Studies On The Synthesis And Bioactivity Of Prenylated Flavonoids And Aminoalkylated Flavones Derivatives

Flavonoids are widely distributed in nature,with a broad spectrum of pharmacological activity and low toxicity,but they have poor solubility and bioavailability,which is a major obstacle in the development of new drugs.Prenylated flavonoids is an important part of flavonoids,the presence of prenylated side chain not only enhance binding affinity toward p-glycoprotein and increase the lipophilicity of flavonoids,make it easier to reach the target through the cell membrane,But also significantly enhance the biological activity of flavonoids,the bioavailability was improved.Therefore,it can be regarded as an important source of new drug development.However,there is a limited source of natural prenylated flavonoids,which are lower in nature plants,which to some extent,negatively influenced their further development and utilization.Therefore,chemical synthesis of prenylflavonoids is particularly important.Nitrogen group is an important pharmacological active group,the introduction of nitrogen containing groups into flavonoids can improve their bioactivity and increase the water solubility via Hofmann alkylation reaction.So,it is importment to study the modification of nitrogen containing groups and biological activities of flavonoids.This paper is attempted to synthesize a series of prenylated flavonoids and novel aminoalkylated flavones at low cost and relatively simple method,Which based on the abundant,cheap and easily available flavonoids naringin,hesperidin and polymethoxyflavones quercetin,myricetin as raw materials,furthermore,their antiproliferative activities were evaluated in vitro on a panel of three human cancer cell lines.1、Naturally occurring 4,7-dimethoxy-5-hydroxyflavone(1)3,4,7-trimethoxy-5-hydroxyflavone(2)and 4’-methoxy-5,7-dihydroxyflavone(11)were synthesized through I2/Pyridine dehydrogenation,glycoside hydrolysis and selective O-methylation,using naringin and hesperidin as raw materials,which are inexpensive,plentiful flavonoids glycosides.8-Prenylatedflavonoid 5、6、7、8 and 6-Prenylatedflavonoid 9、10 were synthesized from 1,by reaction steps includes O-prenylation,Claisen rearrangement,O-methylation.2、Polymethoxyflavone 3,3’,4’,7-tetramethoxy-5-hydroxyflavone(15)and naturally occurring 3,3’,4’,5’,7-fivemethoxy-5-hydroxyflavone(16)were synthesized through O-methylation,using economically accessible quercetin,myricetin as raw materials.8-prenylatedflavonoid 19、20、23 and 6-prenylatedflavonoid 21、22 were synthesized from 15 and 16,by reaction steps includes O-prenylation,Claisen rearrangement,O-methylation.3、Natural product 4’,7-dimethoxy-5-hydroxyflavone(1)with excessive amount of 1,2-dibromoethane or 1,4-dibromobutane occurred Nucleophilic substitution reaction under alkaline condition,resulted in the intermediates 4a,5a.Subsequently,these intermediates were reacted with the corresponding secondary amines via Hofmann alkylation reaction to provide the final aminoalkylated flavones 2a-h,3a-h.4、All the synthetic aminoalkylated flavones derivatives 2a-h and 3a-h were tested in vitro for their antiproliferative activity against three human cancer cell lines(Hela,HCC1954 and SK-OV-3)by the CCK-8 method using cis-Platin,Paclitaxel and Staurosporin as positive controls.The results showed that most of synthesized target compounds toward these three cancer cells.Particularly,all compounds except 2f,2g and 3e aginst HCC1954 cells and compounds 2d,3b and 3d against SK-OV-3 cells were more potent than the positive control cis-Platin.5、Thirty eight prenylated flavonoids and aminoalkylated flavones derivatives were synthesized totally in this thesis,and thirty three of them were new compounds.The structures of all synthesized compounds have been confirmed by 1H NMR,13C NMR and MS techniques.