NUCLEOSIDES WITH ALTERED METABOLISM

代谢改变的核苷

• 批准号: 6563805
• 负责人: JOHN A SECRIST
• 金额: $ 22.84万
• 依托单位: SOUTHERN RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-01 至 2003-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6563805
• 关键词: DNA replication; antineoplastics; biotechnology; carbohydrate analog; chemical structure function; chemical synthesis; computer simulation; cytosine arabinoside; cytotoxicity; drug design /synthesis /production; drug metabolism; enzyme inhibitors; fludarabine; infrared spectrometry; molecular dynamics; neoplasm /cancer pharmacology; nuclear magnetic resonance spectroscopy; nucleoside analog; nucleoside triphosphate; prodrugs; purine /pyrimidine metabolism; purines; structural biology; thiopurine nucleoside; thiopyrimidine

APPLICANT'S DESCRIPTION (provided by Applicant) The long-term goal of this project continues to be the development of new agents for the treatment of human cancers. In order to achieve that goal, a number of analogs of biologically active purine and pyrimidine nucleosides with structural features incorporated to alter their metabolism will be designed and synthesized. Initial target compounds will include modifications in the carbohydrate moiety and in many cases in the nitrogen base, as well. Initially, carbohydrates of interest will include 2-deoxy-4-thioribofuranose, 4-thioarabinofuranose, 2-deoxy- 2-fluoro- arabinofuranose, and 2-deoxy-2-fluoro-4- thioarabinofuranose. Bases will include both aza/deaza purines and modified pyrimidines, including cytosine analogs altered at either C-5 or C-6. A major portion of this project will focus on the preparation of 5 -monophosphate prodrugs of nucleosides that are not metabolized to the monophosphate level, but whose triphosphates, when prepared synthetically, exhibit worthwhile activity. Candidate compounds for prodrug synthesis will include existing nucleosides from previous research, as well as new nucleosides derived from our ongoing work. Newly synthesized nucleosides will be evaluated in vitro in Project 3 and in Core B for their cytotoxic effects. Compounds that exhibit significant cytotoxicity will then be examined for their anticancer activity in animal model systems in Core B. Any compounds that have anticancer activity in vivo, or that have other properties of particular interest, will be evaluated for their mechanism of action in Project 3. All compounds will be considered along the lines suggested by the drug design and development flow chart included herein. Larger quantities of intermediates or final products that are needed for biological evaluations, as well as the triphosphates of any inactive nucleosides, will be prepared through Core A. Future synthetic directions will be dictated by the biological feedback that we receive from the initial compounds.

申请人的描述（由申请人提供） 本项目的长期目标 项目继续是开发新的治疗药物 人类癌症。 为了实现这一目标，许多类似的 具有结构特征的生物活性嘌呤和嘧啶核苷 将被设计和合成以改变其新陈代谢。 初始目标化合物将包括碳水化合物部分的修饰 在许多情况下，也存在于氮基中。 最初，碳水化合物 兴趣包括2-脱氧-4-呋喃硫代核糖、4-呋喃硫代阿拉伯糖、 2-脱氧-2-氟-阿拉伯呋喃糖和2-脱氧-2-氟-4- 呋喃硫代阿拉伯糖。 碱基将包括氮杂/去氮嘌呤和修饰的 嘧啶，包括在 C-5 或 C-6 处改变的胞嘧啶类似物。 一个专业 该项目的一部分将重点关注5-单磷酸盐的制备 不代谢至单磷酸盐水平的核苷前药， 但其三磷酸盐在合成制备时表现出有价值的 活动。 用于前药合成的候选化合物将包括现有的 先前研究的核苷，以及衍生自的新核苷 我们正在进行的工作。 新合成的核苷将在体外进行评估 项目 3 和核心 B 中的细胞毒性作用。 表现出的化合物 然后将检查其显着的细胞毒性的抗癌活性 在核心 B 的动物模型系统中。任何具有抗癌作用的化合物 体内活性，或具有其他特别令人感兴趣的特性，将 在项目 3 中评估其作用机制。所有化合物将 遵循药物设计和开发建议的思路进行考虑 本文包含流程图。 较大数量的中间体或最终产品 生物学评价所需的产品，以及 任何无活性核苷的三磷酸盐将通过核心 A 制备。 未来的合成方向将由生物反馈决定 我们从最初的化合物中得到。