Nucleoside and non-nucleoside IMP dehydrogenase inhibitors as antitumor and antiviral agents

IMP dehydrogenase (IMPDH) is an enzyme which catalyzes the NAD-dependent co nversion of inosine 5'-monophosphate (IMP) to xanthosine 5'-monophosphate ( XMP) at the metabolic branch point in the de novo purine nucleotide synthet ic pathway. IMPDH was shown to be increased significantly in cancer cells a nd therefore considered to be a sensitive target for cancer chemotherapy. B y blocking the conversion of IMP to XMP, IMPDH inhibitors lead to depletion of the guanylate (GMP, GDP, GTP and dGTP) pools. Two isoforms of human IMP DH, designed type I and type II, have been identified and sequenced. Type I is constitutively expressed and is the predominant isoform in normal cells , while type II is selectively up-regulated in neoplastic and replicating c ells. Two types of IMPDH inhibitors, endowed with antineoplastic, antiviral and immunosoppressive activity, have been discovered so far: nucleoside in hibitors, such as ribavirin and tiazofurin, and non-nucleoside, such as myc ophenolic acid. Ribavirin produces IMPDH inhibition via its anabolite 5'-mo nophosphate. Tiazofurin inhibits the enzyme after metabolic conversion into thiazole-4-carboxamide adenine dinucleotide (TAD), an analogue of the cofa ctor NAD. It was hypothesized that the inhibitory activity of tiazofurin is due to an attractive electrostatic interaction between the heterocyclic su lphur atom and the furanose oxygen 1' which constrain rotation about the C- glycosidic bond in tiazofurin and in its active anabolite TAD. To check thi s hypothesis, we studied several C-nucleosides related to tiazofurin and th eir NAD analogues. Non-nucleoside IMPDH inhibitors are also reviewed.