Synthesis And Evaluation Of Anticancer Activity Of Norcantharidin Derivatives

Cantharidin(CTD)exhibited good antitumor activity,is the principle active ingredient of Mylabris(blister beetles).It has been used to treat liver and lung tumors.However its applications are blocked by its severe nephrotoxic and inflammatory side effects.Norcantharidin(NCTD),the demethylated analogue of cantharidin,appears to cause the least nephrotoxic and inflammatory side effects.In recent years,in order to find efficient and low toxic antitumor drugs,more and more medchemists have modified the parent nucleus of norcantharidin and evaluated biological activity.Two series of norcantharidin derivatives from norcantharidin as raw material have been synthesized,and their cytotoxic activity and action mechanism were studied in this thesis.1.Through modifing the norcantharidin cyclic anhydride,we have synthesized a series of norcantharidin derivatives and evaluated their cytotoxic effects on four human tumor cell lines(A-549,HepG2,HeLa,and HCT-8)together with the genetically normal human diploid fibroblast line WI-38.The results suggested that(1S,4R)-3-((4-(4-(4-fluorophenyl)piperazin-1-ylsulfonyl)phenyl)carbamoyl)-7-oxa-bic yclo[2.2.1]heptane-2-carboxylic acid(12)exhibited potent cytotoxic effects on the tumor cell lines HeLa,whereas it was less toxic to WI-38 cells than its parent compound,norcantharidin.In addition,compound 12 inhibited protein phosphatase-1 activity and microtubule formation in HeLa cells,and it also interacts with calf thymus DNA.2.According to the combination principle of drug design,a series of conjugates of deoxypodophyllotoxin and norcantharidin were synthesized by different natural amino acid linkers as spacer.The cytotoxic activity of these compounds against human cancer cell lines(Hela?A549?HCT-8 and HepG2)were evaluated,and consequents indicated that compound 221(HepG2,IC50<0.01 ?M)showed the higher activity than VP-16 and NCTD,whereas it was less toxic to WI-38 cells than its parent compound,VP-16 and NCTD.In addition,compound 221 inhibited TOP-?,and interacted with CT DNA and cleaveged pBR322 plasmid DNA.Compound 221 induced cell cycle arrest in the G2/M phase carried out by raising the expression of cycle proteins cyclinB1 and cdc2.The above results showed that compound 221 inhibited tumor cells proliferation by inhibiting TOP-? and raising the expression of cycle proteins cyclinB1 and cdc2.Two kinds of NCTD derivatives with high proliferation inhibitory activity and less toxicity have been designed and synthesised,and evaluated their partition coefficient.These data provided a material basis that norcantharidin has potential for further development as anticancer agents.