N⁴-Hydroxycytosine Dioxolane Nucleosides and Their Activity Against Hepatitis B Virus

Abstract

Novel racemic, d- and l-β-dioxolane N ⁴-hydroxycytosine nucleosides have been synthesized and evaluated for their activity against hepatitis B virus. None of the synthesized nucleosides demonstrated selective anti-HBV activity.

Keywords:

• HBV
• Dioxolane
• Nucleoside

This research was supported by NIH SBIR grant 1 R43AI056794-01. R. F. Schinazi is founder of Pharmasset Ltd., and his particulars have been reviewed by Emory University's Conflict of Interest Committee. R. F. Schinazi's group is supported by the Department of Veterans Affairs and received no funding from Pharmasset to perform this work.

Notes

*Compound 4: foam, ¹H NMR (CDCl₃) δ 9.87 (s, 1H, NH, D₂O exchangeable), 8.06–7.48 (m, 5H, Bz), 7.45 (d, J = 8.0 Hz, 1H, 6-H), 6.34 (d, J = 4.4 Hz, 1H, 4′-H), 6.13 (dd, J = 1.6, 7.6 Hz, 1H, 5-H), 5.31 (t, J = 2.4 Hz, 1H, 2′-H), 4.70 (m, 2H, 5′-H), 4.25 (m, 2H, 6′-H). Anal Calcd for C₁₅H₁₄N₂O₅S + 0.1H₂O: C, 53.54; H, 4.22; N, 8.33. Found: C, 53.45; H, 4.19; N, 8.26.

^†Compound 3: foam, ¹H NMR (CDCl₃) δ 9.86 (s, 1H, NH, D₂O exchangeable), 8.07–7.46 (m, 5H, Bz), 7.22 (d, J = 8 Hz, 1H, 6-H), 6.46 (dd, J = 1.6, 7.6 Hz, 1H, 5-H), 6.28 (dd, J = 2.4, 5.2 Hz, 1H, 4′-H), 5.81 (t, J = 4 Hz, 1H, 2′-H), 4.45 (m, 3H, 5′-H_A, 6′-H), 4.16 (m, 1H, 5′-H_B). Anal Calcd for C₁₅H₁₄N₂O₅S + 0.1H₂O: C, 53.54; H, 4.22; N, 8.33. Found: C, 53.32; H, 4.18; N, 8.04.

*Compound 6: crystals, mp. 159–161°C. ¹H NMR (DMSO-d ₆) δ 10.00, 9.55 (ss, 2H, NH, NOH, D₂0 exchangeable), 6.94 (d, J = 8.4 Hz, 1H, 6-H), 6.20 (d, J = 4.8 Hz, 1H, 4′-H), 5.58 (d, J = 7.2 Hz, 1H, 5-H), 5.13 (t, J = 6.0 Hz, 1H, OH, D₂O exchangeable), 4.86 (t, J = 3.2 Hz, 1H, 2′-H), 4.05 m 2H, 5′-H), 3.58 (m, 2H, 6′-H). Anal Calcd for C₈H₁₁N₃O₅: C, 41.92; H, 4.84; N, 18.33. Found: C, 42.13; H, 4.84; N, 18.40. HRMS (FAB) obsd, m/z 230.0784, calcd for C₈H₁₁N₃O₅+ H, m/z 230.0777, (M + H)⁺.

^{† 1}H-NMR is identical to that of (±)-nucleoside.