Novel nicotinamide adenine dinucleotide analogues as potential anticancer agents: Quest for specific inhibition of inosine monophosphate dehydrogenase

Synthetic nicotinamide adenine dinucleotide (NAD) analogues containing 5-β- d-ribofuranosylnicotinamide (C-NAD), 6-β- d-ribofuranosylpicolinamide (C-PAD), 3-β- d-ribofuranosylbenzamide (BAD), and 2-β- d-ribofuranosylthiazole-4-carboxamide (TAD) in place of the nicotinamide riboside moiety are described and evaluated as potential inhibitors of inosine monophosphate dehydrogenase (IMPDH). TAD and BAD showed potent inhibitory activity against the enzyme in the form of pyrophosphates, as well as metabolically stable methylene- and difluoromethylene bis(phosphonate)s. Fluorination at the C2′ (ribo and arabino configuration) and C3′ (ribo) of the adenosine moiety of TAD afforded analogues highly potent against IMPDH, but weakly active against alcohol dehydrogenase. With the exception of the methylene bis (phosphonate) analogue of TAD compounds containing a methylene bridge were poor inhibitors of growth of K562 cells. On the other hand, NAD analogues containing difluoromethylene linkage were highly effective in inhibition of K562 cell growth, as well as potent inducers of K562 cell differentiation. Such compounds, therefore, may be of potential therapeutic interest.