Design,Synthesis And Biological Activity For Flavonoid Ligands Of RXR?

Today,cancer continues to be a leading cause of death in the world.Therefore,finding effective anticancer agents is one of the main directions of drug discovery.Flavonoids are an important class of natural compounds,which have several pharmacological benefits(e.g.anticancer,anti-allergic anti-inflammatory,etc.)and are known as effective antioxidants,metal chelators and free radical scavengers.Natural and synthetic flavonoids are therefore of considerable interest in the development of novel therapeutic agents for various diseases and are generally believed to be non-toxic compounds since they are widely distributed in the human diet.On the other hand,adamantyl Retinoid-related molecules are an emerging class of apoptotic agents with promising therapeutic potential in oncology.Herein,the general aim of the study was to design and synthesiz a series of flavonoids containing 1-adamantyl group,and to investigate their antitumor activity and their binding ability with RXRa.The major contents and results of this thesis are as follows:(1)The design for flavonoid ligands of RXRa:The efficient synthetic strategies to afford structurally diverse flavonoid derivatives were proposed.And the optimization in the base-catalyzed Claisen-Schimidt Condensation was done.(2)The synthesis for flavonoid ligands of RXRa:27 flavonoid derivatives including 26 new compounds were synthesized under optimum reaction conditions,and their structures were successfully confirmed by IR,MS,1H-NMR,and 13C-NMR.(3)Bioactivity studies:MTT Assay and Western Blot Analysis were used to test the anti-tumor activity of flavonoids.The experiment results showed that compounds W-4,W-8,W-23 and W-26 had pro-apoptotic effects on tumor cell.(4)Flavonoid ligands of RXRa studies:Biacore experiments showed that compound W-8 had better binding ability with RXRa than positive medicine CD3254.Furthermore,molecular docking was used to study potential structural modifications on the flavonoid structure in order to obtain highly potent derivatives that selectively target the RXRa.