Design, Synthesis And Biological Evaluation Of Indole And Tetrahydroisoquinoline Derivatives

Indole and tetrahydroisoquinoline alkaloids have been shown to be attractive natural products with diverse biological activities,such as antitumoral,antimicrobial and antiviral activities.In particular,a variety of indole and tetrahydroisoquinoline alkaloids have been utilized as antitumor drugs.This thesis focuses on the researches of indole and tetrahydroisoquinoline alkaloids derivatives,and can be divided into two sections,one is the studies on synthesis and biological properties of novel indole derivatives,and the other is the studies on tetrahydroisoquinoline derivatives.In the first chapter,we described the design and synthesis of a series of new indole derivatives and assessment of their antitumor activities.Taking sutent and the 1,3-disubstituted indolin-2-one found by our laboratory as lead compounds,we designed and synthesized three kinds of new indole derivatives:(1) 3-substituted 1-(5-formylfurfuryl)indolin-2-one derivatives;(2) furfurylpiperidine derivatives;(3) bis-indolin-2-one derivatives.The 81 synthesized target compounds were tested in the Pyricularia oryzae inhibition bioassay and the Caco-2,SPC-A1,A549 and HCT-116 cancer strains model in vitro.The results showed that most of the synthesized compounds possess anti Pyricularia oryzae activity and antitumor activities against Caco-2 strain in vitro.The structure-activity relationships were also discussed.Especially the 3-substituted 1-(5-formylfurfuryl)indolin-2-one derivatives possess potent antitumor activities.Among them,IC₅₀ values of eight compounds are below 1.0μM.These compounds could be studied more as antitumor lead compounds.The consents of the second part are the synthesis and antitumor evaluation of noscapine and its derivatives.Noscapine has acted as a weak anticancer agent in certain in vivo models.Recently,many researchers have performed several studies to evaluate the mechanism of action of this anticancer effect and found that noscapine can disrupt tubulin dynamics.Low cost and ready availability of noscapine allow for further exploratory medicinal chemistry of this natural product.Accordingly,our goal was to carry out the total synthesis of noscapine and then identify more potent and orally active analogues of noscapine as potential anticancer agents.The key intermediate-isoquinolinium iodide was prepared by Darkin,methylenation,Vilsmeier formylation,reductive amination,reductive N-methylation,Pomeranz-Fritsch cyclization,deoxygenation,and oxidation reaction. Finally,noscapine was obtained via zinc-promoted reductive coupling reaction of iminium salts with 3-bromo-6,7-dimethoxylphthalide.The total yield of noscapine is 0.5%and it can be prepared by large scale.Furthermore,we selected noscapine as lead compound and synthesized 15 noscapine derivatives.Among them,8 are new compounds.All of target compounds synthesized were tested in A549 cancer strain model in vitro.4 compounds exhibited significant inhibitory activities with IC₅₀ values less than 10μM.The structure-activity relationships were also discussed.