C-nucleoside analogs of tiazofurin and selenazofurin as inosine 5′-monophosphate dehydrogenase inhibitors

Inosine monophosphate dehydrogenase (IMPDH), the rate limiting enzyme in the de novo synthesis of guanine nucleotides, catalyzes the oxidation of inosine monophosphate (IMP) to xanthosine monophosphate (XMP). Because of its critical role in purine biosynthesis, IMPDH is a drug design target for antineoplastic, anttinfective, and immunosuppressive chemotherapy. Two type of IMPDH inhibitors are currently in clinical use or under development: nucleoside inhibitors, such as ribavirin, tiazofurin and mizoribine, and non-nucleoside, as mycophenolic acid. Tiazofurin, and its selenium analog selenazofurin, are C-glycosyl nucleosides endowed with antitumor activity which have to be converted in sensitive cells to the active forms, the dinucleotides NAD(+) analogs TAD and SAD, respectively. It was hypothesized that the inhibitory activity of both tiazofurin and selenazofurin is due to an attractive electrostatic interaction between the heterocyclic sulfur or selenium atom and the furanose oxygen 1'. This interaction constrains rotation about the C-glycosidic bond in tiazofurin and selenazofurin and in their active anabolites TAD and SAD. This hypothesis was confirmed by the investigation of several C-nucleosides related to these compounds. Structure-activity relationships studies revealed that S or Se in position 2 in thiazole or selenazole moiety with respect to the glycosidic bond is essential for cytotoxicity and IMPDH inhibitory activity of tiazofurin and selenazofurin, while the N atom is not. Computational methods suggested that rotational constraint around the C-glycosidic bond is determined both by favorable intramolecular (1-4) electrostatic interaction between the partial positive sulfur or selenium and the negative oxygen of the ribose and unfavorable van der Waals contacts between the heteroatoms and the ribose C2'-H and O4'. (C) 2003 American Chemical Society.