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

Abstract

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.

Keywords: HIV; L-enantiomer; antiviral; nucleoside; phosphonate.

Figure 1

Chemical structures of Abacavir, Tenofovir and its prodrugs TDF and TAF. Structures of the 5’‐norcarbocyclic nucleotides previously described as well as compounds investigated in this study.

Scheme 1

Retrosynthetic pathway used for the racemic synthesis of compound (±)‐1. ^[4b]

Scheme 2

Optical resolution of (±)‐3 with (R)‐O‐acetylmandelic acid. Reagents and conditions: a) i) (R)‐O‐acetylmandelic acid, DCC, DMAP, CH₂Cl₂, rt, 2 h; ii) silica gel chromatography; b) LiOH, THF/H₂O, rt, 4 h.

Figure 2

ORTEP drawing of the X‐ray crystallographic structure of 4 b.

Scheme 3

Synthesis of enantiomers of compound 1 and their corresponding bis(POM) prodrugs. Reagents and conditions: a) 6‐chloropurine, PPh₃, DIAD, THF, rt, 1 h; b) i) NH₃/MeOH, 70 °C, 24 h; ii) DMF‐dimethylacetal, DMF, 50 °C, 15 h; c) i) benzoic acid, PPh₃, DIAD, THF, rt, 3 h; ii) K₂CO₃, MeOH, rt, 2 h; d) i) (EtO)₂POCH₂OTs, LiOtBu, THF, rt, 3 days; ii) AcOH/MeOH/H₂O, rt, 24 h; e) TMSBr, DMF, rt, 16 h; f) i) Bu₄NOH, Et₃N, DMF, rt, 30 min; ii) POMCl, rt, 5 days.