Chemoenzymatic Synthesis of Lysophosphatidylnucleosides

Abstract

5‘- O -Lysophosphatidylnucleosides [5‘- O -(1- O -acyl- sn -glycero-3-phosphoryl)nucleosides] were obtained by a two-step chemoenzymatic synthesis. 5‘- O -( sn -Glycero-3-phosphoryl)nucleosides (5‘-GPNs) were first prepared from a phosphoramidite of 1,2- O -isopropylidene- sn -glycerol and appropriately protected nucleosides, applying the phosphoramidite methodology on the solid phase or in solution. In a following step, the regioselective acylation at the C-1 hydroxyl of the glycerol moiety of 5‘-GPNs was achieved by a lipase-catalyzed transacylation with activated fatty acid esters in organic solvent. Some deoxyribo- and ribonucleosides, as well, were converted into the corresponding lysophosphatidyl derivatives utilizing either saturated or unsaturated fatty acid esters with different length alkyl chains. The synthesis was also applied to the preparation of O -(1- O -palmitoyl- sn -glycero-3-phosphoryl) conjugates of Acyclovir and AZT, of potential pharmacological interest.