Design,Synthesis And Activity Of Dihydroartemisinin Derivatives

Artemisinin with anti-malarial and anti-tumor activities was first isolated and identified by Chinese scientists in 1972.Firstly,this paper provides a detail summary of structural modification and anti-malarial and anti-tumor mechanism about artemisinin derivatives.Base on the literatures and our previous research,the scaffold of 4-quinolylhydrazone or ureas was attached to dihydroartemisinin by the combination principles and bioisosterism principles to get ninety-eight hybrid structures which would be effective against malaria and caner and confirmed by 1H-NMR and ESI-MS.Twenty-eight target compounds were evaluated for inhibitory activities against recombinant falcipain-2.All test target compounds were found to be significant inhibitors of falcipain-2 with IC50 values ranging from 0.15 to 2.28 μM.With the aim of better understanding the binding mode of the target compounds to the biological target,the molecular modeling study was performed by the AutoDock 3.05 program.The docked energy for the most potent compound L-A03 was-11.71 kcal/mol,and the compound L-A03 interacted within the receptor pocket surrounded by residues Cys42,Gly82,Gly83,Gln 171,Leu 172,His 174 and Asp234.Compound L-A03 may form hydrophobic contacts with the residues within the pocket.According to the result of in vitro inhibition assay,eighteen target compounds were tested against Plasmodium berghei ANKA strain infected mice according to the Peters’s 4-day test.A preliminary in vivo assay respectively was shown that thirteen compounds suppressed more than 90%the parasite growth in infected mice at a dose of 75 mg/kg/day and 125 mg/kg/day.The second assay by intraperitoneal injection was shown that compound L-D05(ED50=14.67 mg/kg;ED90=24.93 mg/kg)and compound L-D06(ED50=12.95 mg/kg;ED90=25.14 mg/kg)displayed significant activities in vivo.Forty-three compounds were tested against HeLa,MCF-7,U937,K562,HL60,HCT116,HepG2,A549,A375-S2 and HT1080 cell lines in vitro according to the MTT-based assay,using 5-Fluorouracil as positive control.A preliminary assay was shown that most synthetic derivatives of L-A series、L-D series and L-E were more potent than the positive control 5-Fluorouracil in different degrees as well as the selectivity for some particular cancer cell types.Moreover,it is worth pointing out that most compounds of L-G series and L-H series were more active than the positive control 5-Fluorouracil against the HeLa、MCF-7、HL60 and A549 cells in the same assay.In order to understand the antitumor mechanism,we research the antitumor mechanism ahout the target compound L-A03 that have good antitumor activities.The results showed that L-A03 can cause MCF-7 cell being smaller and round and the cell morphology being changed significantly.It can reduce the pro-caspase3 and increase the shear form caspase3 expression in MCF-7 cell,and prompt LC3 I transforming to LC3 II,and cause apoptosis and autophagy.The experiment showed that target compound L-A03 with low toxicity agaist the peripheral blood mononuclear cells.According to the result.of anti-malarial and anti-tumor activity,the preliminary structure-activity relationships were obtained.These implications would benefit a drug design in future research.