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 [Ki = 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 microM. 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 (IC50 = 1.1 microM) more potently than tiazofurin (IC50 = 12.4 microM) or mycophenolic acid (IC50 = 7.7 microM).
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Adenosine Monophosphate / analogs & derivatives*
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Adenosine Monophosphate / chemical synthesis
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Adenosine Monophosphate / pharmacology
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / pharmacology
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Diphosphonates / chemical synthesis*
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Diphosphonates / pharmacology
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Drug Screening Assays, Antitumor
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Humans
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IMP Dehydrogenase / antagonists & inhibitors*
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IMP Dehydrogenase / chemistry
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IMP Dehydrogenase / metabolism
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Isoenzymes / metabolism
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K562 Cells
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Models, Molecular
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Mycophenolic Acid / analogs & derivatives
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Mycophenolic Acid / chemical synthesis
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Mycophenolic Acid / pharmacology
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NAD / analogs & derivatives*
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NAD / chemical synthesis*
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NAD / pharmacology
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Protein Binding
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Ribavirin / analogs & derivatives
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Ribavirin / chemical synthesis
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Ribavirin / pharmacology
Substances
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Antineoplastic Agents
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Diphosphonates
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Isoenzymes
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P(1)-(7-hydroxy-6-(hydroxyethyl)-5-methoxy-4-methylphthalan-1-one-2-yl)-P(2)-(2-ethyladenosin-5'-yl)methylenebis(phosphonate)
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NAD
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Adenosine Monophosphate
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Ribavirin
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IMP Dehydrogenase
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IMPDH1 protein, human
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IMPDH2 protein, human
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Mycophenolic Acid
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tiazofurin