SYNTHESIS OF A METHYLENEBIS(PHOSPHONATE) ANALOG OF MYCOPHENOLIC ADENINE-DINUCLEOTIDE - A GLUCURONIDATION-RESISTANT MAD ANALOG OF NAD

Mycophenolic alcohol (MPAlc), obtained by reduction of the carboxylic group of mycophenolic acid (MPA), was coupled with 2',3'-O-isopropylid eneadenosine 5'-methylenebis(phosphonate) (4) in the presence of diiso propylcarbodiimide (DIC) to give -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). Co mpound 3, beta-methylene-MAD, was found to be a potent inhibitor of in osine 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 con trast to MPA and mycophenolic alcohol, beta-methylene-MAD was not conv erted into the glucuronide when incubated with uridine 5'dipbosphogluc uronyltransferase.