Synthesis and preliminary in vitro screening of lipophilic alpha, gamma-bis(amides) as potential prodrugs of methotrexate.
Anticancer Drug Des
; 11(3): 253-64, 1996 Apr.
Article
en En
| MEDLINE
| ID: mdl-8663912
As part of a program aimed at studying the feasibility of amide derivatives of methotrexate (MTX) as lipophilic prodrugs, with the aims of increasing passive cellular uptake and obtaining prolonged-release agents, we describe the synthesis of five long-chain alkyl bis(amides) of MTX, from decyl- to octadecylamide, by direct transamidation to the MTX diethyl ester. Compounds were subjected to a preliminary biological screening, to assess their inhibitory activity against bovine liver dihydrofolate reductase (DHFR) and in vitro antitumor activity against human leukemia CCRF-CEM cells. As a general trend, an increase in lipophilicity led to a linear reduction of enzyme inhibition; however, the bis(decyl)amide derivative showed a good intrinsic affinity for DHFR (IC50 6.41 nM), comparable to that of MTX diethyl ester and close to that of MTX (IC50 2.90 nM). In the antitumor assay, lower homologues (C10-C14) displayed an interesting activity profile, suggesting the desirability of additional studies with these and similar compounds.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Profármacos
/
Metotrexato
/
Antimetabolitos Antineoplásicos
Tipo de estudio:
Diagnostic_studies
/
Screening_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Anticancer Drug Des
Asunto de la revista:
ANTINEOPLASICOS
/
FARMACOLOGIA
Año:
1996
Tipo del documento:
Article
País de afiliación:
Italia
Pais de publicación:
Estados Unidos