MECHANISM OF ACTION OF NUCLEOSIDE ANALOGS

申请人的描述（由申请人提供）的总体目标 该项目的目的是设计和合成新的药物，用于治疗 癌 本“核苷类似物的作用机制”的目的是 进行实验，以表征新的生物化学药理学 将在项目2和4中合成的化合物。 的信息 将获得有关这些化合物的作用机制是至关重要的， 这些化合物作为抗癌剂的合理开发。 在 此外，这些信息将提供给有机化学家， 在定期小组会议期间，项目2和4将用于合理性分析 设计新的代理人。 该项目有三个具体目标。 在第一个目标中， 将评估所有化合物对CEM细胞的毒性，以鉴定活性和 不活跃的特工 在第二个目标中，我们将进行生物化学实验， 选择的化合物，以获得其机制的初步了解 行动上 在第三个目标中，我们将对化合物进行广泛的研究， 需要更彻底的评估 计划进行研究，以表征 详细介绍了2种药物的作用机制，这些药物在 体内抗肿瘤活性，4 '-硫代-阿拉伯呋喃糖基胞嘧啶和 2-Cl-2 '-F-2'-脱氧-阿拉伯呋喃糖基腺嘌呤（氯法拉滨）。 这些研究 应导致全面了解新的作用机制， 通过确定这些化合物 与现有的抗癌药物不同。

APPLICANT'S DESCRIPTION (provided by Applicant) The overall goal of the program project is to design and synthesize new drugs for the treatment of cancer. The goal of this "Mechanism of action of nucleoside analogs" is to perform experiments to characterize the biochemical pharmacology of the new compounds that will be synthesized in projects 2 and 4. The information that will be gained about the mechanism of action of these compounds is vital to the rational development of these compounds as anticancer agents. In addition, this information will be provided to the organic chemists in projects 2 and 4 during regular group meetings to be used in the rational design of new agents. This project has 3 specific aims. In the first aim we will evaluate all compounds for toxicity to CEM cells to identify active and inactive agents. In the second aim we will perform biochemical experiments on selected compounds to gain a preliminary understanding of their mechanism of action. In the third aim, we will perform extensive studies on compounds that warrant a more thorough evaluation. Studies are planned to characterize in detail the mechanism of action of 2 agents that have demonstrated excellent in vivo antitumor activity, 4'-thio-arabinofuranosylcytosine and 2-Cl-2'-F-2'-deoxy- arabinofuranosyladenine (Clofarabine). These studies should lead to a comprehensive understanding of the mechanism of action of new agents that will aid in their development by determining how these compounds differ form existing anticancer drugs.