Ribavirin, tiazofurin, and selenazofurin: mononucleotides and nicotinamide adenine dinucleotide analogs. Synthesis, structure, and interactions with IMP dehydrogenase

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Abstract
A series of dinucleotides, analogous to NAD but containing the 5-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 with 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 [mass spectroscopy] and were evaluated for their inhibitory potency against a partially purified preparation of tumoral IMP dehydrogenase (IMPD) from P388 cells. The order of potency found was SAD > TAD [NAD analogs] > > SSD (8f) .simeq. TTD (8e) .simeq. RAD > > > ZAD [ribavarin and 5-amino-4-imidazolecarboxamide ribonucleoside dinucleotide analogs]. 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.