NUCLEOSIDES WITH ALTERED METABOLISM

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 为了实现这一目标，一些类似的 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。 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， 感兴趣是2-脱氧-4-硫代呋喃核糖，4-硫代呋喃阿拉伯糖， 2-脱氧-2-氟-阿拉伯呋喃糖和2-脱氧-2-氟-4-氟-阿拉伯呋喃糖。 硫代阿拉伯呋喃糖。 碱基将包括氮杂/脱氮嘌呤和修饰的嘌呤。 嘧啶，包括在C-5或C-6改变的胞嘧啶类似物。 一个主要 该项目的一部分将集中在制备5 -单磷酸 未代谢至单磷酸水平的核苷前药， 但其三磷酸盐，当合成制备时， 活动 用于前药合成的候选化合物将包括现有的 来自以前研究的核苷，以及来自 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中的细胞毒性效应。 化合物表现出 然后将检查其抗癌活性的显着细胞毒性 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，或具有其他特别感兴趣的性质， 在项目3中对其作用机制进行评价。 所有化合物将 应沿着药物设计和开发建议的路线考虑 流程图包括在此。 大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将通过核心A制备。 未来的合成方向将取决于生物反馈， 我们从最初的化合物中得到的。

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.