Study On The Design,Synthesis And Bioactive Evaluation Of A-Ring Modified Benzo[c]phenanthridine Derivatives

As an important class of isoquinoline alkaloids,the benzo[c]phenanthridines were found widely in poppy and rutaceae plants and most of them exibited a wide rang of pharmacological activities,such as anti-tumor,antiviral,anti-inflammatory,bactericidal and so on.The theme of this dissertation was focused on the design,synthesis and bioactive evaluation of A-ring modified benzo[c]phenanthridine derivatives.The dissertation includes three parts,namely the review,the design and synthesis of the target compounds,and the bioactive evaluation of them.In the review part,the advance in the synthesis,structural modification and bioactivities of benzo[c]phenanthridine derivatives were summarized.In the synthesis part,the preparation and characterization of the A-ring modified benzo[c]phenanthridine derivatives starting from 1-aminonaphthalene were studied.In the bioactive evaluation part,the anticancer propoties and interaction of the target compounds with DNA/topoisomerase I were investigation.In the synthesis part,two key intermediates,4-Chloro-benzo[h]quinoline-3-carbonitrile 5 and 4-Chloro-benzo[h]quinoline-3-carboxylic acid ethyl ester 6 were firstly synthesized starting from 1-aminonaphthalene in three steps.5 or 6,when reacted with guanidine or amidine,could afford five target compounds which A-ring was replaced by a pyrimidine.If 5 or 6 were successively reacted with primary amines,anhydride and finally undergo a ring-closing reaction,another series of target compounds which A-ring was replaced by a pyridine were furnished.The structures of all the target compounds were characterized and confirmed by NMR,HRMS or X-ray diffraction.The anti-tumor activities in vitro of the targeted compounds against MGC-803(human gastric cancer),HepG-2(human liver cancer),NCI-H460(human non-small cell lung cancer),SKOV3(human ovarian cancer)and T-24(human bladder cancer)cells were evaluated by MTT assay.The results indicated that some target compounds possessed excellent inhibitory activitives against the proliferation of the five kinds of cancer cells in vitro.Compound 11cA displayed the best anti-proliferative effect against NCI-H460 cells with IC50 value of 2.01±0.22 ?mol/L,which was better than the 10-hydroxycamptothecin(38.55±1.35 ?mol/L).Cell cycle analysis revealed that compound 11cA could arrest cells in G2 phase and induce apoptosis.The Western Blot assay demonstrated that 11cA could up-regulate the pro-apoptotic proteins while down-regulate the anti-apoptotic proteins.The agarose gel electrophoresis essay showed that 11cA could strongly inhibit the Topo ? to relaxe the double-helix structure of DNA.