Design,Synthesis And Antitumor Activity Of Quinoxalinone Derivatives

Objective:To synthesize a series of new quinoxalinone derivatives,to study the anti-tumor activity and cytotoxicity of the synthesized compounds,and to explore the possible binding of the compound to the target protein.Method:The reaction used ethyl bromoacetate and o-phenylenediamine as starting materials to synthesize quinoxalinone nucleus by condensation,a series of quinoxalinone derivatives were obtained by N1,N4 substitution and C3 acylation reaction.The purity of these compounds are detected by ultra-high performance liq uid chromatography（UPLC）and their structures are determined by hydrogen nuclear magnetic resonance spectroscopy and carbon spectroscopy.The anti-proliferative activity of quinoxalinone compounds on tumor cells and the toxicity on normal cells were determined by MTT method.The binding status of quinoxalinone derivatives with CDK,P-gp,MMP-2,VEGFR2 proteins were determined by molecular Docking simulation analysis.Results:In this study,14 quinoxalinone compounds were synthesized.The results of the MTT method showed that compared with the quinoxalinone core,most of the derivatives have better anti-tumor cell proliferation activity.Among them,compound 6c has stronger anti-proliferation activity against MCF-7 cancer cell lines.(IC₅₀=27.50μM),compound 3c showed strong proliferation inhibitory activity against MCF-7 and HCT-116 cancer cell lines(IC₅₀=36.32μM,IC₅₀=34.98μM),compound 3f showed good resistance to A549 cell lines Proliferation activity(IC₅₀=44.47μM).The cytotoxicity of the three compounds to HVECs of endothelial cells is much less than that of 5-FU.The most effective compounds 3c,3f and 6c were docked with four molecules of CDK,P-gp,MMP-2 and VEGFR2.Among them,compounds 3c and 6c had the high scores for P-gp,which was 4.3633 and 4.3629 respectively.Compound 3f has the highest score for MMP-2,which was 5.2936.3c,3f also have the high scores for VEGFR2（4.8952 and 4.8931 respectively）.Conclusion:（1）A total of 14 quinoxalinone compounds were synthesized in this paper.（2）Most of the 14 quinoxalinone compounds synthesized have good anti-tumor cell proliferation activity,among which compound 3c has the best anti-proliferation activity against HCT116,3f against A549 and 6c against MCF-7 cell line.（3）Based on the docking results of compounds 3c,3f and 6c with CDK,P-gp,MMP-2 and VEGFR2 molecules,it is predicted that compounds 3c,6c and P-gp,3f and MMP-2,3b、3f and VEGFR2 have strong binding ability.