DESIGN AND SYNTHESIS OF NUCLEOSIDES THAT CAN BE ACTIVATED BY E COLI PNP

该计划的目标是开发一种无毒的核苷前药 有毒的嘌呤类似物，将在我们的基因研究中使用 癌症的治疗。具体地说，我们将合成大量的 被大肠杆菌嘌呤核苷切割的候选核苷 磷酸化酶(PNP)，但不是哺乳动物的PNP或5‘-甲硫基腺苷 磷酸化酶。核苷的选择将基于其毒性。 所形成的碱，如6-甲基嘌呤和2-氟腺嘌呤，以及 特别是基于碱基和碱基之间的毒性差异 前体核苷。将有更多的帮助选择的投入 从生物数据和他在实验室的结构工作中。 巴利克。这些核苷将被Parker博士和Sorscher博士用于 项目1和2，以及Waud博士在该项目的科学核心 在肿瘤细胞体内外研究中的应用 用大肠杆菌基因进行了基因转化。一些核苷最初 提议将由已公布的程序编制，但其中大多数将 通过已有先例路线制备的新化合物。

The goal of this program is to develop a nontoxic nucleoside prodrug of a toxic purine base analog that will be of use in our approach to the gene therapy of cancer. Specifically, we will synthesize quantities of candidate nucleosides that are cleaved by E. coli purine nucleoside phosphorylase (PNP), but not by mammalian PNP or 5'-methylthioadenosine phosphorylase. The nucleosides will be selected based upon the toxicity of the bases that are formed, such as 6-methylpurine and 2-fluoroadenine, and in particular based on the differential in toxicities between the base and the precursor nucleoside. Additional input to aid in selection will come from biological data and from the structural work in the laboratory of Dr. Balick. These nucleosides will be utilized by Drs. Parker and Sorscher in Programs 1 and 2 and by Dr. Waud in the scientific core of this application to carry out in vitro and in vivo studies on cancer cells transfected with the E. coli gene. Some of the nucleosides initially proposed will be prepared by published procedures but most of them will be new compounds prepared by well-precedented routes.