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 P -(2‘,3‘-O-isopropylideneadenosin-5‘-yl)-P -(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.