Synthesis and Biological Evaluation of 2′,3′-Didehydro-2′,3′-Dideoxy-9-Deazaguanosine, a Monophosphate Prodrug and Two Analogues, 2′,3′-Dideoxy-9-Deazaguanosine and 2′,3′-Didehydro-2′,3′-Dideoxy-9-Deazainosine

Abstract

2′,3′-Didehydro-2′,3′-dideoxy-9-deazaguanosine (1), its monophosphate prodrug (2), and two analogues, 2′,3′-dideoxy-9-deazaguanosine (3) and 2′,3′-didehydro-2′,3′-dideoxy-9-deazainosine (4), have been synthesized from benzoylated 9-deazaguanosine (5). Basic hydrolysis of 5, selective protection of the 2-amino and 5′-hydroxy functions with isobutyryl and silyl groups, respectively, followed by reaction with thiocarbonyldiimidazole gave the cyclic thiocarbonate, which, upon reaction with triethyl phosphite, followed by deprotection, afforded 1. Treatment of 1 with phenyl methoxyalaninyl phosphochloridate and N-methylimidazole gave 2. Catalytic hydrogenation of 1 gave 3. Hydrodediazoniation of 1 with tert-butyl nitrite and tris(trimethylsilyl)silane gave 4. Compounds 1–4 were found to be inactive against the human immunodeficiency virus and exhibited minimal to no cytotoxic activity against the L1210 leukemia, CCRF-CEM lymphoblastic leukemia, and B₁₆F₁₀ melanoma in vitro.

This research was supported in part by a Drug Discovery and Development Award from GlaxoSmithKline.

Keywords:

• C-Nucleosides
• Synthesis of Unsaturated 9-Deazanucleosides
• Monophosphate Prodrug
• Anti-HIV Activity
• Cytotoxic Activity

Notes

This research was supported in part by a Drug Discovery and Development Award from GlaxoSmithKline.