Discovery of an L-like Configuration for 3'-Fluoro-5'-norcarbonucleoside Phosphonates as Potent Anti-HIV Agents.

Recently, we reported the racemic synthesis of 3'-fluoro-5'-norcarbocyclic nucleoside phosphonates bearing adenine as the heterocyclic base. For this study, to evaluate the antiviral activity of each enantiomer, we synthesized both enantiomers, as well as their corresponding bis(POM) prodrugs. Anti-HIV-1 evaluation against the LAI strain and clinically NRTI-resistant HIV-1 strains are presented. The activities against these different strains show that the activities of bis(POM) prodrug (-)-9 are equivalent or even superior to those of (R)-PMPA.

Crystallization-Induced Diastereomer Transformation of α-Bromo α'-Sulfinyl Ketones. Diastereodivergent Synthesis of (+)-α-Conhydrine and (-)-ß-Conhydrine.

Crystallization-Induced Diastereomer Transformation (CIDT) of α-bromo-α'-(R)-sulfinylketones is reported. This process provides not readily accessible enantiopure stereolabile α-bromoketones, which after diastereoselective carbonyl group reduction lead to the corresponding highly value-added anti and syn-bromohydrins with excellent diastereoselectivities. As an application, a diastereodivergent synthesis of enantiopure hemlock alkaloid (+)-α-conhydrine and its diastereomer (-)-ß-conhydrine is also described.

Synthesis and Antiviral Evaluation of 3'-Fluoro-5'-norcarbocyclic Nucleoside Phosphonates Bearing Uracil and Cytosine as Potential Antiviral Agents.

Carbocyclic nucleoside analogues are an essential class of antiviral agents and are commonly used in the treatment of viral diseases (hepatitis B, AIDS). Recently, we reported the racemic synthesis and the anti-human immunodeficiency virus activities (HIV) of 3'-fluoro-5'-norcarbocyclic nucleoside phosphonates bearing purines as heterocyclic base. Based on these results, the corresponding racemic norcarbocyclic nucleoside phosphonates bearing pyrimidine bases were synthesized. The prepared compounds were evaluated against HIV, but none of them showed marked antiviral activity compared to their purine counterparts.

Synthesis and Antiviral Evaluation of 3'-Fluoro-4'-modified-5'-norcarbocyclic Nucleoside Phosphonates.

The synthesis and anti-HIV evaluation of hitherto unknown 3'-fluoro-5'-norcarbocyclic nucleoside phosphonates bearing adenine with modifications at the 4' position (ethynyl, vinyl, ethyl, hydroxymethyl) is described. One of the synthesized compounds was found to be an inhibitor of HIV-1 replication, but with moderate efficiency relative to (R)-9-(2-phosphonylmethoxypropyl)adenine ((R)-PMPA, tenofovir), with no concomitant cytotoxicity.

CD73 inhibition by purine cytotoxic nucleoside analogue-based diphosphonates.

The ecto-5'-nucleotidase CD73 has emerged as an important drug target in oncoimmunology as well as in other diseases. We describe new ADP analogues as CD73 inhibitors based on the replacement of the adenosine moiety, in the reference inhibitor APCP, by purine nucleoside analogues. Compounds were assessed for CD73 inhibition both on purified recombinant protein and on CD73-expressing cancer cells. The clofarabine-containing compound (2) was shown to be more potent than APCP with IC50 values of 0.18 µM (vs. 3.8 µM) on purified protein and 0.24 µM (vs. 23.6 µM) on CD73 expressed on cells. This work gives additional insights into structure-activity relationship of substrate-analogues as CD73 inhibitors.