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

Article abstract of DOI:10.1021/jm00379a018

A series of dinucleotides, analogues to nicotinamide adenine dinucleotide but containing the five-membered base nucleosides tiazofurin, selenazofurin, ribavirin, and AICAR in place of nicotinamide ribonucleoside, were prepared in greater than 50% yield by reacting the corresponding nucleotide imidazolidates with adenosine 5'-monophosphate (AMP). The symmetric dinucleotides of tiazofurin (TTD) and selenazofurin (SSD), 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 > TAD >> SSD ? TTD ? RAD >>> ZAD. 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.