ASYMMETRIC SYNTHESIS OF L-NUCLEOSIDES AS ANTI-HBV AGENTS

该项目是基于一种氧硫杂环戊烷的初步发现 一类核苷(+/-)-BCH-189及其类似物显示出强效 对人类乙肝病毒的抗病毒活性。我们已经合成了 对映体纯的(-)-L和(+)-D-BCH-189来自L-古罗糖和D- 甘露糖，发现(-)-L-BCH-189是最多的 有效的抗人乙肝病毒(乙肝)异构体。此外， (-)-L-BCH-189的毒性明显低于(+)-D- BCH-189。(-)-L-BCH-189具有较强的抗乙肝病毒活性 基于(+)-D-BCH-189对 脱氧胞苷脱氨酶在(-)-L-BCH-189中完全脱氨 在类似条件下对脱氨酶有抵抗力。因此，这一点 应用程序建议扩展这一令人兴奋的初步发现 合成硫杂环己烷L的各种嘧啶和嘌呤类似物- 全面构效关系研究中的核苷 抗乙肝病毒。此外，还研究了二氧杂环己烷L的不对称合成。 核苷及其C-核苷类似物将被合成。 合成的化合物的体外抗病毒活性 在从HepG2细胞衍生的2.2.15细胞中进行评估 用含有乙肝病毒的质粒组进行转基因。另外，生化方面， 分子生物学和毒理学(体外)研究将 与(-)-L-BCH-189以及其他有希望的药物一起执行 候选人。此外，与国家研究所合作 变态反应和传染病，一个很有前途的候选药物 将在体土拨鼠研究乙肝模型，以评估其抗-HBs 乙肝病毒以及毒性。这个应用程序的长期目标是 发现和开发临床有效、安全的抗病毒药物 对于目前缺乏的乙肝病毒，尽管存在巨大的问题 世界。

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.