WATER SOLUBLE ROBUSTAFLAVONE PRODRUGS AS ANTIHBV AGENTS

Robutaflavone是一种从植物种子仁提取物中分离出来的双黄酮类化合物， 野漆树对B型肝炎病毒具有显著的抗病毒活性 (HBV)体外复制，有效浓度（EC 50）为0.25 mM，选择性指数（IC 50/EC 90）为153。 初始机制 作用研究表明，该化合物抑制HBV复制， 细胞内水平，并建议抑制病毒DNA聚合酶 作为一种可能的作用机制。 罗布斯塔黄酮还抑制 流感病毒A和B体外。 使用A进行初步体内研究 小鼠甲型流感模型在活体中显示抗病毒活性 系统 然而，差的水溶性阻碍了获得抗氧化剂的努力。 抗肝炎的体内活性。 第一阶段项目的目标是 完成了罗布斯塔黄酮的全合成， 已经取得了进展。 一系列水溶性前药 将制备罗布斯塔黄酮的衍生物并进行体外评价， 抗HBV活性。 前药也将在小鼠中进行检查。 流感A模型系统，以获得 前药，以及初步的药代动力学和毒理学数据。 这些数据将用于选择前药候选物以用于药物组合物。 土拨鼠肝炎病毒（WHV）模型体系，建立体内 抗肝炎活性。 建议的商业应用：B型肝炎病毒（HBV）是最常见的 感染人类的重要病毒病原体，被列为第九大 死亡原因世界卫生组织。 据估计 全世界有超过3亿人感染HBV。 目前， 可用于治疗慢性HBV感染的药物很少。 一 HBV复制的非核苷抑制剂，可用于 慢性感染的治疗将具有巨大的市场潜力。

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.