NUCLEOSIDES WITH ALTERED METABOLISM

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APPLICANT'S DESCRIPTION (provided by Applicant) The long-term goal of this project continues to be the development of new agents for the treatment of human cancers. In order to achieve that goal, a number of analogs of biologically active purine and pyrimidine nucleosides with structural features incorporated to alter their metabolism will be designed and synthesized. Initial target compounds will include modifications in the carbohydrate moiety and in many cases in the nitrogen base, as well. Initially, carbohydrates of interest will include 2-deoxy-4-thioribofuranose, 4-thioarabinofuranose, 2-deoxy- 2-fluoro- arabinofuranose, and 2-deoxy-2-fluoro-4- thioarabinofuranose. Bases will include both aza/deaza purines and modified pyrimidines, including cytosine analogs altered at either C-5 or C-6. A major portion of this project will focus on the preparation of 5 -monophosphate prodrugs of nucleosides that are not metabolized to the monophosphate level, but whose triphosphates, when prepared synthetically, exhibit worthwhile activity. Candidate compounds for prodrug synthesis will include existing nucleosides from previous research, as well as new nucleosides derived from our ongoing work. Newly synthesized nucleosides will be evaluated in vitro in Project 3 and in Core B for their cytotoxic effects. Compounds that exhibit significant cytotoxicity will then be examined for their anticancer activity in animal model systems in Core B. Any compounds that have anticancer activity in vivo, or that have other properties of particular interest, will be evaluated for their mechanism of action in Project 3. All compounds will be considered along the lines suggested by the drug design and development flow chart included herein. Larger quantities of intermediates or final products that are needed for biological evaluations, as well as the triphosphates of any inactive nucleosides, will be prepared through Core A. Future synthetic directions will be dictated by the biological feedback that we receive from the initial compounds.