At the same time,using the proton buffer capacity of cyclic polyamines to adjust the dissociation balance of inhibitor molecules,it is hoped to obtain a targeting effect on the low pH tumor microenvironment.Through the construction and activity evaluation of new.inhibitors,explore the consumption of polyamine molecules and ATP The inner link with tumor suppression.The synthesized series of final products pass the LANCE in vitro detection method,the compound inhibits the kinase activity,and establishes the compound test of different concentration gradients.Therefore,the IC50 is calculated,which provides a basis for evaluating the compound’s targeted inhibitory activity in vitro.Drug design with tyrosine kinase inhibitors as the target provides a new design idea and solution to the problem of acquired drug resistance,and also provides for the development of more effective,economical and safe tumor-targeted drugs with independent intellectual property rights Candidate compounds. |
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