N-Acyl-phosphoramidates as potential novel form of gemcitabine prodrugs.
Bioorg Med Chem
; 22(7): 2133-40, 2014 Apr 01.
Article
em En
| MEDLINE
| ID: mdl-24631359
ABSTRACT
Gemcitabine (dFdC) is a cytidine analog remarkably active against a wide range of solid tumors. Inside a cell, gemcitabine is phosphorylated by deoxycytidine kinase to yield gemcitabine monophosphate, further converted to gemcitabine di- and triphosphate. The most frequent form of acquired resistance to gemcitabine in vitro is the deoxycytidine kinase deficiency. Thus, proper prodrugs carrying the 5'-pdFdC moiety may help to overcome this problem. A series of new derivatives of gemcitabine possessing N-acyl(thio)phosphoramidate moieties were prepared and their cytotoxic properties were determined. N-Acyl-phosphoramidate derivatives of gemcitabine have similar cytotoxicity as gemcitabine itself, and have been found accessible to the cellular enzymes. The nicotinic carboxamide derivative of gemcitabine 5'-O-phosphorothioate occurred to be the best inhibitor of bacterial DNA polymerase I and human DNA polymerase α.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Ácidos Fosfóricos
/
Pró-Fármacos
/
Desoxicitidina
/
DNA Polimerase I
/
Inibidores Enzimáticos
/
Amidas
Limite:
Humans
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article