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

Krystyna Lesiak, Kyoichi A. Watanabe, Alokes Majumdar, James Powell, Michael Seidman, Kristen Vanderveen, Barry M. Goldstein, Krzysztof W. Pankiewicz

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

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. 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.

Original languageEnglish (US)
Pages (from-to)618-622
Number of pages5
JournalJournal of Medicinal Chemistry
Volume41
Issue number4
DOIs
StatePublished - Feb 12 1998

Fingerprint Dive into the research topics of 'Synthesis of a methylenebis(phosphonate) analogue of mycophenolic adenine dinucleotide: A glucuronidation-resistant MAD analogue of NAD'. Together they form a unique fingerprint.

Cite this