DEOXY NUCLEOSIDE ANALOGS AS POTENTIAL ANTIVIRAL AGENTS

脱氧核苷类似物作为潜在的抗病毒剂

• 批准号: 2064982
• 负责人: TAI-SHUN LIN
• 金额: $ 18.49万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-03-01 至 1996-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2064982
• 关键词: antiAIDS agent; antiviral agents; cytomegalovirus; cytosine arabinoside; drug design /synthesis /production; drug screening /evaluation; hepatitis B virus group; human immunodeficiency virus 1; mass spectrometry; nuclear magnetic resonance spectroscopy; nucleoside analog; tissue /cell culture; ultraviolet spectrometry

DESCRIPTION: (Adapted from Applicant's Abstract). This investigation has as its goal, the design, synthesis and biological evaluation of a series of thionucleoside analogs of oxetanocin (OXT-A) and other related compounds as potential antiviral, particularly anti-HIV-1, anti-CMV, and anti-HBV agents. If these analogs are phosphorylated by cellular kinases to the respective nucleotides, which have the ability to interfere selectively with the viral or cancer DNA synthesis or being incorporated into DNA, then they could become useful antiviral and/or anticancer agents for chemotherapy. In addition, several 4,6-diamino-5- nitropyrimidine nucleoside analogs of oxetanocin will be synthesized and biologically evaluated in vitro for their activity against HIV, HBV, CMV, and other viruses. In these compounds, the 4,6-diamino-5-nitropyrimidine mimics the adenine base in oxetanocin. Various natural and synthetic cytosine nucleosides such as 1-B-D-arabinofuranosylcytosine (ara-C) and 1-(2-fluoro-2-deoxy-Beta-D-arabinofuranosyl)-5-iodocytosine (FIAC) have been shown to possess potent anticancer and antiviral activity, respectively. However, many of these biologically active cytosine nucleosides either have a therapeutic index that is too low for human use or their anticancer and/or antiviral efficacies are diminished by their susceptibility to rapid deamination to inactive uracil nucleoside analogs. In order to circumvent these problems, the investigators propose to synthesize and evaluate a series of 2'-ethynyl, 2'-ethenyl, 2'-hydroxymethyl, 2'-fluoromethyl, 2'-azidomethyl, and 2'-aminomethyl analogs of ara-C and related compounds. These compounds will be screened primarily for anticancer activity. However, those compounds in this series, found to be non-cytotoxic or much less toxic than ara-C will be tested and developed as potential antiviral agents. The approaches to be employed in this proposal include the development of methodology for the synthesis of these nucleoside analogs, their characterization by NMR, mass spectrum, UV, and other spectroscopic techniques, and the determination of their biological and biochemical effects.

描述：（改编自申请人摘要）。 这次调查 其目标是设计、合成和生物学评价一种 一系列氧杂环丁烷（OXT-A）的硫代糖苷类似物和其它相关的 作为潜在抗病毒剂的化合物，特别是抗HIV-1、抗CMV和 抗HBV药物。如果这些类似物被细胞激酶磷酸化 与相应的核苷酸结合，这些核苷酸能够干扰 选择性地与病毒或癌症DNA合成或被掺入 转化为DNA，那么它们就可以成为有用的抗病毒和/或抗癌药物， 用于化疗的药剂。 此外，几个4，6-二氨基-5- 将合成氧杂环丁烷的硝基嘧啶核苷类似物， 在体外生物学评价它们对HIV、HBV、CMV的活性， 和其他病毒。 在这些化合物中，4，6-二氨基-5-硝基嘧啶 模拟氧杂环丁烷中的腺嘌呤碱基。 各种天然和合成 胞嘧啶核苷如1-B-D-阿拉伯呋喃糖基胞嘧啶（ara-C）和 1-（2-氟-2-脱氧-β-D-阿拉伯呋喃糖基）-5-碘胞嘧啶（FIAC）具有 已显示具有有效的抗癌和抗病毒活性， 分别然而，这些生物活性胞嘧啶中的许多 核苷的治疗指数对于人类使用来说太低 或者它们的抗癌和/或抗病毒功效被它们的 对无活性尿嘧啶核苷快速脱氨敏感性 类似物 为了解决这些问题，研究人员 建议合成并评价一系列2 '-乙炔基、2'-乙烯基， 2'-羟甲基、2'-氟甲基、2'-叠氮基甲基和2'-氨基甲基 阿糖胞苷类似物和相关化合物。 这些化合物将被筛选 主要用于抗癌活性。 然而，这些化合物在这 系列，发现无细胞毒性或毒性远低于阿糖胞苷 作为潜在的抗病毒药物进行了测试和开发。 的途径 包括制定方法， 这些核苷类似物的合成，它们的核磁共振表征， 质谱、紫外线和其他光谱技术，以及 确定其生物学和生物化学效应。