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-1-(2',3'-O-isopropylideneadenosin-5'-yl)-P-2-(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 dinueleotide(MAD). Compound 3, beta-methylene-MAD, was found to be a potent inhibitor of inosine monophosphate dehydrogenase (IMPDH) type II (K-i = 0.3 mu M) as well as an inhibitor of growth of K562 cells (IC50 = 1.5 mu M). In contrast to MPA and mycophenolic alcohol, beta-methylene-MAD was not converted into the glucuronide when incubated with uridine 5'dipbosphoglucuronyltransferase.