Synthesis Of Tetrandrine Derivatives And Their Activities Study

Objective:The natural product tetrandrine exhibits excellent antitumor effect.In the early stage of our research group,a series of tetrandrine derivatives modified at C-5 position were synthesized and screened for their antitumor activities.The results showed that the antitumor activities of the C-5 position structures were improved.On this basis,this paper continues with tetrandrine as a lead compound,through the transformation of its structure,hoping to find new antitumor compounds more effective,and then make a preliminary study on the antitumor mechanism of selected high activity compounds.Methods:Tetrandrine was used as lead compound,the bromide generation at C-5 position of tetrandrine was done firstly under low temperature.Then,a series of new tetrandrine derivatives were synthesized by Suzuki coupling reaction.The structures of the compounds were confirmed by MS(mass spectrometry),1H NMR(1H nuclear magnetic resonance),13 C NMR(13C nuclear magnetic resonance)and melting point determination.CCK-8 method was used to screen the antitumor activity in vitro.The lead compound tetrandrine was used as a positive control drug.We investigate the antitumor activities of target compounds in P388(mouse leukemia cells)and A549(human lung cancer cells)by inhibition rate.The antitumor mechanism of target compounds were exploration preliminarily.The target compound h5 with higher activity was screened from 13 target compounds,and the effects of target compounds on apoptosis and apoptosis cycles of A549 cells weredetermined by flow cytometry.Results:In this paper,we synthesized 13 new tetrandrine derivatives,which have not been reported in our analysis and related literatures.The structures of the compounds were identified by MS,1H NMR and13 C NMR melting point determination.The in vitro antitumor activities of CCK-8 method showed that the IC50 value of most compounds were less than 10?M.The activities of 13 new compounds were screened in P388 cell line,then we found that the activities of the target compounds h5,h11 and h13 were better than tetrandrine.The activities of 13 new compounds were screened in A549 cell line,the results showed that the activities of the 13 target compounds were better than tetrandrine.Flow cytometry analysis showed that the target compound h5 could promote the apoptosis of A549 cells,and it had a certain concentration dependence.Compound h5 has a certain effect on cell cycle arrest of A549 cells,the period of S and G2.Conclusions:It was identified that 13 new tetrandrine derivatives were target compounds,and the13 structures have not been reported in our analysis and related literatures.CCK-8method was used to screen the inhibitory activity in P388 and A549 cells in vitro.The results showed that the compounds h5,h11 and h13 had higher biological activities on two kinds of tumor cells.Here are some preliminary structure activity relationships: the introduction of heterocyclic groups involved N,O,S are helpful to improve the antitumor activities of the leading compounds.The biological activity of the benzo furan in the structure is better than that of the benzo thiophene,which indicates that furan may have a better improvement effect than thiophene.When the group introduced for benzo six membered heterocyclic ring system,we found that the bond connected with the lead compound in the heterocycle ring have more efficient antitumor activity than benzenering.The results provide a reference for further searching for more effective antitumor compounds through structural optimization.The target compound,h5,induced the apoptosis of A549 cells blocking the cell cycle in a concentration-dependent manner.