SYNTHESIS & BIOLOGICAL EVALUATION OF ANTI-HIV NUCLEOSIDE

在过去的五年里，我们已经合成了200多个新的核苷 类似物 Emory的Raymond Schinazi博士进行的生物学评价 大学/VA医学中心建议，几种靶向化合物 在人淋巴细胞中具有强效和选择性抗HIV-1活性。 从 通过这些努力，我们已经鉴定出至少六种有希望的化合物。 这些 包括3 ′-叠氮基-2 ′，3 ′-双脱氧尿苷（AzddU、AZDU或CS-87）、3 ′-叠氮基- 2 '，3'-二脱氧-5-甲基胞嘧啶（AZMdC），N6-Me-ddA，N6-甲基-2 '-F-ddA，3'- 脱氧-3 '-氟-5-甲基胞嘧啶和9-β-（2，3-二脱氧呋喃核糖基）-6-甲基胞嘧啶。 氯嘌呤（6-CI-P）。 在这些核苷中，AZdU已经经历了 艾滋病患者的临床试验和艾滋病相关综合征。 为了 以确定其他核苷的有用性，生化， 药理学和毒理学研究正在进行中。 我们计划继续探索3 '- 叠氮基-2 '，3'-二脱氧-2 '，3'-二脱氧-和2 '，3'-二氮基-2 '，3'-二脱氧- 核苷 本实验室发展的立体选择性合成方法 将用于促进合成。 此外，新类别的 抗HIV核苷、BCH-189和二氧戊环-T类似物及其C- 核苷将被合成并作为潜在的抗HIV剂进行评估。 1，3-二氧戊环和1，3-氧硫戊环部分的不对称合成具有 最近我们的团队从手性模板，D-甘露糖， 其可用于与各种杂环部分缩合， 产生对映体纯的核苷。 此外，我们还计划 合成氧杂环辛类似物和三元碳环， 核苷 如果时间允许，具有各种取代基的核苷 核糖环中的杂原子（硫、氧、氮和硒） 将被合成以研究详尽的结构-活性 碳水化合物和杂环部分的关系。 长 本申请长期目标是发现改进的和新的抗HIV 与现有的抗HIV抗体不显示交叉耐药性的核苷 核苷 此外，还将对拟定化合物进行评价 在其它抗病毒筛选系统中，包括HCMV、疱疹、RSV、人 B型肝炎病毒

During the past five years, we have synthesized over 200 new nucleosides analogues. Biological evaluation by Dr. Raymond Schinazi of Emory University/VA Medical Center suggested that several targeted compounds had potent and selective anti-HIV-1 activities in human lymphocytes. From these efforts we have identified at least six promising compounds. These include 3'-azido-2',3'-dideoxyuridine (AzddU, AZDU or CS-87), 3'-azido- 2',3'-dideoxy-5-methylcytosine (AZMdC), N6-Me-ddA, N6-methyl-2'-F-ddA, 3'- deoxy-3'fluoro-5-methylcytosine, and 9-beta-(2,3-dideoxyribofuranosyl)-6- chloropurine (6-CI-P). Among these nucleosides, AZdU has been undergoing clinical trials in patients with AIDS and AIDS-related complex. In order to determine the usefulness of the other nucleosides, biochemical, pharmacological, and toxicological studies are in progress. We plan to continue exploring the structure-activity relationships of 3'- azido-2',3'-dideoxy-,2',3'-dideoxy-and 2',3'-didehydro-2',3'-dideoxy- nucleosides. Stereoselective synthetic methods developed in our laboratory will be used to facilitate the synthesis. Additionally, new classes of anti-HIV nucleosides, BCH-189 and dioxolane-T analogues and their C- nucleosides will be synthesized and evaluated as potential anti-HIV agents. Asymmetric synthesis of 1,3-dioxolane and 1,3-oxothiolane moieties have recently been accomplished by our group from a chiral template, D-mannose, which can be used for condensation with various heterocyclic moieties, resulting in enantiomerically pure nucleosides. Additionally, we also plan to synthesize oxetanocin analogs and three-membered carbocyclic ring nucleosides. If time permits, nucleosides with various substituted heteroatoms (sulfur, oxygen, nitrogen, and selenium) in the ribose ring will be synthesized to study the exhaustive structure-activity relationships of the carbohydrates and heterocyclic moieties. The long term goal of this application is to discover improved and new anti-HIV nucleosides that do not show cross-resistance with the existing anti-HIV nucleosides. Additionally, the proposed compounds will also be evaluated in other anti-viral screening systems including HCMV, herpes, RSV, human hepatitis B virus.