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

Research output: Contribution to journalArticle

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

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Inosine Monophosphate
Adenine
tiazofurin
NAD
Inhibitory Concentration 50
Oxidoreductases
Protein Isoforms
IMP Dehydrogenase
Mycophenolic Acid
Organophosphonates
K562 Cells
thiazole-4-carboxamide adenine dinucleotide

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Probing binding requirements of type I and type II isoforms of inosine monophosphate dehydrogenase with adenine-modified nicotinamide adenine dinucleotide analogues. / Chen, Liqiang; Gao, Guangyao; Felczak, Krzysztof; Bonnac, Laurent; Patterson, Steven E.; Wilson, Daniel; Bennett, Eric M.; Jayaram, Hiremagalur N.; Hedstrom, Lizbeth; Pankiewicz, Krzysztof W.

In: Journal of Medicinal Chemistry, Vol. 50, No. 23, 15.11.2007, p. 5743-5751.

Research output: Contribution to journalArticle

Chen, L, Gao, G, Felczak, K, Bonnac, L, Patterson, SE, Wilson, D, Bennett, EM, Jayaram, HN, Hedstrom, L & Pankiewicz, KW 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, vol. 50, no. 23, pp. 5743-5751. https://doi.org/10.1021/jm070568j
Chen, Liqiang ; Gao, Guangyao ; Felczak, Krzysztof ; Bonnac, Laurent ; Patterson, Steven E. ; Wilson, Daniel ; Bennett, Eric M. ; Jayaram, Hiremagalur N. ; Hedstrom, Lizbeth ; Pankiewicz, Krzysztof W. / Probing binding requirements of type I and type II isoforms of inosine monophosphate dehydrogenase with adenine-modified nicotinamide adenine dinucleotide analogues. In: Journal of Medicinal Chemistry. 2007 ; Vol. 50, No. 23. pp. 5743-5751.
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AU - Bonnac, Laurent

AU - Patterson, Steven E.

AU - Wilson, Daniel

AU - Bennett, Eric M.

AU - Jayaram, Hiremagalur N.

AU - Hedstrom, Lizbeth

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