The objective of the proposed research will be to synthesize certain bicyclic diazolo[1,3]oxazine nucleosides from the appropriate monocyclic nucleosides. This study will provide analogs of the naturally occurring nucleosides (inosine, adenosine, guanosine and xanthosine), which will then be tested as substrates and/or inhibitors of the enzymes adenosine deaminase (ADase), adenosine kinase, purine nucleoside phosphorylase (PNPase), and hypoxanthine-guanine phosphoribosyltransferase (HGPRTase). Additional derivatives will be synthesized as deemed necessary in order to establish a structure activity relationship. Physico-chemical studies involving tautomeric forms, pKa's, etc., will be undertaken in efforts to correlate some of these factors with their biological and chemotherapeutic activity. These nucleosides will also be evaluated as anticancer agents both in vitro (in house) and in vivo (NCI). Studies will also be conducted in order to determine if these nucleosides are acting as purine-like compounds, pyrimidine-like compounds or perhaps as a pro-drug of the monocyclic nucleosides which we will be using as our starting materials.
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