PHOSPHOTRIESTERASE CATALYZED TRANSESTERIFICATION

LUCAS DETTORRE; ELIZABETH LEWKOWICZ; ADOLFO IRIBARREN

PAMPLONA

Congreso; BIOSPAIN2010; 2010

Nucleoside analogs are well known antiviral and anticancer drugs, being the active compounds the corresponding 5?-triphosphate derivatives. The therapeutic potential of nucleosides analogs could be improved by using mononucleotides carrying masked phosphate groups with different functions. This approach may provide two benefits: on one side the enhanced lipophilicity of the parent nucleoside could improve its penetration though the cell membrane and on the other one, this strategy makes possible the liberation of the active nucleotide intracellularly, skipping the first and more difficult phosphorylation step that is carried out by specific kinases. This kind of prodrugs is known as ?pronucleotides?. For example, 5?-monophosphate derivatives of 3-deaza-ddA in the form of dialkyl phosphate triesters have shown anti-HIV activity while the parent nucleoside was inactive. In a first approach to get pronucleotides by means of biocatalyzed reactions, we explored the synthesis of nucleoside dialkyl phosphates through the tansesterification reaction catalyzed by phosphotriesterases. The results obtained using different nucleosides as substrates and some activated phosphotriesters as phosphate donors will be discussed. Reaction conditions such as solvents, nucleoside/phosphate donor ratios and concentrations will be also analyzed.