Design,Synthesis Of The Hepatic Targeting MTS Derivatives And Their Anti-HBV Activities

Matijin-Su[N-(N-benzoyl-L-phenylalanyl)-O-acetyl-L-phenylalanol,MTS],a natural anti-hepatitis B virus(HBV)derivative of dipeptide,was isolated from ethnic drug Matijin(Dichondra repens Forst.)by our research group.A series of MTS derivatives with anti-HBV activity was synthesized by structural modification of MTS.One of the MTS derivative named "Tyrophentide"(Y101)was finished pre-clinical research by the group and was approved clinical study of phase I by China Food and Drug Administration(the approval number of clinical trial:2013L02491,2014L00070)The preliminary pharmacokinetic experiments showed that Y101 was widely distributed in many organs in the rat body,and the concentration in liver was low.Therefore,to improve the drug concentration in the liver tissue and increase drug therapeutic activity with minimal side effects,a series of hepatic targeting galactosyl derivatives of MTS was designed and synthesized.In this project,two synthesis strategies were explored,the first strategy was to bind of galactosyl and carboxyl of MTS derivatives with ethylene glycol、triethylene glycol、tetraethylene glycol as linking arm by indirect glycosylation;the second strategy was to bind of three galactosyl and carboxyl of MTS derivatives with tris(hydroxymethyl)methyl aminomethane、y-aminobutyric acid formed by indirect connection arm.In this project,the 23 hepatic targeting galactosyl derivatives of MTS were synthesized and their structures were confirmed by 1H-NMR,13C-NMR,1H-1H COSY,HMQC and ESI-MS et al.In this project,the anti-HBV activity of the 23 target compounds was evaluated in HepG2 2.2.15 cells.The screening results showed that all compounds had inhibitory effect on HBV DNA replication in HepG2 2.2.15 cells.The inhibition rates of compounds 57(59.50%),69(72.44%),79(65.34%)were better than other tested compounds in concentration of 50 μg·mL-1.The results can provide reference for further research of hepatic targeting MTS derivatives.For the evaluation of the hepatic target distribution of galactopyranosyl derivatives of MTS,compound 69 with best anti HBV activity was selected to do tissue distribution experiments in vivo.Through discovery and comparative study with MTS(40)and Y101,compound 69 could improve the concentration in liver lesion tissue and increase the anti-HBV activity.The research results showed that the MTS galactopyranosyl derivatives had a certain absorption distribution trend and expected to improve its hepatic targetdistribution.