Synthesis And Anti-tumor Activities Of 3-(Benzo[d]thiazol-2-yl)-quinolin-4(1H)-one Derivatives

Quinolinone derivatives have been extensive reported to exhibit a broad-spectrum of biological activities,such as antioxidant,antimycobacterial,antiinflammatory,antivirus and antiproliferative.Synthesis and biological activity of the quinolinone derivatives have drawn more attention.30 3-benzothiazolyl-4(1H)-quinolinone compounds were synthesized,molecular docking study found that can be used as DNA-Topo I inhibitors.The results of antitumor activity showed that the compounds 6 had good antiproliferation activity against HepG2,Bel-7402 and Bel-7404 cell lines,and 6h showed the remarkable inhibitory activities against HepG2 with IC50 being 5.72±0.24 ?M.This thesis is divided into four chapters as follows:In chapter one,the research progress of topoisomerase I and its inhibitors are reviewed,also introduces the design ideas of the subj ect briefly.In chapter two,a series of 3-(benzo[d]thiazol-2-yl)-quinolin-4(1H)-one derivatives were synthesized and characterized.Aniline reacted with diethyl 2-(ethoxymethylene)malonate to afford compound 2,compound 3 was obtained by intramolecular Friedel-Crafts reaction of 2,then 3 condensed with 2-aminobenzene-thiol to afford intermediate 4,which was treated with 2-chloro-N,N-dimethylethan-1-amine or 3-chloro-N,N-dimethylpropan-1-amine to furnish target compounds 5 and 6,respectively.Compound 4 reacted with 1,3-dibromopropane,and then reacted with piperidine or morpholine to obtain target compounds 7.30 compounds were synthesized,and characterized by 1H NMR,13C NMR and HRMS.The structure of compound 5a was further confirmed by X-ray diffraction.In chapter three,molecular docking calculations were performed to show compounds with Topo I combined with-52.39?-44.00 kcal/mol,form a stable complex compound.6h,6k and 6o could interact with the DNA-Topo I complex.In chapter four,their cytotoxicities of compounds 5,6 and 7 were evaluated by the MTT assay against four cell lines(HepG2,Bel-7402,Bel-7404 and HL-7702),compounds 6 showed potent antiproliferative activitties against four cell lines.Among them,6b,6h and 6o arrested the cell cycle at S,G2/M and G2/M phase,respectively.Triggered collapse of mitochondrial transmembrane potential,elevated intracellular superoxide ROS levels,induced HepG2 cells in apoptosis.Western blotting was performed to examine the levels of autophagy proteins that upregulation of LAMP1,AKT,Beclin?,p62,LC3B ? and LC3B ?.the most increase was in the levels of pro-apoptotic protein Bax,Bak and Bim,while the most striking decrease was in anti-apoptotic protein Bcl-2 and Bcl-xL.It was proved that 6h could induce apoptosis of HepG2 cells by autophagy.The results of agarose gel electrophoresis showed that the compound 6h could inhibit the catalytic activity of Topo ?.Hence,6h exhibited inhibitory activity via induction to Topoisomerase ? and autophagy-dependent apoptosis in HepG2 cells.The compound 6h may be an useful therapeutic agents to against liver cancer.