NEW APPROACH TO ANTIVIRAL NUCLEOSIDE ANALOGUES

抗病毒核苷类似物的新方法

• 批准号: 3777950
• 负责人: PETER SCHEINER
• 金额: --
• 依托单位: YORK COLLEGE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3777950
• 关键词: antiAIDS agent; antiviral agents; chemical addition; chemical structure; 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

Although certain 9-cyclohexylpurines exhibit biological activity, antiviral ring-expanded carbocyclic nucleoside analogs have not been reported. The antiviral activity of cyclobutane derivatives (cyclobut-A,G) suggests ring- size as an important variable. To examine this hypothesis, 6-membered unsaturated nucleoside analogs will be stereo-specifically synthesized and evaluated for antiviral activity. These compounds are homologs of carbovir, a promising carbocyclic anti-HIV agent. Cis and trans 4- hydroxymethyl and 4-hydroxy derivatives will be prepared to assess N1-OH spacing, conformation and 1o vs 2o hydroxyl functionality. Four bases will be used: guanine, adenine, 2-amino-6-chloropurine and thymine. Saturated and unsaturated 3-substituted ring-expanded carbocyclics will also be synthesized. The stereospecific methods employed should be generally useful for nucleoside synthesis. Thus nucleophilic ring-opening of 1,2- anhydro sugars will be examined, and novel isonucleosides will be obtained from available epoxides. Enzymatic kinetic resolution techniques will be applied to racemic products to develop practical general procedures for the preparation of enantiomerically pure nucleoside analogs. New products will be screened for antiviral activity.

尽管某些9-环己基嘌呤表现出生物学活性，但抗病毒 尚未报道环环核苷核苷类似物。 这 环丁烷衍生物（Cyclobut-A，G）的抗病毒活性表明环 大小是重要的变量。 为了审查这一假设，六位元素 不饱和核苷类似物将被立体特定合成，并 评估抗病毒活性。 这些化合物是 Carbovir，一种有前途的碳环抗HIV剂。 顺式和反式4- 羟甲基和4-羟基衍生物将准备评估N1-OH 间距，构象和1O vs 2O羟基功能。 四个基地 使用：鸟嘌呤，腺嘌呤，2-氨基-6-氯吡啶和胸腺素。 饱和 和不饱和的三取代环的碳细胞也将是 合成。 采用的立体特定方法通常应该是 用于核苷合成。 因此1,2-的亲核环开放 将检查链酸糖，并将获得新型的异核苷 来自可用的环氧化物。 酶促分辨率技术将是 应用于外围产品，以制定实用的一般程序 制备对映体纯核苷类似物的制备。 新产品将 筛选抗病毒活性。