Probing binding requirements of type I and type II isoforms of inosine monophosphate dehydrogenase with adenine-modified nicotinamide adenine dinucleotide analogues

Liqiang Chen, Guangyao Gao, Krzysztof Felczak, Laurent Bonnac, Steven E. Patterson, Daniel Wilson, Eric M. Bennett, Hiremagalur N. Jayaram, Lizbeth Hedstrom, Krzysztof W. Pankiewicz

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Abstract

Novel tiazofurin adenine dinucleotide (TAD) analogues 25-33 containing a substituent at C2 of the adenine ring have been synthesized as inhibitors of the two isoforms of human IMP-dehydrogenase. The 2-ethyl TAD analogue 33 [K i = 1 nM (type I), Ki = 14 nM (type II)] was found to be the most potent. It did not inhibit three other cellular dehydrogenases up to 50 μM. Mycophenolic adenine bis(phosphonate)s containing a 2-phenyl (37) or 2-ethyl group (38), were prepared as metabolically stable compounds, both nanomolar inhibitors. Compound 38 [Ki = 16 nM (type I), Ki = 38 nM (type II)] inhibited proliferation of leukemic K562 cells (IC 50 =1.1 μM) more potently than tiazofurin (IC50 = 12.4 μM) or mycophenolic acid (IC50 = 7.7 μM).

Original languageEnglish (US)
Pages (from-to)5743-5751
Number of pages9
JournalJournal of Medicinal Chemistry
Volume50
Issue number23
DOIs
StatePublished - Nov 15 2007

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ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Chen, L., Gao, G., Felczak, K., Bonnac, L., Patterson, S. E., Wilson, D., Bennett, E. M., Jayaram, H. N., Hedstrom, L., & Pankiewicz, K. W. (2007). Probing binding requirements of type I and type II isoforms of inosine monophosphate dehydrogenase with adenine-modified nicotinamide adenine dinucleotide analogues. Journal of Medicinal Chemistry, 50(23), 5743-5751. https://doi.org/10.1021/jm070568j