FAT AND SLIM NUCLEOSIDES AND NUCLEOTIDES

脂肪和细长的核苷和核苷酸

• 批准号: 2443252
• 负责人: Ramachandra S Hosmane
• 金额: $ 23.1万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE COUNTY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-07-15 至 1999-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2443252
• 关键词: adenosine deaminase; aminohydrolases; antiAIDS agent; antineoplastics; antiviral agents; chemical structure; conformation; drug design /synthesis /production; enzyme inhibitors; heterocyclic compounds; murine leukemia virus; nucleic acid structure; nucleoside analog; nucleosides; nucleotide analog; phosphorylases

Synthesis, chemistry and biochemistry of a family of "fat" nucleosides and nucleotides possessing the following 5:7-fused heterocyclic base systems will be studied: I) imidazo(4,5,e)(1,3,4)triazepine; II) imidazo(4,5-e)(1,4)diazepine; and III) imidazo(4,5,d)(1,3)diazepine. The novel rearrangement discovered in the heterocyclic system of category I will be further explored for wide synthetic utility. The mono- and diphosphate derivatives of nucleosides of category II will be prepared. The diphosphates will be polymerized by using the enzyme polynucleotide phosphorylase and the resulting homopolymer templates will be evaluated for substrate/inhibitory activity against Moloney murine leukemia virus (M-MuLV) reverse transcriptase. These studies will be extended to "fat" nucleoside/nucleotide systems of categories I & III. The target and intermediate nucleosides and heterocycles will be screened for potential antitumor activity by the National Cancer Institute. The ongoing collaborative arrangements with Professor E. De Clercq of Katholieke University, Leuven, Belgium will enable testing of the above compounds for antiviral activity in a broad range of viral assay systems. Preliminary studies on the 5:8-fused heterocylic systems will be continued. As a secondary goal, double helical complexes will be prepared by pairing the above "fat" nucleotide homopolymers with appropriate pyrimidine counterparts, and investigated for stability, stacking interactions and conformational characteristics.

一类“脂肪”的合成、化学和生物化学 具有以下5：7-融合的核苷和核苷酸 杂环碱体系将被研究：i) 咪唑并(4，5，e)(1，3，4)三氮卓； 和iii)咪唑(4，5，d)(1，3)二氮杂卓。新奇的改编 在第一类杂环系统中发现的将进一步 探索了广泛的合成用途。一磷酸和二磷酸 将制备第二类核苷的衍生物。这个 二磷酸盐将通过使用该酶进行聚合 多核苷酸磷酸化酶及其均聚物 将评估模板的底物/抑制活性 抗Moloney鼠白血病病毒(M-MuLV)逆转 转录酶。这些研究将扩展到“胖”。 第一类和第三类核苷/核苷酸系统：靶标 和中间体核苷和杂环将被筛选 国家癌症研究所潜在的抗肿瘤活性。 与E.de教授正在进行的合作安排 比利时鲁汶Katholieke大学的Clercq将启用 上述化合物的广泛的抗病毒活性测试 一系列病毒检测系统。5：8熔断器的初步研究 杂环系统将继续存在。作为次要目标， 将上述物质配对，制备双螺旋络合物 含有适量嘧啶的“脂肪”核苷酸均聚体 并对稳定性、堆叠相互作用进行了研究 和构象特征。