1The Chemistry of Nucleoside and Dinucleotide Inhibitors of Inosine Monophosphate Dehydrogenase (IMPDH)

Abstract

Thiazole-C-nucleoside, tiazofurin (2-β-D-ribofuranosylthiazole-4-carboxamide, TR) was synthesized as a potential antiviral agent. Investigation of the potent anticancer activity of tiazofurin showed that it is not active as the nucleoside but is uniquely metabolized into an active metabolite, thiazole-4-carboxamide adenine dinucleotide (TAD), an analog of the cofactor nicotinamide adenine dinucleotide (NAD). The first step in the biosynthesis of TAD is the phosphorylation of TR by adenosine kinase to give tiazofurin monophosphate (TRMP). The replacement of the nicotinamide nucleoside moiety of NAD by tiazofurin afforded a cofactor analog that cannot participate in hydride transfer. TAD is therefore a potent and specific inhibitor of NAD-dependent inosine monophosphate dehydrogenase (IMPDH), an important target in cancer chemotherapy. The development of TR prompted synthesis of pyridine C-nucleosides, such as C-nicotinamide riboside (C-NR), C-picolinamide riboside (C-PR), and C-isonicotinamide riboside (C-IR). These synthetic compounds are isosteric to nicotinamide riboside (NR). It was expected that like tiazofurin, these C-nucleosides might be converted into the corresponding NAD analogs, offering an alternative means of IMPDH inhibition.