Synthesis of a methylenebis(phosphonate) analogue of mycophenolic adenine dinucleotide: A glucuronidation-resistant MAD analogue of NAD

Mycophenolic alcohol (MPAlc), obtained by reduction of the carboxylic group of mycophenolic acid (MPA), was coupled with 2',3'-O- isopropylideneadenosine 5'-methylenebis(phosphonate) (4) in the presence of diisopropylcarbodiimide (DIC) to give P¹-(2',3'-O-isopropylideneadenosin- 5'-yl)-P²-(mycophenolic alcohol-6'-yl)methylenebis(phosphonate) (8) in 32% yield. Deisopropylidenation of 8 with CF₃COOH/H₂O afforded the methylenebis(phosphonate) analogue 3 of mycophenolic adenine dinucleotide (MAD). Compound 3, β-methylene-MAD, was found to be a potent inhibitor of inosine monophosphate dehydrogenase (IMPDH) type II (K(i) = 0.3 μM) as well as an inhibitor of growth of K562 cells (IC₅₀ = 1.5 μM). In contrast to MPA and mycophenolic alcohol, β-methylene-MAD was not converted into the glucuronide when incubated with uridine 5'-diphosphoglucuronyltransferase.