Synthesis And Anti-hepatitis B Virus Activities Of N-Methylated Derivatives Of MTS

Tyrophentide(Y101),a derivative of the lead compound Matijin-Su(MTS,N-(N-benzoyl-L-phenylalanyl)-O-acetyl-L-phenylalanol),is a novel drug candidate for the treatment of hepatitis B virus(HBV)infection.Phase ? clinical trials of Y101 showed that the major metabolite of Y101 was M8 which was same as the preclinical pharmacokinetic study of Y101.However,M8 showed no anti-HBV activity in vitro.In this paper,a series of new derivatives of N-methyl-MTS was synthesized and evaluated for their ant-HBV activity in order to explore new target derivative of MTS with better hydrolysis stability and anti-HBV activity.Basis on the previous study,two synthetic methods were used to modify the amide bond of MTS by N-methylation,and a series of new MTS derivatives was designed and synthesized.(1)Starting from L-Phenylalanine,N-Fmoc-L-phenylalanine(J-05)was obtained by Fmoc protection.Condensation of J-05 with N-methyl-L-phenylalaninol(J-04)provided J-06,Deprotection of the Fmoc group of J-06 provided intermediates J-07 Condensation of J-07 with different derivatives of benzoic acid provided six novel N-methyl derivatives of MTS(XY-01?XY-06).(2)Staring from L-tyrosine,N-Fmoc-L-tyrosine(J-08)was obtained by Fmoc protection,The intermediate J-09 was synthesized by acetylation protection of J-08.Condensation of J-09 with N-methyl-L-phenylalaninol(J-04)provided J-10,Deprotection of the Fmoc group of J-10 provided intermediates J-11,Condensation of J-11 with different derivatives of benzoic acid provided fourteen novel N-methyl derivatives of MTS(XY-07-XY-20).There are two ways to synthesize intermediate N-methyl-L-phenylalaninol(J-04):(1)Using L-phenylalaninol as raw material,N-methyl-L-phenylalaninol(J-04)was synthesized in four steps of benzylation,debenzylation,methylation and hydrogenation reactions.(2)Staring from L-phenylalanine methyl ester hydrochloride,N-methyl-L-phenylalaninol(J-04)was synthesized in four steps of condensation,reduction,methylation and hydrogenation reactions.Twenty unreported N-methylated modified MTS derivatives were synthesized according to two synthetic methods(1)and(2).The structures of target compounds(XY-01-XY-20)were characterized by MS(ESI),1H NMR,13C NMR,1H-1H COSY and HMQC.In this study,we used MTT method to evaluate the anti-HBV activity of N-Methylated Derivatives of MTS in HepG2 2.2.15 cell model.The results showed that a few target compounds had weak inhibitory effect.In addition to the above work,the stereoisomers of Y101 with different configurations were synthesized.