Novel ring-expanded nucleoside analogs exhibit potent and selective inhibition of hepatitis B virus replication in cultured human hepatoblastoma cells

Abstract Novel ring-expanded nucleoside (REN) analogs ( 1 – 3 ) containing 5:7 fused ring systems as the heterocyclic base were found to be potent and selective inhibitors of hepatitis B virus (HBV) replication in cultured human hepatoblastoma 2.2.15 cells. The most active compound, 6-amino-4,5-dihydro-8 H -1-(β- d -ribofuranosyl)imidazo[4,5- e ][1,3]diazepine-4,8-dione ( 1 ), inhibited the synthesis of intracellular HBV replication intermediates and extracellular virion release in 2.2.15 cells with 50% effective concentration (EC 50 ) of 0.604 and 0.131 μM, respectively. All three compounds had no effect on the synthesis of viral ribonucleic acids (RNA) in 2.2.15 cells. These compounds also exhibited low cellular toxicity in stationary and rapidly growing cell systems.