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

该项目的目标是开发一种无毒的核苷前体药物， 有毒的嘌呤碱基类似物，将用于我们的基因方法， 治疗癌症。 具体来说，我们将合成大量的 被E.大肠杆菌嘌呤核苷 磷酸化酶（PNP），但不通过哺乳动物PNP或5 '-甲硫基腺苷 磷酸化酶核苷将基于以下物质的毒性来选择： 形成的碱基，如6-甲基嘌呤和2-氟腺嘌呤，以及 特别是基于碱和 前体核苷。其他输入，以帮助选择将来 从生物学数据和博士实验室的结构工作。 Balick这些核苷将由帕克博士和索尔舍博士在 程序1和2，并由Waud博士在科学的核心， 用于对癌细胞进行体外和体内研究的应用 转染E. coli基因。一些核苷最初 建议将通过公布的程序编制，但其中大多数将 通过良好的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.