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.
Borrell
J I
JI
Departament de Química Orgànica, Institut Químic de Sarrià, Universitat Ramon Llull, Via Augusta 390, E-08017 Barcelona, Spain.
Teixidó
J
J
Martínez-Teipel
B
B
Matallana
J L
JL
Copete
M T
MT
Llimargas
A
A
García
E
E
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