Synthesis of 3-deazaguanine, 3-deazaguanosine, and 3-deazaguanylic acid by a novel ring closure of imidazole precursors.

P. D. Cook, R. J. Rousseau, A. M. Mian, P. Dea, R. B. Meyer, R. K. Robins

Research output: Contribution to journalArticle

78 Scopus citations

Abstract

3-Deazaguanine [6-aminoimidazo[4,5-c]pyridin-4(5H)-one (4)], 3-deazaguanosine [6-amino-1-β-D-ribofuranosyl-imidazo[4,5-c]pyridin-4(5H)-one (17)], and 3-deazaguanylic acid [6-amino-1-β-D-ribofuranosylimidazo[4,5-c]pyridin-4(5H)-one 5′-phosphate (24)] have been synthesized for the first time by a novel base-catalyzed ring closure of 5(4)-cyanomethylimidazole-4(5)-carboxamide (3), 5-cyanomethyl-1-β-D-ribofuranosylimidazole-4-carboxamide (12), and 5-cyanomethyl-1-β-D-ribofuranosylimidazole-4-carboxamide 5′-phosphate (23), respectively. The imidazole 3 was prepared from the ammonolysis of methyl 5(4)-cyanomethylimidazole-4(5)-carboxylate (2). The imidazole nucleoside 12 was obtained from the stannic chloride-catalyzed condensation of methyl 5(4)-cyanomethyl-1-trimethylsilylimidazole-4(5)-carboxylate (5) and a fully acylated β-D-ribofuranose (6 or 7), followed by ammonolysis of the blocking groups and the ester function. The imidazole nucleotide 23 was obtained from the phosphorylation of 12 with phosphoryl chloride in trimethyl phosphate. The yield and ratio of the ribofuranosyl derivatives of imidazole 2 markedly depends on the ratio of stannic chloride to trimethylsilylimidazole 5 and the fully acylated β-D-ribofuranose. The structures of the nucleosides were established by the use of carbon-13 and proton NMR. 3-Deazaguanine (4), 3-deazaguanosine (17), and 3-deazaguanylic acid (24) have demonstrated a potent broad spectrum activity in vitro against various DNA and RNA viruses, as well as potent in vivo activity against L1210 leukemia and adenocarcinoma 755 in mice.

Original languageEnglish (US)
Pages (from-to)1492-1498
Number of pages7
JournalJournal of the American Chemical Society
Volume98
Issue number6
DOIs
StatePublished - Mar 17 1976

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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