Discovery of an Orally Active and Liver-Targeted Prodrug of 5‑Fluoro-2′-Deoxyuridine for the Treatment of Hepatocellular Carcinoma

We report a series of novel O-(substituted benzyl) phosphoramidate prodrugs of 5-fluoro-2′-deoxyuridine for the treatment of hepatocellular carcinoma. Through structure optimization, the o-methylbenzyl analog (1t) was identified as an orally bioavailable and liver-targeted lead compound. This lead prodrug is well-tolerated at a dose up to 3 g/kg in Kuming mice via oral administration. An efficacy study demonstrated that it possesses good inhibitory effect (61.67% and 72.50%, respectively) on tumor growth in a mouse xenograft model. A metabolism study in Sprague–Dawley rats suggested that 1t can release the desired 5′-monophosphate in the liver with high liver-targeting index.