RING EXPANDED 1,3-DIHETERO NUCLEOSIDES

扩环 1,3-二杂核苷

• 批准号: 6240120
• 负责人: PETER SCHEINER
• 金额: $ 22.52万
• 依托单位: YORK COLLEGE
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-06-01 至 1998-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6240120
• 关键词: Herpesviridae disease; antiAIDS agent; antiviral agents; chemical addition; chemical structure function; chemical substitution; chromatography; drug design /synthesis /production; drug screening /evaluation; enzyme activity; heterocyclic compounds; hydroxyl group; infrared spectrometry; nuclear magnetic resonance spectroscopy; nucleoside analog; stereochemistry; stoichiometry; thin layer chromatography

The antiviral (HIV, HBV) properties of the unnatural L-nucleoside analogs e.g. Dioxolane-T, 3TC, FTC, as well as their remarkably low cytotoxicities, are well established. Unfortunately, the rapid onset of high-level HIV drug resistance associated with the L-enantiomers (but not with the more cytotoxic D-family) nullifies the effectiveness of these drugs. Ring- expanded 1,3-dihetero nucleoside analogs, athe higher homologs of the 'unnatural' compounds, incorporate structural features of potential importance in the design of new antiviral agents. The synthesis of these compounds will be undertaken and their biological properties investigated. Appropriate placement of heteroatoms (O,S) can provide conformational control and allow-access to 6-membered nucleosides possessing axial heterobases. Resembling natural beta-nucleosides, this conformation is favorable for kinase-mediated 5'-phosphorylation. Achiral cis-1,3-dihetero nucleosides should be a non--cytotoxic due to lack of recognition by host cell enzymes. But, like their lower homologs, they may well be potent RT inhibitors. Furthermore, their symmetry properties suggest a structure- based method to avoid the rapid drug resistance associated with the l- family. To examine these possibilities and to provide new structure-activity correlations, three series of nucleosides will be synthesized; 1,3- dioxanes, 1,3-dithianes, and 1,3-oxathianes. The compounds will be obtained starting from glycerol or 3-mercapto-1,2-propanediol, utilizing Mitsunobu-type alkylation. Asymmetric synthesis will used in athe 1,3- oxathiane series. Configurations and conformations will be established by NMR techniques. The compounds will be collaboratively screened for activity against HIV, herpes and HBV and, if warranted, for drug resistance.

非天然L-核苷类似物的抗病毒（HIV，HBV）特性 例如二氧烷-T，3TC，FTC及其细胞毒性非常低， 建立得很好。 不幸的是，高级艾滋病毒的快速发作 与L-替代物相关的耐药性（但没有更多 细胞毒性D-家庭无效这些药物的有效性。 戒指- 扩展的1,3-二核苷类似物，较高的同源物 “不自然”化合物，结合了潜力的结构特征 在新的抗病毒剂设计中的重要性。 这些的综合 将进行化合物，并研究其生物学特性。 适当放置杂原子（O，S）可以提供构象 对照和允许到具有轴向的6元核苷 异酶。 类似于天然β-核苷，这种构象是 有利于激酶介导的5'-磷酸化。 Achiral cis-1,3-dihetero 由于宿主缺乏识别，核苷应该是一种非胞毒性 细胞酶。 但是，像他们的同源物一样，它们很可能是有效的RT 抑制剂。 此外，它们的对称特性表明结构 基于避免与L-相关的快速耐药性的方法 家庭。 检查这些可能性并提供新的结构活动 相关性，将合成三个系列核苷。 1,3- 二恶英，1,3-迪西亚人和1,3-氧化氢。 化合物将是 从甘油或3-甲基-1,2-丙二醇开始，利用 Mitsunobu型烷基化。 不对称合成将在1,3-中使用 奥马斯蒂安系列。 配置和构象将由 NMR技术。 这些化合物将进行协作筛选 针对艾滋病毒，疱疹和HBV的活动，如果有必要进行毒品 反抗。