Bis-S-acyl-2-thioethyl (sate)-bearing monophosphate prodrug of β-L-FD4C as potent anti-HBV agent

The S-acyl-2-thioethyl (SATE)-bearing 5′-monophosphate prodrug of β-L-FD4C (8) was synthesized and evaluated for its activity against HBV in the 2.2.15 cell line. This pronucleotide (8) exhibited an excellent inhibitory effect against HBV with an EC50 value that is more than eight fold lower than that of the parent nucleoside (4) under some assay conditions. It is also important to note that pronucleotide (8) was capable of inhibiting HBV replication by 90%; whereas its parent, β-L-FD4C (4), could only inhibit virus replication no greater than 70% in the same assay. When evaluated in the standard cytotoxicity assay in CEM cell line, pronucleotide (8) exhibited an IC50 value of 52 μM, which was four times less toxic than parent β-L-FD4C (4) (IC50 = 13 μM).