Design,Synthesis And Anticancer Activity Studies Of Novel Quinoline And Coumarin Derivatives

In recent years,with the increasing number of new cancer cases,cancer has become one of the major threats to human health.Currently,chemotherapy,radiotherapy and other therapies have been widely used in the clinic with great success in suppressing tumor proliferation and prolonging patient survival.But the cancer therapies were faced many challenges,such as multidrug resistance(MDR)of tumors,which is one of the responsible for the ineffectiveness of chemotherapy.Quinoline and coumarin derivatives have various biological activities and are potential antitumor active skeletons.Therefore,quinoline and coumarin were chose to design and synthesize two series of target compounds.The antitumor activities of these compounds were evaluated in vitro to discover new lead compounds with potential antitumor activities.1.By using nucleophilic substitution reactions,C-C coupling reactions and C-N coupling reactions,a total of 25 quinoline derivatives and 25 coumarin derivatives were synthesized.The structures of those compounds were characterized by 1H nuclear magnetic resonance(1H NMR),13C nuclear magnetic resonance(13C NMR)and high resolution mass spectrometry(HR-MS).2.The antiproliferative activities of target compounds were evaluated against human gastric cancer cells MGC-803,human colon cancer cells HCT-116,human breast cancer cells MCF-7 and esophageal cancer cells KYSE-450 use MTT assay.The results indicated that quinoline derivatives Ⅰ-3e and I-7b(MY-169)showed potent antitumor activities against MGC-803 cells,with IC50 values of 1.38 and 0.58μM,respectively,which were much lower than the positive control drug 5-Fu(IC50=6.82 μM).And the coumarin derivatives II-8b(MY-413)showed excellent antitumor activity against MGC-803 cells,with an IC50 value of 11 nM,which was almost 6-fold of positive control colchicine(IC50=62 nM).3.Compound MY-169 and compound MY-413 were selected to study the anticancer mechanisms in vitro.The results showed that compound MY-169 significantly inhibited the proliferation of gastric cancer cells,and induced an intrinsic apoptosis in MGC-803 and HGC-27 cells.Meanwhile,compound MY-169 arrested MGC-803 and HGC-27 cells at the G2/M phase.Compound MY-413 showed potent inhibitory activity against several human tumor cells,especially for gastric cancer cells.Compound MY-413 exhibited potential antitumor activities by targeting the colchicine binding site of tubulin,which was confirmed by tubulin polymerization assay,EBI assay and molecular docking assay.