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.
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