Ribavirin, Tiazofurin, and Selenazofurin: Mononucleotides and Nicotinamide Adenine Dinucleotide Analogues. Synthesis, Structure, and Interactions with IMP Dehydrogenase

Gulilat Gebevehu, Victor E. Marquez, Anne Van Cott, David A. Cooney, James A. Kelley, Hiremagalur N. Jayaram, Gurpreet S. Ahluwalia, Robert L. Dion, Yvonne A. Wilson, David G. Johns

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Abstract

A series of dinucleotides, analogous to nicotinamide adenine dinucleotide but containing the five-membered base nucleosides tiazofurin (1a), selenazofurin (1b), ribavirin (2), and AICAR (3) in place of nicotinamide ribonucleoside, were prepared in greater than 50% yield by reacting the corresponding nucleotide imidazolidates (6a-d) with adenosine 5'-monophosphate (AMP). The symmetric dinucleotides of tiazofurin (TTD, 8e) and selenazofurin (SSD, 8f) were also prepared by a similar methodology. These dinucleotides were characterized by 1H NMR and fast atom bombardment MS and were evaluated for their inhibitory potency against a partially purified preparation of tumoral inosine monophosphate dehydrogenase (IMPD) from P388 cells. The order of potency found was SAD (8b) > TAD (8a) >> SSD (8f) ≃ TTD (8e)≃RAD (8c) >>> ZAD (8d). On kinetic analysis none of the dinucleotides produced competitive inhibition of IMPD with NAD as a variable substrate. In addition to their superior IMPD inhibitory activity, SAD and TAD appear to be the only dinucleotides, besides NAD, that are formed naturally by the NAD pyrophosphorylase from P388 lymphoblasts.

Original languageEnglish (US)
Pages (from-to)99-105
Number of pages7
JournalJournal of Medicinal Chemistry
Volume28
Issue number1
DOIs
StatePublished - Jan 1985

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Gebevehu, G., Marquez, V. E., Cott, A. V., Cooney, D. A., Kelley, J. A., Jayaram, H. N., Ahluwalia, G. S., Dion, R. L., Wilson, Y. A., & Johns, D. G. (1985). Ribavirin, Tiazofurin, and Selenazofurin: Mononucleotides and Nicotinamide Adenine Dinucleotide Analogues. Synthesis, Structure, and Interactions with IMP Dehydrogenase. Journal of Medicinal Chemistry, 28(1), 99-105. https://doi.org/10.1021/jm00379a018