Synthesis,Molecular Modeling,and Biological Evaluation Of Quinazoline Derivatives Containing 1,3,4-oxadiazole Scaffold As Novel Inhibitors Of VEGFR2

The malignant tumor is currently the first murderer which threaten the human’s health and life in the world.Angiogenesis is a pivotal step during the formation of cancer which regulated by angiogenesis factors and angiogenesis inhibitors.Vascular endothelial growth factor receptor(VEGFR)play a significant role in tumor angiogenesis and the biological functions of VEGFR are achieved through the interaction with the VEGF.The VEGFR family is transmembrane tyrosine kinases and consists of three members,VEGFR1,VEGFR2 and VEGFR3.VEGFR2 exists in lymphatic endothelial cells and vascular endothelial cells and plays a main role in the process of tumor metastasis.VEGFR2 is an important signal molecule of some major signal transduction pathways such as MAPK pathways and PI3K pathways.Therefore,VEGFR2 targeted antihumor drugs is becoming a worldwide focus in cancer research.In recent years,a number of compounds have been reported as potent inhibitors of VEGFR2 such as Tivozanib,Vatalanib,Vandetanib,sunitinib.Most of the known inhibitors of VEGFR2 contain quinazoline.Quinazoline compounds are a class of nitrogenous heterocyclic compounds with a range of biological activity,such as anti-malarial,antibacterial,antiviral,antidepressant,anticancer.Quinazoline compounds have good tytosine kinase inhibitory effect primarily because they are competitive inhibitor of ATP.Furthermore,it pointed that as the special structure:good bioisosteres of amides and esters,1,3,4-oxadiazole derivatives can improve the pharmacological activity via hydrogen bonding interactions with the receptors.Therefore,based on our proceeding work on VEGFR2 inhibitors of our laboratory and the activity superposition principle,we have introduced 1,3,4-oxadiazole structure to quinazoline.We designed a series of new 4-alkoxyquinazoline derivatives containing 1,3,4-oxadiazole moiety as VEGFR2 inhibitors.We have synthesized 22 quinazoline derivatives containing 1,3,4-oxadiazole via the computer aid drug design(CADD)method and chemical method.Their structures were confirmed by1H NMR,13C NMR,MS and 18 of them were new compounds.Their inhibitory activities were tested against A549,MCF-7 and Hela via MTT method.Compound 4j showed the most potent inhibitory activity.(IC50=0.23 μM for MCF-7,IC50=0.38μM for A549 and IC50=0.32 μM for Hela)and the effect was better than the positive control drug Tivozanib(IC50=0.38μM for MCF-7,IC50=0.62 μM for A549 and IC50=0.34 μM for Hela).All compounds of the series and Tivozanib were subjected to in vitro VEGFR2,EGFR,bFGF and PDGFR kinase inhibitory assays,the results were consistent with the results of inhibitory activities.Furthermore,docking simulation was performed to position compound 4j into the VEGFR2 active site to determine the probable binding model.Compound 4j showed the lowest interaction energy-50.5831 kcal/mol.These results suggested that compound 4j with potent VEGFR2 inhibitory activity may be a potential anticancer agent.