Synthesis And Biological Activity Evaluation Of Scutellarin Derivatives

This dissertation was divided into five major chapters.In the first chapter,a systemic review was provided about the research overview of progress in structural modification methods of flavonoids,including the ether reaction,formation of metal complexes,biotransformation and preparation of Mannich derivatives.There were two for the hydrolysis of the flavonoids,which were chemical deglycosylated synthesis and enzymatic hydrolysis.The pharmacological effects of flavonoids scutellarin were also summarized,including protection of cerebral ischemia and reperfusion loss,vasorelaxation,improve microcirculation,myocardial protection,inhibition of platelet aggregation anti-inflammatory and so on.The problems and solutions of scutellarin in clinical use were also summarized,which provided a new approach to improve its solubility and bioavailability for the further development.In the second chapter,firstly,the different conditions for the scutellarin hydrolysis were investigated and optimized.Secondly,scutellarein was taken as a lead compound and the synthetic routes on the structural modification of the 6,7,4’ three positions of scutellarein were designed.Forthermore,the reactivity of the eighth hydrogen atom on the A ring was investigated,then Mannich derivatives were synthesized.In the third chapter,the in vitro antioxidant activity of scutellarein derivatives was evaluated by DPPH radical-scavenging activity assays,protective effects on H2O2-induced cytotoxicity in PC 12 cells using MTT assay method,and in vitro anticoagulant activity.The results showed as follows:1.In the DPPH test,almost all the alkyl derivatives had little antioxidant activity,but Ⅰ-7 showed a higher antioxidant activity than scutellarin;Mannich derivatives showed a high antioxidant activity,which was close with glycosides and aglycones at high concentrations,however,they was less effective at low concentrations.2.Almost all the alkyl compounds,showed inhibitory effect against hydrogen peroxide-induced cytotoxicity in PC 12 cells.Especially,compound Ⅰ-7 showed the most potent activity in thedifferent concentrations3.Coagulation test results showed that compared with scutellarin and scutellarein,mannich derivatives can be extended a shorter plasma clotting time in TT.The other three tests showed no effect in PT、FIB and、APTT.Platelet aggregation experiments showed that,compared with scutellarin and scutellarein,mannich derivatives had less activity in platelet aggregation.4.Compared with scutellarin and scutellarin aglycone,water-soluble of Mannich derivatives have significantly increased,alkyl derivatives water-soluble poor.5.During the lipid-water partition coefficient found,in neutral and alkaline environments,mannich derivatives have higher the concentration in the aqueous phase than that in the organic phase,corresponding to IgP is negative and smaller;in the three pH environment,the water phase concentration of alkyl derivatives is higher than that in the organic phase,corresponding to lgP are negative.In the fourth chapter,the synthesis of specific experiments was mainly described.Finally,forty-five compounds were synthesized,including twenty-six intermediate compounds,twelve alkyl derivatives and seven Mannich derivatives.In the fifrth chapter,the research work was summarized.The compound structures and the corresponding NMR spectra were attached.