Design,Synthesis And Antitumor Evaluation Of Benzophenanthridine Alkaloids Analogues

Benzo[c]phenanthridine alkaloids are a class of important isoquinoline alkaloids that exhibit broad-spectrum bioactivities such as anticancer,antiviral,anti-inflammatory and antifungal activities.In this dissertation,the design,synthesis two kinds of benzo[c]phenanthridine analogues in the guidance of bioisosterism were studied and their antitumor activity was evaluated.The dissertation consists of four chapters.In the first chapter the studies on the synthesis,structural modification of benzo[c]phenanthridine alkaloids and their antitumor evaluation reported in literature were reviewed.In the second chapter the synthesis of B-,C-ring modification of benzo[c]phenanthridine based on the bioisosterism were studied.23 B-,C-ring modification of benzo[c]phenanthridine derivatives were synthesized starting from isochroman-3-one and aryl amines.The key steps involved in the synthetic scheme including the reaction of condensation,the ring-closing reaction promoted by POCl3 and oxidation.The structure of the targeted compounds were confirmed and characterization by NMR and HRMS.In the third chapter the synthesis of A-,B-,C-ring modification of benzo[c]phenanthridine were studied.Aryl amines and 2-cyano-3-ethoxy-acrylic acid ethyl ester were as the starting material.The key intermediate 4-chloro-quinoline-3-carbonitrile was synthesized through three steps starting from the material.Then 4-chloro-quinoline-3-carbonitrile was further coveted to a three rings compound via reacted successively with primary amines and anhydride,then following by a ring-closing reaction under basic condition.Finally the three rings compound was reacted with 1,1,3,3-tetraethoxyl-propane to furnish the 9 A-,B-,C-ring modification of benzo[c]phenanthridine analogues.The structure of the targeted compounds were also confirmed and characterization by NMR and HRMS.In the fourth chapter the antitumor of the targeted benzo[c]phenanthridine analogues were evaluated via MTT assay.The in vitro inhibition on the proliferation against some common cancer cell line including MGC-803(human gastric cancer),HepG-2(human hepatocellular carcinoma),NCI-H460(human non-small cell lung cancer),SKOV3(human ovarian cancer)and T24(human bladder cancer)were screened.The results indicated that many target compounds exhibited potent anticancer activity and worth further exploration.