This Phase I proposal is to study the feasibility of developing convenient, cost-effective methods of synthesis for L-sugar nucleoside and nucleotide analogue chemotherapeutic agents and to investigate their phosphorylation and uptake by malignant cells in tissue culture. L-sugar-based therapeutic agents have potential as anticancer, antiviral, and antiparasitic drugs. During Phase I, we will (a) develop pilot scale synthesis of the L-series sugars L-ribose and L-deoxyribose as the building blocks for L- nucleosides/nucleotides from a common synthetic precursor L- erythuronolactone; (b) synthesize both the alpha- and beta-isomers of the L-ribonucleosides and L-deoxyribonucleosides derived from the bases adenine, cytosine and 5-fluorouracil; (c) synthesize the corresponding 5'- nucleotides of the compounds in (b) and the 5'-triphosphates; (d) establish tissue culture assays to measure intracellular phosphorylation of the nucleoside in (b) by kinases; and (e) evaluate the in vitro anti- tumor activity of the synthesized L-nucleosides.
