DEOXYNUCLEOSIDE ANALOGS AS POTENTIAL ANTIVIRAL AGENTS

描述：(改编自申请人摘要)。这项调查 它的目标是设计、合成和生物评价一种 奥沙诺星(Oxetanocin)的硫代核苷类似物(oxt-A)及其他相关化合物 化合物作为潜在的抗病毒，特别是抗HIV-1，抗CMV，和 抗乙肝药物。如果这些类似物被细胞激酶磷酸化 与各自的核苷酸结合，这些核苷酸有能力干扰 选择性地与病毒或癌症的DNA合成或被结合 转化成DNA，然后它们就可以成为有用的抗病毒和/或抗癌药物 化疗药物。此外，几种4，6-二氨基-5- 将合成奥昔洛星的硝基嘧啶核苷类似物，并 体外生物活性评价其抗艾滋病毒，乙肝病毒，巨细胞病毒， 和其他病毒。在这些化合物中，4，6-二氨基-5-硝基嘧啶 模仿奥昔洛星中的腺嘌呤碱基。各种天然的和合成的 胞嘧啶核苷，如1-B-D-阿拉伯呋喃核苷(Ara-C)和 菲亚特(1-(2-fluoro-2-deoxy-Beta-D-arabinofuranosyl)-5-iodocytosine)拥有 已被证明具有强大的抗癌和抗病毒活性， 分别进行了分析。然而，其中许多具有生物活性的胞嘧啶 核苷的治疗指数要么太低，不适合人类使用 或者它们的抗癌和/或抗病毒效果会因为它们的 对灭活的尿嘧啶核苷的快速脱氨敏感性 类比。为了绕过这些问题，调查人员 建议合成并鉴定一系列2‘-乙炔基，2’-乙烯基， 2‘-羟甲基、2’-氟甲基、2‘-叠氮甲基和2’-氨基甲基 Ara-C的类似物和相关化合物。这些化合物将被筛选出来 主要用于抗癌活性。然而，这种化合物中的那些化合物 系列，被发现没有细胞毒性或比Ara-C毒性小得多 作为潜在的抗病毒药物进行了测试和开发。解决问题的方法 将在本提案中采用的方法包括制定 这些核苷类似物的合成，其核磁共振表征， 质谱学、紫外光和其他光谱技术，以及 它们的生物和生化效应的测定。

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.