Synthesis,Biological Evaluations Of Tanshinone ⅡA Prodrug Analoeues And Homoisoflavonoids Derived From Natural Products

Tanshinone ⅡA,a liposoluble constituent with strong activities of anti-tumor,anti-oxidant and cardiovascular protection from Danshen,a traditional Chinese herb,was limited in clinical application because of its obvious drawbacks such as its low bioavailability and short half-time.In this thesis,four series consisting of 30 tanshinone ⅡA prodrug analogues all together were synthesized from tanshinone ⅡA by reduction and esterification according to the principle of prodrug,nine of which are fairly well soluble in water.Meanwhile,a novel skeleton tanshinone ⅡA derivative was obtained accidentally.Some of compounds were evaluated for anti-tumor activities in HL60 cells.The results revealed that 8 compounds could inhibit HL60 cells obviously,among which 5 compounds demonstrated the potent activities with IC50<3μM.Further antitumor test in S180 sarcoma mice model revealed that T25,T27 and T28 could inhibit sarcoma remarkably at the dose of 25mg/kg/d,among which T27 demonstrated the potent activity with the anti-tumor rate value of 38.4%.Moreover,antimicrobial test in vitro revealed that T17,T18 and T27 show the potent antimicrobial effects on several types of bacteria,among which T18 showed the significant activities against 5 types of bacteria with MIC<2μg/ml.In the second part of this thesis,the synthesis and bioactivities of homoisoflavonoids,another natural products showed anti-tumor and cardiovascular protective effect,were studied.Firstly,8-Formylophiopogonone B(HF1)and 6-Aldehydoisoophiogonone B(HF2),two natural homoisoflavonoids could protect myocardium effectively obtained from Ophiopogon japonicas,were synthesized from phloroglucinol by 8 steps of organic reactions,meanwhile,another 41 homoisoflavonoids were obtained by simple organic reactions.In vitro activity of compounds showed that 13 homoisoflavonoids such as HF23-HF26 and HF53 could protect H9C2 cells effectively,while some compounds exhibit toxicity to cells.Additionally,24 compounds were chosen for hepatoprotective activity test in vitro,it showed 5 compounds have potent protective effect on LO2 cells,among which HF14 showed the activity equal to positive control(Potenline).In conclusion,the above research provides a reliable experimental and theoretical basis for further research and development of new drugs based on Tanshinone ⅡA and homoisoflavonoids.