DESIGN OF NEW NUCLEOSIDES BASED ON ENZYME SPECIFICITIES

基于酶特异性的新核苷设计

• 批准号: 6563806
• 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/6563806
• 关键词: X ray crystallography; alcohol phosphotransferase; antineoplastics; biotechnology; carbohydrate analog; chemical structure function; chemical substitution; chemical synthesis; computer simulation; crystallization; cytotoxicity; deoxycytidine; drug design /synthesis /production; drug metabolism; enzyme induction /repression; enzyme inhibitors; enzyme mechanism; molecular dynamics; molecular site; neoplasm /cancer pharmacology; nucleoside analog; nucleoside monophosphate; nucleoside triphosphate; prodrugs; purine /pyrimidine metabolism; structural biology

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. Most nucleosides require activation to the monophosphate level by one or more cellular kinases, followed by further activation to the triphosphate level prior to exerting their cytotoxic effects. We propose to continue our focused program of obtaining new structure-activity relationship (SAR) information on these key enzymes as we pursue new anticancer agents. Our initial targets are a series of nucleosides, both purine and pyrimidine, that have variously altered carbohydrate moieties. Building on knowledge derived from our laboratory and others, our first targets will include mainly new 4'-substituted nucleosides. A series of 3'-ethynyl- substituted nucleosides are also proposed as initial targets. Newly synthesized nucleosides will be evaluated in vitro in Project 3 and in Core B for their cytotoxic effects. In parallel, compounds will be sent to the laboratories of our collaborators, Drs. Staffan Eriksson and Donna Shewach, to determine their behavior with the cellular kinases that are responsible for initial metabolism of nucleosides. Compounds that exhibit significant cytotoxicity in our cell lines 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. Our data as well as that supplied from Drs. Eriksson and Shewach will be utilized as described 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 any triphosphates of inactive nucleosides, will be prepared through Core A. Depending upon the results from these compounds, we will focus on certain directions, or expand our targets based upon SAR to date. A key addition to this project is structural biology. Dr. Steven Ealick formally joins the project with an initial goal of obtaining structures for complexes of deoxycytidine kinase with phosphate donors and substrate/ inhibitors. As we obtain active site information, we will be able to apply all of that information to the design of new molecules, or to the modification of existing ones.

申请人的描述（由申请人提供）的长期目标， 项目继续是开发新的治疗药物， 人类癌症 大多数核苷需要活化到单磷酸水平 通过一种或多种细胞激酶，然后进一步激活 在发挥其细胞毒性作用之前， 我们建议 继续我们的重点项目，获得新的结构-活性关系 (SAR)这些关键酶的信息，因为我们追求新的抗癌药物。 我们最初的目标是一系列核苷，包括嘌呤和嘧啶， 它们的碳水化合物部分发生了不同的变化。 以知识为基础 从我们的实验室和其他地方得出，我们的第一个目标将主要包括 新的4 '-取代核苷。 一系列3 '-乙炔基取代的 还提出核苷作为初始靶。 新合成 将在项目3和核心B中对核苷进行体外评价， 细胞毒性作用。 与此同时，化合物将被送往实验室， 我们的合作者，斯塔凡埃里克森博士和唐娜Shewach，以确定他们的 与负责初始代谢的细胞激酶的行为 的核苷。在我们的细胞中表现出显著细胞毒性的化合物 然后在动物模型中检查细胞系的抗癌活性 核心B中的系统。 任何在体内具有抗癌活性的化合物，或 具有其他特别感兴趣的属性，将对其进行评估， 项目3的作用机制。 我们的数据以及博士提供的数据。 Eriksson和Shewach将按照药物设计所述使用， 开发流程图包括在此。 大量的中间体或 生物学评价所需的最终产品，以及任何 无活性核苷的三磷酸将通过核心A制备。 根据这些化合物的结果，我们将重点关注某些 方向，或扩大我们的目标的基础上SAR的日期。 这个项目的一个关键补充是结构生物学。史蒂文·伊里克博士 正式加入该项目，其最初目标是获得 脱氧胞苷激酶与磷酸供体和底物的复合物 抑制剂的当我们获得活跃的网站信息，我们将能够应用所有 将这些信息用于新分子的设计或修饰 现有的。