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

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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.