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

  • J Med Chem. 1998 Feb 12;41(4):618-22. doi: 10.1021/jm970705k.
K Lesiak  1 ,  K A Watanabe ,  A Majumdar ,  J Powell ,  M Seidman ,  K Vanderveen ,  B M Goldstein ,  K W Pankiewicz
Affiliations
  • 1. Division of Medicinal Chemistry, Codon Pharmaceuticals, Inc., Gaithersburg, Maryland 20877, USA.
PMID: 9484510 DOI: 10.1021/jm970705k
Abstract

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. Deisopropy-lidenation of 8 with CF3COOH/H2O afforded the methylenebis(phosphonate) analogue 3 of mycophenolic adenine dinucleotide (MAD). Compound 3, beta-methylene-MAD, was found to be a potent inhibitor of inosine monophosphate dehydrogenase (IMPDH) type II (Ki = 0.3 microM) as well as an inhibitor of growth of K562 cells (IC50 = 1.5 microM). In contrast to MPA and mycophenolic alcohol, beta-methylene-MAD was not converted into the glucuronide when incubated with uridine 5'-diphosphoglucuronyltransferase.