Synthesis And Anticancer Mechanism Of Novel Quinazolinone Derivatives

Human epidermal growth factor receptor(EGFR)has received significant attention as an important drug target due to its fundamental role in signal transduction pathways in oncology.Recently,the synthesis of novel EGFR inhibitors has become a hotspot of pharmaceutical research,and the most attractive skeleton of representing EGFR inhibitors is quinazoline.Quinazolinone(quinazoline-4(3H)-one),has broad biological activities,especially in antitumor activity.In this manuscript,we have designed and synthesized a series of compounds containing quinazolinone skeleton as EGFR inhibitors.All of the compounds were characterized by 1H NMR spectra.In addition,the biological activities of these target compounds such as anti-proliferative activity and inhibits tyrosine phosphorylation of EGFR were studied.The results were described briefly below.A series of EGFR inhibitors containing quinazolinone and phenylpiperazine skeletons has been synthesized according to the introduction of phenylpiperazine skeletons.The biological activities of the synthesized compounds(3a-3q)were tested,and the structure-activity relationships were discussed.The results exhibited that all of the compounds had anti-proliferation activity.In the comprehensive analysis of the tested compounds,the compound 3p showed the best anti-tumor cell proliferation activity(IC50＝7.41,uM for MCF-7,IC50=6.04,uM for HepG2,IC50=19.78,uM for SGC,IC50=15.57,uM for A375),comparable to the positive control 5-FU(5-fluorouracil)(IC50=30.52,uM for MCF-7,IC50=34.61,μM for HepG2,IC50=39.27μM for SGC,IC50=28.07 μM forA375).Further studies have shown that the compound promotes the apoptosis of cancer cells by down-regulating the anti-apoptotic protein Bcl-2 and suppresses protein expression levels of phosphorylated EGFR.The results of molecular docking studies showed that compound 3p has interaction with key residues in the active site of EGFR(Phe699,Lys392 and Lys721).And the hydrogen bonding,7r-cation interactions,and π-π interactions between EGFR activity center and compound 3p provide a strong theoretical support for quinazolinone derivatives as EGFR inhibitors.