Synthesis And Bioactive Evaluation Of 4-Aminoquinoline Derivatives

Quinoline,also known as azaphthalene,is a very important ring containing nitrogen.Its derivatives have pharmacological activities such as antimalarial,antimicrobial,anti-HIV,anti-inflammatory,anti-tuberculosis and anti-tumor.It is widely used in the field of drug chemistry.Therefore,the synthesis and pharmacological activity of quinoline derivatives have been paid much attention to by organic and pharmaceutical chemists.The synthesis and bioactivity of 4-amino quinoline-3-formate compounds were studied in this paper.The thesis is divided into five chapters:In chapter one,the progress of quinoline activity,especial those with 4-substituent compounds was reviewed.In chapter two,the synthesis of 4-amino quinoline-3-formate compounds with aromamine as the main raw material was studied.The reaction of aromamine with diethyl ethoxy fork malonate in ethanol to form aromine diethyl methylamate 2 and 3,2 and 3 undergoes an intramolecular cyclic reaction in the reflux of phosphorus oxychloride to produce4-chloroquinoline-3-formate compounds 4 and 5,The nucleophilic substitution reaction of 4 and5 with ammonia compounds resulted in the synthesis of 30 4-amino quinoline-3-formate target compounds 6 and 7.In addition,two compounds of 6 were subsequently converted to synthesize compounds 8?10.A total of 37 target compounds were synthesized and characterized by ¹H NMR,¹³C NMR and HRMS.In chapter three,the anti-tumor activity of target compound 4-amino quinoline-3-formate in vitro was studied.The MTT method was used to test the compounds against MGC-803(human gastric cancer cells),T-24(human bladder cancer cells),Skov-3(human ovarian cancer cells),Hep G-2(human liver cancer cells)and DU-145(human prostate cancer cells).In vitro proliferative inhibition and toxicity of tumor cell lines to HL-7702(normal human liver cells).The results showed that some of the compounds had good anti-proliferation activity against common cancer cell strains.The IC₅₀ values of compound 6ab,6ad to inhibit proliferation of T-24 cell lines in vitro were 5.34±0.22 and 6.48±0.07?M,respectively.It is slightly superior to positive contrast 10-hydroxyhigylline,and has the same activity as doxorubicin,exhibited less cytotoxicity to human normal liver cells HL-7702.The preliminary structure-activity relationship of the targeted compound was also discussed and summarized in this chapter.In chapter four,the anti-tumor mechanism of compound 6ab in vitro was studied.The effects of compound 6ab on cell cycle,apoptosis,ROS,calcium concentration and activation effects of Caspase-8,Caspase-9 and Caspase-3 were detected by flow cytometry.The results showed that 6ab could block cell cycle in S stage,increase ROS level and calcium concentration,activate caspase-8,caspase-9 and caspase-3 and induce tumor cell apoptosis.The interaction between compound 6ab and p BR322 plasmid DNA and DNA-Topo I was studied by agarose gel electrophoresis.The results showed that there was no direct interaction between compound 6ab and superhelix DNA.The expression of 6ab to?H2AX and the phosphorylation level of p53protein S15 sites were also measured.The results showed that compound 6ab could insert DNA by Topo I.In chapter five,the main content of the dissertation were summarized.