The objective of the proposed research will be to provide a biochemical basis for the rational synthetic design of potentially active chemotherapeutic pyrimidine, pyrimidine-like heterocycles and the corresponding nucleosides. Evaluation of in vitro cytotoxicity will be accomplished for all compounds synthesized on our NIH grants. We also propose to study the effects on cellular pyrimidine metabolism as well as DNA and RNA synthesis for specific compounds (this will initially include some compounds which have been previously synthesized in our laboratory) of interest as based on the preliminary screens (in vitro (our laboratory) and in vivo (NCI evaluation)). Elucidation of the structural and physicochemical requirements for substrate activity of uridine-cytidine kinase, nucleoside phosphorylases, and deaminases will be studied. Using the series of related compounds available from the synthetic program, and considering the studies on the reversal of in vitro cytotoxicity and cellular metabolic effects, by naturally occurring nucleosides, it may be possible to gain some insight into which metabolic effects are required for chemotherapeutic activity.