Design,Synthesis And Antitumor Activity Of 7-methoxy Coumarono[3,2-b]quinolin Derivatives

Natural products are important source of new drugs.To date,using the structure of naturally active compounds as framework,modifying the structure,screening drugs,then studying the quantitative structure-activity relationship has been the most important way in new drug discovery.Coumaronochromone,as the framework of compounds with various activities,its derivatives have a wide range of biological activities,especially antitumor activity.According to the principle bioisostere,NH substitution for the O oxygen on the Furan or Pyrane ring of the natural coumarone ketonone,not only increases the modification site of the compound,obtaining structurally diverse compounds;It is also possible to improve its anti-tumor effect strength and selectivity,produce new routes of action or give compounds new pharmacological activities.synthesis,activity screening,structure-activity relationship and mechanism of action of antitumor active compounds based on the maternal skeleton to find efficient,good selectivity,low toxicity of lead compounds of new anticancer drugs.In this paper,inexpensive,readily available 4-methoxy-phenoxyacetic acid and anthranilic acid as the starting material,synthesis of a series of 7-methoxy coumarone[3,2-b]quinolin derivatives and evaluation of their antitumor activity and their antitumor mechanism.The main work in the dissertation could be summarized as follow:1.The natural and synthesized coumaronochromone derivitaves and pharmacological activities of quinolones were reviewed.The design idea,synthesis method and research content of this subject are briefly introduced.2.Synthesis of compound 2 with 4-methoxy phenoxy acetic acid and o-aminophenyl benzoic acid as raw materials,synthesis of 7-methoxy coumarone[3,2-b]quinolinone matrix by microwave ring closure.The compound 3-1a～3-6b was obtained by reflux reaction with different substituents in acetone solvent under alkaline conditions.The structures of all target compounds were characterized by¹H NMR,¹³C NMR and HRMS.3.The anti-tumor activities in vitro of target compounds against MGC-803,T-24,SKOV3,NCI-H460,Hep G-2 and MCF-7 cells were screened by MTT assay.The results indicated that most of the compounds exhibited excellent inhibitory activity against the selected cell lines.Compound 3-2b and 3-5a demonstrated potent inhibitory activity with IC₅₀values of 7.56±1.99、8.25±3.84μmol/L against Hep G-2cells,respectively.It’s show that side chain and linker length of these compounds play a significant role on the anticancer activities by structure-activity relationship analysis.Take 3-2b as the object of investigation,the mechanism of anti-tumor activity of the compound was studied.4.Cell and molecular biological experiments were carried out to further investigate the anticancer effects of the most potent compound 3-2b and 3-5a on human liver cancer cells（Hep G-2）and the mechanism was also discussed.In summary,eighteen new coumarono[3,2-b]quinolin derivatives were prepared from basic organic compounds.Their structures were all characterized by¹H NMR,¹³C NMR and HRMS.Besides,we evaluated their inhibitory activities in vitro toward the cancer cell lines and further clarified the antitumor preliminary mechanism in human liver cancer cells（Hep G-2）about 3-2b and 3-5a,which may provide some theoretical guidance and experimental data basis for further exploitation and application of coumaronochromone derivatives.