Chemoenzymatic synthesis of nucleoside prodrugs: dialkylphosphotriesters and phosphatidyl nucleosides

LUCAS DETTORRE; ESTEBAN D. GUDIÑO; LUIS E. IGLESIAS; ELIZABETH S. LEWKOWICZ; ADOLFO M. IRIBARREN

Hamburgo

Congreso; 6th International Congress on Biocatalysis; 2012

Hamburg University of Technology

Nowadays, several commercial antiviral and anticancer drugs are nucleoside analogues. However, these compounds have several desadvantages when administered, they are rapidly catabolised to inactive derivatives, have poor bioavailability and in some cases the first enzymatic phosphorylation necessary to produce the active drug (nucleoside 5’-triphosphate) has been shown to be the rate limiting step in human cells. The modification of nucleosides with several chemical groups can partially avoid these drawbacks producing what is commonly referred to prodrugs, which after administration undergoes enzymatic reactions that produce the parent drug. Among the different procedures that were assayed in our lab are the biocatalysed syntheses of dialkylphosphotriesters and phosphatidyl nucleosides. The regio-selective synthesis of 5’-(3-sn-phophatidyl) nucleosides employing phospholipase D (PLD) as biocatalyst affords, in yields ranging from 52 to 97%, potential prodrugs with a non-toxic carrier moiety which protect the drug from inactivation and have a high affinity for cell membranes. On the other hand, 5’-Dialkylphosphotriesters provides enhanced lipophilicity and also make possible the intracellular release of the parent nucleotide thus skipping the first and more difficult phosphorylation step. The transesterification reaction catalysed by phosphotriesterases (PTE) is carried out in anhydrous solvent and affords the regioselective 5’-derivatives. Different reaction conditions and over-expression of the enzyme are now being analysed.