Probing binding requirements of type I and type II isoforms of inosine monophosphate dehydrogenase with adenine-modified nicotinamide adenine dinucleotide analogues.
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).
Chen
Liqiang
L
Center for Drug Design, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Gao
Guangyao
G
Felczak
Krzysztof
K
Bonnac
Laurent
L
Patterson
Steven E
SE
Wilson
Daniel
D
Bennett
Eric M
EM
Jayaram
Hiremagalur N
HN
Hedstrom
Lizbeth
L
Pankiewicz
Krzysztof W
KW
D000249:Adenosine Monophosphate / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D004164:Diphosphonates / Q000138:chemical synthesis* / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D020014:K562 Cells; D008958:Models, Molecular; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D009243:NAD / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D011485:Protein Binding; D012254:Ribavirin / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology
D000970:Antineoplastic Agents; D004164:Diphosphonates; D007527:Isoenzymes; C525470:P(1)-(7-hydroxy-6-(hydroxyethyl)-5-methoxy-4-methylphthalan-1-one-2-yl)-P(2)-(2-ethyladenosin-5'-yl)methylenebis(phosphonate); D009243:NAD; D000249:Adenosine Monophosphate; D012254:Ribavirin; D007168:IMP Dehydrogenase; C488211:IMPDH1 protein, human; C501687:IMPDH2 protein, human; D009173:Mycophenolic Acid; C033706:tiazofurin