Synthesis and anti-HIV activity of (-)-beta-D-(2R,4R)-1,3-dioxolane-2,6-diamino purine (DAPD) (amdoxovir) and (-)-beta-D-(2R,4R)-1,3-dioxolane guanosine (DXG) prodrugs

Abstract

Prodrugs of (-)-beta-D-(2R,4R)-1,3-dioxolane-2,6-diamino purine (DAPD), organic salts of DAPD, 5'-L-valyl DAPD and N-1 substituted (-)-beta-D-(2R,4R)-1,3-dioxolane guanosine (DXG) have been synthesized with the objective of finding molecules which might be superior to DAPD and DXG in solubility as well as pharmacologic profiles. Synthesized prodrugs were evaluated for anti-HIV activity against HIV-1(LAI) in primary human lymphocytes (PBM cells) as well as their cytotoxicity in PBM, CEM and Vero cells. DAPD prodrugs, modified at the C6 position of the purine ring, demonstrated several folds of enhanced anti-HIV activity in comparison to the parent compound DAPD without increasing the toxicity. The presence of alkyl amino groups at the C6 position of the purine ring increased the antiviral potency several folds, and the most potent compound (-)-beta-D-(2R,4R)-1,3-dioxolane-2-amino-6-aminoethyl purine (8) was 17 times more potent than that of DAPD. 5'-L-Valyl DAPD 20 and organic acid salts 21-24 also exhibited enhanced anti-HIV activity in comparison to DAPD, while DXG prodrugs 16 and 17 exhibited lower potency than that of DXG or DAPD.

Fig. 1

Scheme 1. Synthesis of DAPD and DXG prodrugs

Reagents and Conditions: (a) LiAl(OBu^t)₃H, THF, -78 °C (b) DMAP, (CH₃CO)₂O, -20 °C (c) TMSI, CHCl₃, -20 °C, 2 h, (d) (NH₄)₂SO₄, -20 °C, 2 h, rt, 8 h, gentle reflux, 2 h (e) saturated methanolic ammonia, 0 °C, 2 h, room temperature, overnight (f) HOC₂H₄SH, NaOMe, MeOH, 3.5 h reflux, (i) NaN₃, DMF (ii) methylamine 40% solution in H₂O, MeOH (iii) ethylamine, MeOH (iv) dimethylamine 40% solution in H₂O, MeOH (v) isopropylamine, MeOH (vi) NaOMe, MeOH (vii) cyclopropylamine, MeOH (vii) cyclobutylamine, MeOH (ix) benzylamine, MeOH (x) KOH, DMF, diphenylsulfoniumtetrafluoroborate (xi) NaH, C₆H₅CH₂Br.

Scheme 2. Synthesis of 5′-O-valyl-DAPD

Reagents and conditions: (i) DCC, DMAP, DMF (ii) DCM, TFA, 0-5 °C (iii) IPA, PL-HCO₃ resin.