WATER SOLUBLE ROBUSTAFLAVONE PRODRUGS AS ANTIHBV AGENTS

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Robutaflavone, a bioflavonoid isolated from the seed-kernel extracts of Rhus succedanea, exhibited impressive activity against hepatitis B virus (HBV) replication in vitro, with an effective concentration (EC50) of 0.25 mM and a selectivity index (IC50/EC90) of 153. Initial mechanism of action studies showed that this compound inhibits HBV replication at the intracellular level, and suggested inhibition of the viral DNA polymerase as a possible mechanism of action. Robustaflavone also inhibited influenza viruses A and B in vitro. Preliminary in vivo studies using a murine influenza A model demonstrated antiviral activity in a living system. However, poor water solubility has hampered efforts to obtain in vivo activity against hepatitis. The goals for this Phase I project are to complete a total synthesis of robustaflavone, of which significant progress has already been made. A series of water soluble prodrug derivatives of robustaflavone will be prepared and evaluated for in vitro anti-HBV activity. The prodrugs will also be examined in the murine influenza A model system to obtain in vivo antiviral activity of the prodrugs, as well as preliminary pharmacokinetic and toxicological data. These data will be used to select a prodrug candidate to be used in the woodchuck hepatitis virus (WHV) model system, to establish in vivo activity against hepatitis. PROPOSED COMMERCIAL APPLICATION: Hepatitis B virus (HBV) is the most significant viral pathogen infecting man, listed as the ninth leading cause of death by the World Health Organization. It is estimated that over 300 million persons are infected with HBV worldwide. Currently, there are few drugs available for treatment of chronic HBV infection. A non-nucleoside inhibitor of HBV replication that could be used for the treatment of chronic infection would have enormous market potential.