NUCLEOSIDES WITH ALTERED METABOLISM

该项目的长期目标仍然是开发新的代理商 用于治疗人类癌症。为此，一些类似的例子 具有生物活性的嘌呤和嘧啶核苷的结构 将设计并加入改变其新陈代谢的功能 合成的。将对这些新化合物的活性进行评估 在体外和在适当的情况下，使用决策网络 在拨款中列明。令人感兴趣的化合物将是 更详细地研究，以获得关于它们的机制的信息 行动。要制备的化合物包括在 碳水化合物，在氮基和两个部分中。我们计划 集中在嘌呤，地氮嘌呤，和某些8-氮杂嘌呤。这个 我们感兴趣的碳水化合物部分是2-脱氧-2- 氟阿拉伯呋喃糖和4-硫代呋喃糖。沿着这些路线的努力 将是该项目合成有机成分的主要推动力。 此外，我们将研究某些可能的用途 我们以前制备的核苷，但没有代谢 到细胞中的磷酸盐衍生物。这项工作将从获取 检测这些化合物的三磷酸盐对各种分离物的作用 酵素。我们还将致力于合成某些非常具体的类型 单磷酸盐类似物和前药。重点将放在三酯上 5‘-核苷酸和5’-磷酸甲氧基类似物的衍生物 已经被证明可以穿透细胞膜。这个项目将 产生大量关于嘌呤活性部位的信息- 嘧啶代谢酶及其结合方式的研究 地点，主要是由于结构变化对底物的影响 具体细节。

The long-term goal of this project remains the development of new agents for the treatment of human cancers. Toward that end, a number of analogs of biologically active purine and pyrimidine nucleosides with structural features incorporated to alter their metabolism will be designed and synthesized. These new compounds will be evaluated for their activities both in vitro and, when appropriate, in vivo, using the decision network set forth within the grant. Compounds of considerable interest will be examined in greater detail to gain information about their mechanisms of action. Compounds to be prepared include series that are modified in the carbohydrate, in the nitrogen base, and in both moieties. We plan to concentrate on purines, deazapurines, and certain 8-azapurines. The carbohydrate moieties we are interested in ar the 2-deoxy-2- fluoroarabinofuranose and the 4-thiofuranose. Efforts along these lines will be the main thrust of the synthetic organic component of the project. In addition, we will be looking into the possible utility of certain nucleosides that we have prepared previously, but which are not metabolized to phosphate derivatives in cells. This work will begin by obtaining the examining the triphosphates of these compounds against various isolated enzymes. We will also pursue the synthesis of certain very specific types of monophosphate analogs and prodrugs. The focus will be on triester derivatives of 5'-nucleotides and 5'-phosphonomethoxy analogs of the type that have been shown to penetrate cell membranes. This project will generate a great deal of information about the actives sites of purine- pyrimidine metabolizing enzymes and about the modes of binding to these sites, primarily from the effect of structural alterations on substrate specificities.