Design And Construction Of Small Mecule Egfr-tki

Epidermal growth factor receptor(EGFR)family plays a key role in the growth,development,proliferation and metastasis of tumors and is an important target of tumor therapy.Small Mecule tyrosine kinase inhibitors(TKI)acting on EGFR have been widely used in the treatment of advanced non-small cell lung cancer.In this paper,a novel substituted aniline quinazoline small Mecule was designed and synthesized by referring to exatinib and Lapatinib and introducing macrocyclic polyamines into quinazoline ring system.In this paper,the structure of quinazoline was retained,and the 4-position design of quinazoline was used to connect the 3-chloro-4-(trifluorobenzoxy)aniline side chain of lapatinib.The 3-chloro-4-(trifluorobenzyl)aniline side chain of Lapatinib has two benzene ring structures and a large spatial structure,which can well compete with ATP to occupy the hydrophobic cavity inside EGFR and play a role in inhibiting the phosphorylation of kinase.the ring ether of the quinazoline ring system in Ecotinib was replaced by a macrocyclic polyamine structure containing an amide bond.Macrocyclic polyamine can improve the water solubility of quinazoline and hydrolyze ATP.Together with quinazoline,it can occupy the binding site of ATP to EGFR.Thus,it can inhibit the phosphorylation of kinase and block the downstream signal transmission,and enhance the efficacy of quinazoline structural drugs.In this paper,the binding sites between small molecules and kinases were simulated by computer,and the binding modes of the compounds were analyzed.Using 7-chloro-6-nitroquinazoline-4-ketone as the starting material,two synthetic routes were tried,and the quinazoline-ring system was substituted with 4-aniline and 6-7 substitution rings by different strategies.The reaction route was optimized from various parameters,mainly the side chain of quinazoline grafted with aniline was optimized,and the reaction was simplified into one step from the previous four steps of grafting protection,chlorination,c-n bond formation and deprotection.Finally,a small molecule inhibitor containing macrocyclic polyamines was designed.On the one hand,this paper expands the biological activity of macrocyclic polyamines and provides a new idea for the development and synthesis of tyrosine kinase inhibitors.On the other hand,it provides potential small Mecules for the development of new tyrosine kinase inhibitors with low toxicity and high target.