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: 3148700
• 负责人: Chung K Chu
• 金额: $ 22.36万
• 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 1997-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3148700
• 关键词: antiviral agents; drug design /synthesis /production; drug screening /evaluation; hepatitis B virus group; nucleoside analog; stereoisomer; tissue /cell culture; transfection

This project is based on the preliminary findings that an oxothiolane class of nucleosides (+/-)-BCH-189 and its analogues have shown potent antiviral activity against human hepatitis B virus. We have synthesized an enantiomerically pure (-)-L and (+)-D-BCH-189 from L-gulose and D- mannose, respectively, and discovered that (-)-L-BCH-189 is the most potent isomer against human hepatitis B virus (HBV). Furthermore, the (-)-L-BCH-189 was found to be significantly less toxic than the (+)-D- BCH-189. The superior anti-HBV activity of (-)-L-BCH-189 may be explained based on the fact that (+)-D-BCH-189 is susceptible to deamination by deoxycytidine deaminase while (-)-L-BCH-189 is completely resistant to the deaminase under the similar conditions. Thus, this application proposes the extension of this exciting preliminary findings to synthesize various pyrimidine and purine analogues of oxathiolane L- nucleosides for exhaustive structure-activity relationship studies against HBV. Additionally, assymmetric synthesis of dioxolane L- nucleosides as well as their C-nucleoside analogues will be synthesized. In vitro antiviral activity of the synthesized compounds will be evaluated in the 2.2.15 cells derived from HepG2 cells that were transfected with a plasmid containing HBV. Additionally, biochemical, molecular biological and toxicological (in vitro) studies will be performed with the (-)-L-BCH-189 as well as other promising drug candidates. Furthermore, in collaboration with the National Institute of Allergy and Infectious Diseases, a certain promising drug candidate will be studied in vivo woodchuck hepatitis B model to assess the anti- HBV as well as the toxicity. The long term goal of this application is to discover and develop clinically effective and safe antiviral agents for HBV which is currently lacking despite enormous problems in the world.

该项目是基于一个草皮素的初步发现 核苷类（+/-） - BCH-189及其类似物已经显示出有效的 针对人肝炎病毒的抗病毒活性。 我们已经合成了 从l-gulose和d-中 甘露糖，分别发现（ - ） - L-BCH-189是最大的 针对人乙型肝炎病毒（HBV）的有效异构体。 此外， （ - ） - 发现L-BCH-189的毒性明显低于（+） - d- BCH-189。 （ - ） - L-BCH-189的上级抗HBV活性可能是 根据（+）-D-BCH-189容易受到影响的事实解释 脱氧胞苷脱氨酶脱氨酸，而（ - ） - L-BCH-189完全是 在相似条件下对脱氨酶的抗性。 因此，这个 申请提出了这个令人兴奋的初步发现的扩展 合成黄氧化甲醇L-的各种嘧啶和嘌呤类似物 用于详尽的结构活性关系研究的核苷 反对HBV。 另外，二氧烷L-的囊合成合成 将合成核苷及其C-核苷类似物。 合成化合物的体外抗病毒活性将是 在来自HEPG2细胞的2.2.15细胞中进行评估 用含有HBV的质粒转染。 此外，生化， 分子生物学和毒理学（体外）研究将是 使用（ - ） - L-BCH-189以及其他有前途的药物进行 候选人。 此外，与国家研究所合作 在过敏和传染病中，某种有前途的候选药物 将研究体内木质肝炎模型，以评估抗 - HBV以及毒性。 该应用程序的长期目标是 发现和开发临床有效且安全的抗病毒剂 对于目前缺乏的HBV，尽管有很多问题 世界。