Synthesis and biological activity of some unsaturated 6-azauracil acyclonucleosides.

A useful route is described for obtaining Z and E unsaturated alkylating agents 3 and 4. Coupling 6-azauracils 5 and 6 with unsaturated alkylating agent followed by the deprotection with H+ resin gave acyclonucleosides 11-14 in good overall yields. Unsaturated acyclonucleosides phosphonates 19 and 20 were prepared using potassium carbonate as base and 4-bromobut-2-enyl diethyl phosphonate 16 as the alkylating agent.

Synthesis and biological evaluation in human monocyte-derived macrophages of N-(N-acetyl-L-cysteinyl)-S-acetylcysteamine analogues with potent antioxidant and anti-HIV activities.

We synthesized a series of N-(N-acetyl-L-cysteinyl)-S-acetylcysteamine (10) analogues bearing various acyl groups on thiol cysteine or cysteamine residues, to investigate the structure-activity relationship for pro-GSH and anti-HIV properties in human macrophages. The S-substituents were ranked in the following order of efficacy: H > or = acetyl > isobutyryl > pivaloyl > benzoyl. We found that none of these derivatives had pro-GSH or antiviral activities in vitro higher than that of 10, but several displayed similar levels of anti-HIV activity, making them possible candidates for use as adjuvant therapies in conjunction with HAART, for treating neurological aspects of HIV infection.

S-acyl-2-thioethyl phosphoramidate diester derivatives as mononucleotide prodrugs.

The synthesis and in vitro anti-HIV activity of phosphoramidate diester derivatives of 3'-azido-2',3'-dideoxythymidine (AZT) bearing one S-pivaloyl-2-thioethyl (tBuSATE) group and various amino residues are reported. These compounds were obtained from an H-phosphonate strategy using an amidative oxidation step. Most of these derivatives appeared to inhibit HIV-1 replication, with EC(50) values at micromolar concentration in thymidine kinase-deficient (TK-) cells, revealing a less restrictive intracellular decomposition process than previously reported for other phosphoramidate prodrugs.

S-acyl-2-thioethyl aryl phosphotriester derivatives of AZT: synthesis, antiviral activity, and stability study.

The synthesis, antiviral activity, and stability study of phosphotriester derivatives of 3'-azido-2',3'-dideoxythymidine (AZT) bearing modified l-tyrosinyl residues are reported. These compounds were obtained via phosphoramidite (P(III)) chemistry from the appropriate aryl precursors. All the derivatives were evaluated for their in vitro anti-HIV activity, and they appeared to be potent inhibitors of HIV-1 replication in various cell culture experiments, with EC(50) values between the micro- and nanomolar range, especially in thymidine kinase deficient (TK(-)) cells, showing their ability to act as mononucleotide prodrugs.

Uptake and quantification of intracellular concentration of lipophilic pro-oligonucleotides in HeLa cells.

Several lipophilic prodrugs of oligonucleotides (T12 and T20) bearing enzymolabile protecting groups and labeled with fluorescein were synthesized. Their cellular uptake was studied by three different approaches using fluorescence: fluorescence microscopy, flow cytometry and spectrofluorometry. The corresponding prooligonucleotides (pro-oligos) were rapidly and efficiently taken up by HeLa cells and were found homogeneously in the cytoplasm and in the nucleus.

Increase of the adenallene anti-HIV activity in cell culture using its bis(tBuSATE) phosphotriester derivative.

The bis(S-pivaloyl-2-thioethyl) phosphotriester derivative of 9-(4'-hydroxy-1',2'-butadienyl)adenine (adenallene) was synthesized. This mononucleotide prodrug proved to be more effective than the parent nucleoside in inhibiting HIV-1 replication in several human T4 lymphoblastoid cell lines.

Synthesis and Studies of Mononucleoside Glucosyl Phosphotriester Derivatives.

The synthesis and stability studies in several aqueous media of mononucleoside glucosyl phosphotriester derivatives of 3'-azido-3'-deoxythymidine are reported herein. Such neutral mononucleotides, which incorporate beta-glucopyranosidyl moieties associated to a thioethyl linker as phosphate protecting groups were designed to act as "pronucleotides", giving rise to the corresponding 5'-mononucleotide through a glucosidase-mediated activation mechanism.