Synthesis of a methylenebis(phosphonate) analogue of mycophenolic adenine dinucleotide: a glucuronidation-resistant MAD analogue of NAD.
J Med Chem
; 41(4): 618-22, 1998 Feb 12.
Article
en En
| MEDLINE
| ID: mdl-9484510
ABSTRACT
Mycophenolic alcohol (MPAlc), obtained by reduction of the carboxylic group of mycophenolic acid (MPA), was coupled with 2',3'-O-isopropylideneadenosine 5'-methylenebis(phosphonate) (4) in the presence of diisopropylcarbodiimide (DIC) to give P1-(2',3'-O-isopropylideneadenosin-5'-yl)-P2-(mycophenolic alcohol-6'-yl)methylenebis(phosphonate) (8) in 32% yield. Deisopropy-lidenation of 8 with CF3COOH/H2O afforded the methylenebis(phosphonate) analogue 3 of mycophenolic adenine dinucleotide (MAD). Compound 3, beta-methylene-MAD, was found to be a potent inhibitor of inosine monophosphate dehydrogenase (IMPDH) type II (Ki = 0.3 microM) as well as an inhibitor of growth of K562 cells (IC50 = 1.5 microM). In contrast to MPA and mycophenolic alcohol, beta-methylene-MAD was not converted into the glucuronide when incubated with uridine 5'-diphosphoglucuronyltransferase.
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Banco de datos:
MEDLINE
Asunto principal:
Glucuronosiltransferasa
/
IMP Deshidrogenasa
/
Ácido Micofenólico
/
NAD
/
Antineoplásicos
Límite:
Humans
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
1998
Tipo del documento:
Article
País de afiliación:
Estados Unidos