Synthesis and Biological Activity of 4-Amino-7-oxo-Substituted Analogues of 5-Deaza-5,6,7,8-tetrahydrofolic Acid and 5,10-Dideaza-5,6,7,8-tetrahydrofolic Acid

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...

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Published in:Journal of medicinal chemistry Vol. 41; no. 18; pp. 3539 - 3545
Main Authors: Borrell, José I, Teixidó, Jordi, Martínez-Teipel, Blanca, Matallana, Josep Lluís, Copete, M. Teresa, Llimargas, Ana, García, Eva
Format: Journal Article
Language:English
Published: Washington, DC American Chemical Society 27-08-1998
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Summary: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 methyl benzoates (9a − c) and methyl 2-(bromomethyl)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.
Bibliography:ark:/67375/TPS-361FCRTP-P
istex:3C54147E7A6260D1F8288976D894C047DD4580BE
ISSN:0022-2623
1520-4804
DOI:10.1021/jm9801298