Design,Synthesis And Biological Activities Of Isosteviol And Ursolic Acid Derivatives

Teipenoids are a kind of polymers composed of isoprene groups and their derivatives.which are widely distributed in nature.It has been active in the field of medicinal chemistry because of its complex,diverse and extensive biological activities.Meanwhile,teipenoids are also one of the significant sources for finding natural products with certain biological activities.Based on the combination principles of medicinal chemistry,in this paper,isosteviol and ursolic acid,which are tetracyclic diterpenoid and pentacyclic triterpenoid,respectively,were selected as the lead compounds.Then,designed and synthesised 68 novel compounds,all target compounds were characterized via 1H-NMR,13C-NMR,and high-resolution mass spectrometry.The aim of this study was to obtain effective and low toxic anti-tumor or anti-Toxoplasma gondii active compounds.In chapter 1,six series of 32 novel isosteviol derivatives were designed and synthesized,and their anti-tumor activity was evaluated against three human cancer cell lines(HCT-116,BEL-7402,HepG2)and the human L02 normal cell line in vitro.Most of the derivatives tested here exhibited improved antiproliferative activity with low cytotoxicity when compared with the parent compound isosteviol and the positive control drug 5-Fluorouracil.Among these derivatives,compound 5d(2-oxo-2-(((1-(p-tolyl)-1H-1,2.3-triazol-4-yl)methyl)amino)ethyl(4R,4aS,6aR,9S,11aR,11 bS)-4,9,11b-trimethyl-8-oxotetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4-carb oxylate)exhibited the most potent antiproliferative activity with low cytotoxicity(IC50 in HCT-116 cells:5.38±0.26?M;IC50 in BEL-7402 cells:15.91±0.41?M;IC50 in HepG2 cells:8.92±0.44 ?M;selective index:29.93,10.12,and 18.05,respectively),demonstrating better results than isosteviol and 5-Fluorouracil.In addition,compound 5d inhibited the colony formation of HCT-116 cells in a concentration-dependent manner.Further studies revealed that compound 5d arrested the HCT-116 cell cycle in the S phase,and western blot analysis demonstrated the mechanism may be correlated with a change in the expression of cyclin A,cyclin Bl,and cyclin El.Furthermore,the results of a docking study that involved placing compound 5d into the CDK2/cyclin A binding site revealed that its mode of action was possibly as a CDK2/cyclin A inhibitor.In chapter 2,three series of 36 novel ursolic acid derivatives were designed and synthesized and evaluated their anti-Toxoplasma gondii activity both in vitro and in vivo.Some derivatives exhibited an improved anti-T.gondii activity in vitro when compared with UA(parent compound),whereas compound 9d(2-(3-(4-nitrophenyl)-4H-1,2,4-triazol-4-yl)ethyl(1 S,2R,4aS,6aS,6bR,8aR,12aR,12bR,14bS)-10-hydroxy-1,2,6a,6b,9,9,12a-heptamethyl-1,3.4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b.13,14b-octadecahydropicene-4a(2H)-carboxylate)exhibited the most potent anti-T.gondii activity in vivo(SI=1.77,Inhibitory rate of T gondii:70.4%).Spiramycin served as the positive control.Additionally,determination of biochemical parameters,including the liver and spleen indexes,indicated compound 9d to effectively reduce hepatotoxicity and significantly enhance anti-oxidative effects,as compared with UA.Furthermore,the molecular docking study indicated compound 9d to possess a strong binding affinity for T.gondii calcium-dependent protein kinase 1(TgCDPK1).Based on these findings,I conclude that compound 9d,a derivative of UA,could act as a potential inhibitor of TgCDPKl.In summary,two new compounds were found in this study-the highly selective anti-tumor compound 5d and the highly effective with low-toxic anti-Toxoplasma gondii compound 9d.These results can provide a certain experimental basis for the subsequent development of teipenoid active natural products,and provide a favorable reference for further research in this field.