ASYMMETRIC SYNTHESIS OF L-NUCLEOSIDES AS ANTI-HBV AGENTS

作为抗 HBV 药物的 L-核苷的不对称合成

• 批准号: 2003902
• 负责人: Chung K Chu
• 金额: $ 25.95万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-02-01 至 2001-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2003902
• 关键词: antiviral agents; drug design /synthesis /production; drug screening /evaluation; hepatitis B virus group; nucleoside analog; stereoisomer; tissue /cell culture; transfection

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.

描述：P.I。注意到，尽管有安全的安全性 有效的疫苗，丙型肝炎病毒（HBV）感染仍然是严重的 当今的全球健康问题，因此，这项续签申请交易 继续跨学科的合作努力 佐治亚大学和耶鲁大学药物设计，合成和 核苷类似物作为潜在抗HBV药物的生物学评估。 P.I.指出该项目基于他们最近的发现， L-核苷是一类新的抗HBV剂。 他报告了这一点 在当前赠款支持的毒品发现工作中 发现β-L-2'-氟-5-甲基 - 阿拉伯尿酸尿瘤（L-FMAU）被发现为 在体外2.2.15细胞以及在 鸭肝炎病毒模型的体内，目前正在L-FMAU 由制药公司视为临床候选人。 他指出 鉴于这些极为令人鼓舞的初步结果， 应用，建议继续进行化学合成和 具有不自然构型核苷的生物学评估 （l-核苷）作为潜在的抗HBV剂。 据说 提出的特定目的是：a）2'-氟化L-螺旋线的合成 核苷（I类），b）3'-杂原子取代的合成 2'，3'-脱氧核苷类似物（II类），c）合成 2'，3'-不饱和 - 和2'，3'-二氧l-核苷（III类），D） L-碳环核苷（IV类）的合成，E） 3'-羟基甲基取代的L-核苷（V类），F）合成 链氯核苷，g）评估体外A 2.2.15中抗HBV功效 细胞系统以及与其他抗HBV药物的组合研究，h） 体外细胞毒性研究以确定初步毒性，i）研究 有希望的抗HBV代理的作用方式，以及j）以评估 发现有希望的抗HBV核苷作为潜在的临床 候选人，在北京鸭和木质肝炎模型中进行体内研究 将与法国的调查员合作进行 NIH。 该应用程序的长期目标是发现安全和 有效的抗HBV药物，可以用作单一药物或 与其他临床有效且安全的抗HBV药物结合使用 不同的作用方式和毒性。