Design And Synthesis Of1,4-bis(2,3-dihydropyrrol-5-one-4-yl)-1,3-butadienes As A New ErbB3Tyrosine Kinase Inhibitor

ErbB3tyrosine kinase is related to the formation of tumor blood vessels, tumorstage, metastasis, prognosis and chemotherapy tyrosine kinase. As a new therapeutictarget of cancer, it has attracted more and more attention. Based on the studies ofstructure-activity relationships of the ErbB3tyrosine kinase inhibitors, a series of1,4-bis(2,3-dihydropyrrol-5-one-4-yl)-1,3-butadienes have been designed as ErbB3tyrosine kinase inhibitors. The studies on the synthesis and inhibitory activities willprovide theoretical and experimental basis for the development of new ErbB3tyrosinekinase inhibitors.Bases on the study of binding mode of ErbB3tyrosine kinase and its inhibitors,the binding models were found. Using a structure-based drug design approach,1,4-bis(2,3-dihydropyrrol-5-one-4-yl)-1,3-butadienes have been designed as potentialErbB3tyrosine kinase inhibitors. These inhibitory activities of46targe compoundswere virtual screened by docking algorithm of Computer-Aided Drug Design on theplatform of AutoDock4.0. The relationships between binding mode and inhibitoryactivity of these compounds had been studied to confirm the structures of the targetcompounds.Based on the review of the synthesis of1,4-hydropyrroles, the synthetic route for1,4-bis(2,3-dihydropyrrol-5-one-4-yl)-1,3-butadienes was designed. The designedmoleculars were synthesized by the condensation of glyoxal and dimethyl2-aminomaleate catalyzed by toluenesulfonic acid, the intermediate dimethyl2-aminomaleate was prepared by the reaction of primary amine and dimethyl butyne.The reaction conditions were optimized on the influence factors of solvents, times andothers. The structures of synthesized compounds were identified by1H NMR,13CNMR, HRMS and X-ray diffraction patterns.By using a method of3-dimensional celltoxicity test method with EC9706esophageal cell, the inhibitory activities of1,4-bis(2,3-dihydropyrrol-5-one-4-yl)--1,3-butadienes were tested. The results show that the1,4-bis(2,3-dihydropyrrol-5-one-4-yl)-1,3-butadienes bearing aryl groups have obvious anti-EC9706cell activities.