Design And Synthesis Of L-phenylalanine Dipeptide Derivatives And Their Anti-tumor Activities

As one of the major public health problems in the world,cancer is a great threat to human health.It is urgent to find new antitumor drugs as the current clinical use of anti-tumor drugs prevalent toxic,poor tolerance and other shortcomings.Matijin-Su[N-(N-benzoyl-L-phenylalanyl)-O-acetyl-L-phenylalanol,MTS],a derivative of dipeptide,was isolated from ethnic medicine Matijin(Dichondra repens Forst.)by our research group.Previous works indicated that some MTS derivatives could increase the level of intracellular reactive oxygen species(ROS),up-regulated P38MAPK pathway,stabilized P53 and activated transcription of P21,showed a good anti-cancer activity.In this study,as a development of the previous research works,we designed and synthesized a series of L-phenylalanine dipeptide derivatives by structural modification of MTS and testing their inhibitory effects on cancer cells.In this project,two types of L-phenylalanine dipeptide derivatives were designed:(?)Starting from L-tyrosine or L-phenylalanine,9 compounds were synthesized by reactions such as Schotten-baumann,condensation,nucleophilic substitution,and alkylation etc;(?)Starting from L-tyrosine methyl ester hydrochloride,6 compounds were synthesized by reactions such as condensation,hydrolysis etc.In addition,3 stable isotope labeled compounds of Y101 and its metabolites were synthesized.Overall,the 18 new derivatives of L-phenylalanine were synthesized and their structures were confirmed by 1H-NMF,13C-NMR,1H-1H COSY,HMQC and ESI-MS et al.In this study,the anti-tumor activities of the synthesized phenylalanine dipeptide derivatives were evaluated by thiazolyl blue tetrazolium bromide method(MTT).Some compounds showed promising bioacticities against PC3,K562 and HEL cell lines.The screening results showed that the activity of the phenylalanine dipeptide derivative synthesized by the synthetic route 2 was better than that of the synthetic route 1.The inhibition rates of the above mentioned three cell lines of compound 22 were 77.46%,81,20%,68.42%,when the concentration of the derivative was 5 ?M.The results can provide theoretical basis for further research of the anti-tumor activity of phenylalanine dipeptide derivatives.