Synthesis and biological activity of 4-amino-7-oxo-substituted analogoues of 5-Deaza-5,6,7,8-tetrahydrofolic acid and 5,10-dideaza-5,6,7,8- tetrahydrofolic acid

J. I. Borrell, J. Teixido, B. Martinez-Teipel, J. L. Metallana, M. T. Copete, A. Llimargas, E. Gracia

Producción científica: Artículo en revista indizadaArtículorevisión exhaustiva

31 Citas (Scopus)

Resumen

The 4-amino-7-oxo-substituted analogues of 5-deaza-5,6,7,8- tetrahydrofolic acid (5-DATHF) and 5,10-dideaza-5,6,7,8-tetrahydrofolic acid (DDATHF) were synthesized as potential antifolates. Treatment of the α,β- unsaturated esters 11a-c, obtained in one synthetic step from commercially available para-substituted benzoates (9a-c) and methyl 2-(bromomethly)- acrylate (10), with malononitrile in NaOMe/MeOH afforded the corresponding pyridones 12a-c. Formation of the pyrido[2,3-d]pyrimidines 13a-c was accomplished upon treatment of 12a-c with guanidine in methanol. After the hydrolysis of the ester group present in 13a-c, the resulting carboxylic acids 14a-c were treated with diethyl cyanophosphonate in Et3N/DMF and coupled with L-glutamic acid dimethyl ester to give 15a-c. Finally, the basic hydrolysis of 15a-c yielded the desired 4-amino-7-oxo-substituted analogues 16a-c in 20-27% overall yield. Compounds 16a-c were tested in vitro against CCRF-CEM leukemia cells. The results obtained indicated that our 4-amino-7- oxo analogues are completely devoid of any activity, the IC50 being higher than 20 μg/mL for all cases except 14c for which a value of 6.7 μg/mL was obtained. These results seem to indicate that 16a-c are inactive precisely due to the presence of the carbonyl group in position C7, the distinctive feature of our synthetic methodology.

Idioma originalInglés
Páginas (desde-hasta)3539-3545
Número de páginas7
PublicaciónJournal of Medicinal Chemistry
Volumen41
N.º18
DOI
EstadoPublicada - 27 ago 1998

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Profundice en los temas de investigación de 'Synthesis and biological activity of 4-amino-7-oxo-substituted analogoues of 5-Deaza-5,6,7,8-tetrahydrofolic acid and 5,10-dideaza-5,6,7,8- tetrahydrofolic acid'. En conjunto forman una huella única.

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