This grant will 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.Commercial ApplicationsL sugar nucleosides and nucleotides have potential application as anticancer, antiviral and antiparasitic agents. Since L sugar compounds are metabolized differently from the natural D series, derivatives of L sugars offer the promise of being more selective and/or less toxic as therapeutic agents. Such drugs against cancer, viral and parasitic diseases have tremendous commercial potential.National Cancer Institute (NCI)
