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 alpha,beta-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 microg/mL for all cases except 14c for which a value of 6.7 microg/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.
Departament de Química Orgànica, Institut Químic de Sarrià, Universitat Ramon Llull, Via Augusta 390, E-08017 Barcelona, Spain.
J I
JI
Borrell
J
J
Teixidó
B
B
Martínez-Teipel
J L
JL
Matallana
M T
MT
Copete
A
A
Llimargas
E
E
García
D000964:Antimetabolites, Antineoplastic / Q000138:chemical synthesis / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005493:Folic Acid Antagonists / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D013329:Structure-Activity Relationship; D013763:Tetrahydrofolates / Q000138:chemical synthesis / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D005493:Folic Acid Antagonists; D013763:Tetrahydrofolates; C060147:5-deaza-5,6,7,8-tetrahydrofolic acid; C045894:lometrexol