Mao Liu, M. Luo, D. E. Mozdziesz
Feb 1, 2005
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Nucleosides, Nucleotides & Nucleic Acids
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.