Synthesis of 3′(2′)-O-Lysophosphatidylnucleosides − a Further Application of a Chemoenzymatic Strategy

Abstract

Mono[(2R)-2,3-dihydropropyl] esters of the four 3Ј-nucleotides of DNA, prepared from protected nucleoside phosphoramidites and [(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methanol, were regioselectively acylated at the C-1 hydroxyl of the glycerol moiety by a lipase-catalyzed transacylation with activated palmitic acid ester in organic solvent, giving the relevant 3Ј-O-lysophosphatidyl-2Ј-deoxynucleosides. The synthesis was also adapted for the preparation of 3Ј-O-lyso-

Synthesis of Very Short Chain Lysophosphatidyloligodeoxynucleotides

“…The above mild acid treatment had been set up in our previous work ( , ) to remove the isopropylidene ketal protecting group from the glycerol moiety of various glycerophosphorylnucleosides. The removal of this protecting group is commonly accomplished by using 80% AcOH at room-temperature overnight, but depurination may occur under these conditions.…”

“…The enzymatic synthesis and the purification of the title compounds were accomplished following the optimized experimental conditions reported in our previous work (10). Each 5′-GPOdN (25 µmol) was first converted into the relevant TBA salt by passing it through a column of Dowex-50 W (TBA + form).…”

“…In a subsequent step, selective acylation at 1-OH of the glycerol moiety of GPNs was achieved by a lipase-catalyzed (Lipozyme) transacylation with activated fatty acid esters in organic solvent. By this procedure, lysophosphatidyl derivatives of pharmacologically active nucleoside analogues were also prepared, which showed a clearly enhanced ability to penetrate model lipid monolayers over that of free nucleoside counterparts (10).…”

“…In our previous work ( , ) we developed a general synthetic preparation of 5‘(3‘ or 2‘)- O -lysophosphatidyl conjugates of deoxyribo- and ribonucleosides as well. Following a two-step chemoenzymatic strategy, mono[(2 R )-2,3-dihydroxypropyl] esters of the pertinent 5‘(3‘ or 2‘)-mononucleotides (glycerophosphorylnucleosides, GPNs) were first prepared by opportunely applying the phosphoramidite chemistry on solid phase or in solution.…”