Synthesis, purification, and characterization of the potent inhibitor of inosine monophosphate dehydrogenase: oxanosine monophosphate

Oxanosine monophosphate (OxMP) is a novel nucleotide and one of the lesions generated from reactive nitrogen species (RNS) damage of free nucleotides. Inosine monophosphate dehydrogenase (IMPDH) catalyzes the rate-limiting step of guanine nucleotide biosynthesis. IMPDH is a target for immunosuppressive and antiviral medications. IMPDH is also a promising drug target for cancers and parasitic infections as well, in part because of its great stature in nucleotide biosynthesis. In this study, a novel one-step synthesis of OxMP is presented. In addition, characterization of OxMP reveals that it is a potent, fully competitive inhibitor of IMPDH with Ki = 240 ± 50 nM. OxMP was also observed to inhibit guanosine monophosphate reductase (GMPR) with IC50 = 210 ± 40 nM.