Design,Synthesis And Antitumor Activity Of Novel EGFR Inhibitors Derived From Shikimic Acid

As the most valuable therapeutic targets for cancer,epidermal growth factor receptor(EGFRs)plays an indispensable role in cancer cell proliferation,survival,adhesion,migration,and differentiation.Based on a large amount of literature,Combining the anti-tumor activity of shikimic acid.Shikimic acid was used as a starting material,synthetic EGFR inhibitors,to find new compounds with high anticancer activity.The main contents are as follows:on the basis of the summarizing the structure characteristics and structure-activity relationships of small molecule EGFR inhibitors containing the quinazoline nucleus structure reported in the literature,through the study of the pharmacophore characteristics of quinazoline EGFR inhibitors and enzyme combination,adopting the principle of bioisostere,adopting the principle of bioisostere and skeleton transition,the benzofurano[2,3-d]pyrimidine group as a new structural master,Structural modification and optimization with multiple substituents,A Novel Structure of 4-Animinalbenzofurano[2,3-d]pyrimidine EGFR Kinase Inhibitors was designed,to screen out better antitumor compounds.23 target compounds were designed and synthesized,which have not been reported in literatures.A synthetic route of the target compounds was developed.Taking shikimic acid as staring material,the target compounds SZ-1~SZ-23 were synthesized followed by seven steps of esterification,cyclization and oxidation.All the target compounds were confirmed by MS and~1H-NMR.Human lung cancer cell A549 as test cell line,target compounds were evaluated for their cells cytotoxic activities and EGFR kinase inhibition activity using Gefitinib as the positive control by MTT.The cytotoxicity results showed that most of the target compounds show significant antitumor activity against A549 cell lines,among them,SZ-2,SZ-3,SZ-4,SZ-5,SZ-7,SZ-8 and SZ-13 displayed more potent activities than Gefitinb against A549 cell lines,with in-depth research value.According to the anti-tumor activity test results of the compound,the primary structure-activities relationships of the target compounds were discussed:When benzene ring was at the end activity,it was better than thiophene,2-pyridine,adamantane,the introduction of electron-withdrawing groups(especially:fluorine,chlorine)over the end of the benzene ring is better than that of electron-donating groups,4-position substitution is better than ortho and meta;If Linker is partially extended,activity will decrease.