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.

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

“…To achieve the preparation of 3′‐ O ‐lysophosphatidylnucleosides we planned to follow the same two‐step chemoenzymatic strategy as previously used for the preparation of 5′‐ O ‐lysophosphatidylnucleosides 1. Therefore, mono[(2 R )2,3‐dihydroxypropyl] esters of 3′‐nucleotides (3′‐GPNs) had to be prepared first, possibly with modification of the chemical step.…”

“…It has been reported that various lipases (including Lipozyme) in organic solvents in the presence of substrates bearing different kinds of alcoholic functions preferentially acylate the primary ones 4,5. Thus, in the case of 5′‐GPdNs,1 bearing only one primary and two secondary hydroxyls, it had not been surprising to find that the enzyme had been able to acylate the primary hydroxyl of the glycerol moiety selectively. In 3′‐GPdNs there are two primary hydroxyls − both, in principle, susceptible to enzymatic acylation − present in the molecule, in addition to a secondary hydroxyl.…”

“…Commercially purchased solvents and reagents were all of reagent quality. Triethylamine (TEA), petroleum ether, t BuOH, dichloromethane, and diethyl ether were freshly dried and stored under argon as previously reported 1. TFEP was prepared by a reported procedure,15 and its purity was checked by its chromatographic and spectroscopic properties.…”

“…The constant quest to produce biologically active compounds with ever better capabilities to interact with cell membranes has recently encouraged us to develop a general synthetic preparation of 5′‐ O ‐lysophosphatidyl conjugates of nucleosides, some of these being nucleoside analogues of pharmacological interest 1. The basic idea behind this approach is that lipophilic moieties conjugated to nucleosides may significantly enhance the cellular uptake of these polar molecules, as a consequence of the affinity of the lipophilic moieties for membrane structures.…”

Chemoenzymatic synthesis, characterization, and controlled release of functional polymeric prodrugs with acyclovir as pendant

“…Acyclovir (9‐(2‐hydroxyethoxymethyl)guanine) is an acyclic nucleoside analogue that has shown a potent antiviral activity, and it is known to inhibit the replication of herpes viruses and hepatitis B virus 18–20. However, acyclovir has rather short plasma half‐life (about 2–3 h in adults without renal impairment) and limited selectivity 21, 22.…”