ASYMMETRIC SYNTHESIS OF L-NUCLEOSIDES AS ANTI-HBV AGENTS

描述：私家侦探注意到，尽管有安全和 有效的疫苗，乙肝病毒(乙肝)感染仍然严重 今天的全球健康问题，因此，这项续签申请涉及 随着跨学科合作的持续努力， 佐治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的抗乙肝药物的生物学评价。 私家侦探表示，这个项目是基于他们最近的发现 L核苷是一类很有前途的新型抗乙肝药物。他报告说 在他们的药物发现工作中，由目前的拨款支持 Beta-L-2‘-fluoro-5-methyl-arabinofuranosyluracil(L-FMAU)被发现为 一种高效、无毒的抗乙肝病毒药物在2.2.15细胞和 在鸭肝炎病毒模型中的活体和L-FMAU目前正在 被制药公司认为是临床候选药物。他指出， 鉴于这些令人鼓舞的初步结果，在这方面 应用方面，建议继续进行化学合成和 非自然构型核苷的生物学评价 (L-核苷)作为潜在的抗乙肝药物。据指出，本局 建议的具体目标是：a)合成2‘-氟代L嘌呤 核苷(I类)，b)3‘-杂原子取代的合成 2‘，3’-二脱氧核苷类似物(II类)，c)合成 2‘，3’-不饱和-和2‘，3’-双脱氧-L-核苷(III类)，d L-碳环核苷(IV类)，e)的合成 3‘-羟甲基取代L核苷(V类)，f)的合成 无环核苷，g)体外抗乙肝病毒效果评价 细胞系统以及与其他抗乙肝药物的联合研究，h) 用于确定初步毒性的体外细胞毒性研究，I)研究 有希望的抗乙肝药物的作用模式，以及j)以评估 新发现的具有潜在临床应用前景的抗乙肝核苷 候选：北京鸭和土拨鼠肝炎模型的体内研究 将与法国和法国的调查人员合作进行 国家卫生研究院。此应用程序的长期目标是发现安全和 有效的抗乙肝药物，可作为单一药物或在 与其他临床有效、安全的抗乙肝药物联合 不同的作用模式以及毒性。

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.