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） 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。 大多数核苷需要激活至单磷酸盐水平 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的三磷酸水平。 我们建议 继续我们获得新的结构-活性关系的重点计划 当我们寻求新的抗癌药物时，有关这些关键酶的（SAR）信息。 我们最初的目标是一系列核苷，包括嘌呤和嘧啶， 具有不同程度改变的碳水化合物部分。 以知识为基础 来自我们的实验室和其他实验室，我们的首要目标将主要包括 新的 4'-取代核苷。 一系列3'-乙炔基取代的 核苷也被提议作为初始目标。 新合成 核苷类药物将在项目 3 和核心 B 中进行体外评估 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，博士。 Staffan Eriksson 和 Donna Shewach 确定了他们的 负责初始代谢的细胞激酶的行为 核苷。在我们的细胞中表现出显着细胞毒性的化合物 然后将在动物模型中检查品系的抗癌活性 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 中的作用机制。我们的数据以及 Drs 提供的数据。 Eriksson 和 Shewach 将按照药物设计和描述的方式使用 本文包含开发流程图。 较大数量的中间体或 生物学评估所需的最终产品以及任何 无活性核苷的三磷酸盐，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，或根据迄今为止的 SAR 扩大我们的目标。 该项目的一个重要补充是结构生物学。史蒂文·埃利克博士 正式加入该项目，最初目标是获得结构 脱氧胞苷激酶与磷酸供体和底物的复合物/ 抑制剂。当我们获得活动站点信息时，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。