The Preparation And Anti-tumor Activities Evaluation Of Novel Indole And Quinolone Derivatives

Indole and quinolone ring are the common backbone structure which existed in the aryl alkyl acids,triptans,xacins and other drug molecules.Along with developing of drug molecular structure transformation strategy,some interesting new pharmaceutical uses of molecules based on the traditional indole and quinolone structure,were reported in recent years.Therefore,in order to enrich the new application of these traditional compounds,finding new methods for modifying the indole rings and quinolone rings is of significant importance.This paper,accordingly,has carried out the following three parts:1.Based on the methodology study of Cu(I)-catalyzed C-S functionalization on indole rings,a novel method was established to construct 3-alkylthioindoles and 2,3-bis(alkylthio)indole with cheap catalysts in mild conditions.With substituted indoles as raw materials,diphenyl disulfides as sulfur sources,CuI as catalyst and DMSO as solvent,seventeen 3-indole sulfide derivatives and fifteen 2,3-indole bisulfide derivatives were obtained in excellent yields.In addition,the prepared compounds were tested by CCK8 method for antitumor activity.The results showed that some of the compounds displayed certain inhibitory effect on the growth of hepatocellular carcinoma cells Huh7 and SNU449.Furthermore,three of them demonstrated better activity than that of the control drug cisplatin.2.A series of novel 1-propargyl-substituted quinolones have been designed and prepared with choosing the substituted aniline as the starting material.These quinolones precursors provided a good tool in the developing of novel quinolone derivatives of anti-tumor activity.With these compounds in hand,new quinolone derivatives containing 1-glucosyl triazole structural modification were synthesized through the Cu(I)-catalyzed click reactions.The anti-cancer activity to Huh7 and SNU449 tumor cells of these quinolone derivatives(15 new compounds)were conducted through CCK8 method.The inhibition activities of some compounds were enhanced after the introduction of glucosyl.Among them,the 3-6c compound showed much superior IC50 value compared to the control drug cisplatin in the inhibition of the proliferation of Huh7 cell line.3.In the research on urea/thiourea structural modification of the newly listed antilung cancer medicine osimertinib,which contains an indole ring in its molecular structure.We designed and prepared 10 novel urea/thiourea modified osimertinib analogues with isocyanates/isothiocyanates as raw materials in excellent yields.The inhibitory effects on A549 tumor cell proliferation of the prepared osimertinib analogues were evaluated.The biological activity improvement strategy of these new molecules is prospected as well.