Probing binding requirements of type I and type II isoforms of inosine monophosphate dehydrogenase with adenine-modified nicotinamide adenine dinucleotide analogues.
J Med Chem
; 50(23): 5743-51, 2007 Nov 15.
Article
em En
| MEDLINE
| ID: mdl-17958343
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).
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Coleções:
01-internacional
Temas:
Geral
Base de dados:
MEDLINE
Assunto principal:
Monofosfato de Adenosina
/
Difosfonatos
/
IMP Desidrogenase
/
NAD
/
Antineoplásicos
Limite:
Humans
Idioma:
En
Revista:
J Med Chem
Assunto da revista:
QUIMICA
Ano de publicação:
2007
Tipo de documento:
Article
País de afiliação:
Estados Unidos