Synthesis and evaluation of 3'-azido-2',3'-dideoxypurine nucleosides as inhibitors of human immunodeficiency virus

Abstract

Based on the promising drug resistance profile and potent anti-HIV activity of beta-d-3'-azido-2',3'-dideoxyguanosine, a series of purine modified nucleosides were synthesized by a chemical transglycosylation reaction and evaluated for their antiviral activity, cytotoxicity, and intracellular metabolism. Among the synthesized compounds, several show potent and selective anti-HIV activity in primary lymphocytes.

Figure 1

Some important 3′-azido nucleosides.

Scheme 1

Reagents and conditions: (a) TMSCl, (i-BuCO)₂O, pyridine, rt, 4 h, 75%; (b) Bz₂O, DMF, Et₃N, rt 2 h, 74%; (c) (i) Tf₂O, DCM, pyridine, 0 °C, (ii) H₂O, (iii) MeOH, NaHCO₃; 32%; (d) (i) MsCl, DCM, DMAP, 0 °C, 40 min, (ii) NaN₃, DMF, 120 °C, 2 h, 65%, two steps; (e) NaOCH₃/MeOH, DCM 45 °C, 4 h, 82%.

Scheme 2

Reagents and conditions: (a) TosCl or TPPSCl, Et₃N, DMAP, DCM, rt, 18 h 99%; 80%; (b) (i) R¹H, (ii) NaOMe/MeOH, DCM 45 °C, 18 h, 55–73%.

Scheme 3

Reagents and condition: (a) (i) BSA, CH₃CN, 78 °C, 30 min, then TMSOTf, 75 °C, 18 h, 43%, (ii) TBAF, THF, rt, 4 h; (b) (i) anomer separation on silica gel, 43%, (ii) NH₃/CH₃OH, 110 °C, 18 h, 71%.

Scheme 4

Reagents and condition: (a) (i) TBSCl, imidazole, DMF, rt, overnight, 80%, (ii) DIAD, TPP, 80 °C, 30 min, 75%, (iii) LiN₃, DMF, 100 °C, 24 h, 70%; (b) purine base, BSA, TMSOTf, CH₃CN, 70 °C, 18 h, 34–61%; (c) (i) TBAF/acetic acid (v/v: 1:0.2), THF, rt, 4–6 h, (ii) anomer separation on silica gel, (iii) nucleophilic reagents in the case of 2- and/or 6-chloro purines in one to three steps in 20–95% yield.