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 group. A series of MTS derivatives with anti-HBV activitiy was synthesized by structural modification of MTS. One of MTS derivatives named “Tyrophentide” had been finished pre-clinical research and has been approved to do 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 it was widely distributed in many organs, and the concentration in liver was low. Hepatic targeting drug delivery system(HTDDS) can selectively deliver drugs to the targeted liver lesion sites and increase the drug concentration in liver lesion tissue. Galactose can be recognized and bound specifically by asialoglycoprotein receptor(ASGP-R) expressed on the plasma membrane of mammalian hepatocytes. Therefore, to improve drug concentration in liver lesion 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, three synthesis strategies were explored: the first strategy is to conjugate of galactosyl and alcoholic hydroxyl of MTS derivatives by the direct glycosylation; the second strategy is to bind of galactosyl and phenolic hydroxyl of MTS derivatives with triethylene glycol as linking arm by the indirect glycosylation; the third strategy is to connect galactosyl with azido and MTS derivatives with propargyl via a copper(I)-mediated dipolar cycloaddition of terminal azides to alkynes(“click”) by the indirect glycosylation. In this project, 19 hepatic targeting galactosyl derivatives of MTS were synthesized and their structures were confirmed by 1H NMR, 13 C NMR, 1H-1H COSY, HMQC and ESI-MS et al.In this project, the anti-HBV activities of 14 target compounds were evaluated in HepG2 2.2.15 cells. The screening results showed that 12 compounds had inhibitory effect on HBV DNA replication in Hep G2 2.2.15 cells. The IC50 of compounds 87(16.76 μg·m L-1), 89(28.67 μg·m L-1), 91(18.65 μg·m L-1) of the inhibition on the replication of HBV DNA were better than other tested compounds. The results can provide reference for further research of hepatic targeting MTS derivatives.