Design,Synthesis And Biological Evaluation Of Novel Privileged Structure-Based Topo ? Inhibitor

Cancer is a fatal disease seriously threating to human health.The search for high efficiency,low toxicity anti-tumor drugs has become a very important field in medical chemistry.In this dissertation,a series of novel privileged structure-based anti-tumor compounds targeting to Topo I were designed,synthesised in the guidance of a pharmacophore model constructed in our group and their bioactivities were investigated.This dissertation includes the review and the experiment parts.In the review part,the research progress on camptothecins,indenoisoquinolines,indolocarbazoles as Topo I inhibitors,and the synthesis,bioactive evaluation of the compound with the privileged structure motif—quinoline or benzothiazole(benzoxazole)were summarized.In the experiment part,the design,synthesis of the privileged structure-based targeted compounds,as well as their structural characterization and bioactive evaluation were studied.In the synthesis and structural characteration section,17 targeted compounds were synthesized in 5 steps starting from aryl amines and 2-ethoxymethylene-malonic acid diethyl ester.Their structure were characterized and confirmed by NMR and HRMS.In the biological evaluation section,the anti-tumor activities in vitro of target compounds against HepG-2(liver cancer cell),T-24(bladder cancer cell),MGC-803(gastric cancer cell),NCI-H460(lung cancer cell)and HL-7702(liver cell)were screened using MTT assay.The results indicated that most of the compounds possessed excellent inhibitory activity against the proliferation of the selected cells,with an IC50 value in range of 1~3 pmol/L.Cell cycle analysis revealed that compound 7h and 7i caused HepG-2 cell cycle arrest at G2/S phase and G1 phase respectively,activated the caspase-3 and induced cell apoptosis.Western Blot assay demonstrated that the pro-apoptotic proteins Bax were up-regulated,while the anti-apoptotic proteins Bcl-2 were down-regulated when the cancer cells treated with compound 7h.The agarose gel electrophoresis essay showed that compound 7h could interact with DNA via intercalation and could inhibit the Topo I to relaxe the double-helix structure of DNA as well.The in vivo evaluation of 7h on the growth of HepG2 tumor xenografts in nude mice indicated that 7h exhibited 42.4%tumor inhibition rate in 12 mg/kg does.