Probing binding requirements of type I and type II isoforms of inosine monophosphate dehydrogenase with adenine-modified nicotinamide adenine dinucleotide analogues

Novel tiazofurin adenine dinucleotide (TAD) analogues 25-33 containing a substituent at C2 of the adenine ring have been synthesized as inhibitors of the two isoforms of human IMP-dehydrogenase. The 2-ethyl TAD analogue 33 [K _i = 1 nM (type I), K_i = 14 nM (type II)] was found to be the most potent. It did not inhibit three other cellular dehydrogenases up to 50 μM. Mycophenolic adenine bis(phosphonate)s containing a 2-phenyl (37) or 2-ethyl group (38), were prepared as metabolically stable compounds, both nanomolar inhibitors. Compound 38 [K_i = 16 nM (type I), K_i = 38 nM (type II)] inhibited proliferation of leukemic K562 cells (IC ₅₀ =1.1 μM) more potently than tiazofurin (IC₅₀ = 12.4 μM) or mycophenolic acid (IC₅₀ = 7.7 μM).