Alpha/Beta L-Nucleosides--Synthesis & Biological Action

This grant will study the feasibility of developing convenient, cost-effective methods of synthesisfor L-sugar nucleoside and nucleotide analogue chemotherapeutic agents and to investigate theirphosphorylation and uptake by malignant cells in tissue culture. L-sugar-based therapeutic agents havepotential as anticancer, antiviral, and antiparasitic drugs. During Phase I, we will (a) develop pilot scalesynthesis of the L-series sugars L-ribose and L-deoxyribose as the building blocks for L-nucleosides/nucle-otides from a common synthetic precursor L-erythuronolactone; (b) synthesize both the alpha- andbeta-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) andthe 5'-triphosphates; (d) establish tissue culture assays to measure intracellular phosphorylation of thenucleoside in (b) by kinases; and (e) evaluate the in vitro anti-tumor activity of the synthesizedL-nucleosides.