ASYMMETRIC SYNTHESIS OF L-NUCLEOSIDES AS ANTI-HBV AGENTS

别名：The PI注意到，尽管安全和 乙型肝炎（B）病毒（HBV）感染是一种严重的传染病。 今天的全球健康问题，因此，这一更新申请涉及 继续进行跨学科合作， 格鲁吉亚大学和耶鲁大学的药物设计，合成和 核苷类似物作为潜在抗HBV药物的生物学评价。 私家侦探该项目是基于他们最近的发现， L-核苷类药物是一类很有前途的新型抗HBV药物。 在描述刺刀 在他们的药物发现工作中， β-L-2 '-氟-5-甲基-阿拉伯呋喃糖基尿嘧啶（L-FMAU）被发现为 在体外2.2.15细胞中以及在 体内鸭肝炎病毒模型，L-FMAU目前正在 被制药公司视为临床候选人。 他注意到 鉴于这些非常令人鼓舞的初步结果， 应用，建议继续进行化学合成， 非天然构型核苷的生物学评价 （L-核苷）作为潜在的抗HBV剂。 陈述到 提出的具体目标是：a）合成2 '-氟化L-嘌呤 核苷（I类），B）3 ′-杂原子取代的 2 '，3'-双脱氧核苷类似物（II类）， 2 '，3'-不饱和-和2 '，3'-双脱氧-L-核苷（III类），d） L-碳环核苷的合成（IV类），e） 3 '-羟甲基-取代的L-核苷（V类）， g）体外抗HBV功效的评价a 2.2.15 细胞系统以及与其他抗HBV药物的联合研究，h）在 确定初步毒性的体外细胞毒性研究，i）研究 有前途的抗HBV药物的作用方式，和j）为了评估 发现的有前景的抗HBV核苷作为潜在的临床 候选人，在北京鸭和土拨鼠肝炎模型的体内研究 将与法国的调查人员合作进行， 国家卫生研究院 该应用程序的长期目标是发现安全且 有效的抗HBV药物，可作为单一药物或 与其他临床有效和安全的抗HBV药物联合使用， 不同的作用方式以及毒性。

DESCRIPTION: The P.I. notes that despite the availability of safe and effective vaccines, hepatitis B virus (HBV) infection remains a serious global health issue today and that therefore, this renewal application deals with a continuation of interdisciplinary collaborative efforts at the University of Georgia and Yale University for drug design, synthesis and biological evaluation of nucleoside analogues as potential anti-HBV agents. The P.I. states that this project is based on their recent findings that L-nucleosides are a new promising class of anti-HBV agents. He reports that during their drug discovery efforts supported by the current grant beta-L-2'-fluoro-5-methyl-arabinofuranosyluracil (L-FMAU) was discovered as a potent and non-toxic anti-HBV agent in in vitro 2.2.15 cells as well as in vivo in the duck hepatitis virus model and that L-FMAU is currently being considered as a clinical candidate by a pharmaceutical firm. He notes that in view of these highly encouraging preliminary results, in this application, it is proposed to continue on the chemical synthesis and biological evaluation of the nucleosides with unnatural configuration (L-nucleosides) as potential anti-HBV agents. It is stated that the proposed specific aims are: a) synthesis of 2'-fluorinated L-purine nucleosides (Class I), b) synthesis of 3'- heteroatom-substituted 2',3'-dideoxynucleoside analogues (Class II), c) synthesis of 2',3'-unsaturated- and 2',3'-dideoxy-L- nucleosides (Class III), d) synthesis of L-carbocyclic nucleosides (Class IV), e) 3'-hydroxymethyl-substituted L-nucleosides (Class V), f) synthesis of acyclonucleosides, g) evaluation of anti-HBV efficacy in in vitro a 2.2.15 cell system as well as combination studies with other anti-HBV agents, h) in vitro cytotoxicity studies to determine the preliminary toxicity, i) studies of mode of action of promising anti-HBV agents, and j) in order to assess the discovered promising anti-HBV nucleosides as potential clinical candidates, in vivo studies in the Pekin duck and woodchuck hepatitis models are to be conducted in collaboration with investigators in France and at the NIH. The long term goal of this application is to discover safe and effective anti-HBV drugs, which can be used as a single agent or in combination with other clinically effective and safe anti-HBV agents with different modes of action as well as toxicity.