Synthesis and biological activity of 5,11-methylenetetrahydro-5- deazahomofolic acid.
The synthesis of 5,11-methylene-5-deazatetrahydrohomofolate (5), a stable, semirigid mimic of 5,10-methylenetetrahydrofolate (4) is reported as a potential inhibitor of thymidylate synthases (TS). The key intermediate 3-amino-1-oxo-tetrahydropyrimido[4,5-c] [2,6]naphthyridine (6) was obtained by the regiospecific cyclocondensation of 2,4,6-triaminopyrimidine with ethyl 1-benzyl-3-oxo-4-piperidinecarboxylate followed by halogenation (of the resulting lactam 9) and catalytic hydrogenolysis. Selective reduction of 6 followed by arylation with tert-butyl p-fluorobenzoate, saponification, and coupling with diethyl L-glutamate followed by saponification afforded the target compound 5. The title compound was tested as an inhibitor of the growth of Manca human lymphoma cells and also as an inhibitor of TS from Manca cells and Lactobacillus casei and was found to be inactive. In addition, compound 5 also failed to inhibit glycinamide ribonucleotide formyltransferase from L. casei and from Manca cells.
Gangjee
A
A
Department of Pharmaceutical Chemistry and Pharmaceutics, School of Pharmacy, Duquesne University, Pittsburgh, Pennsylvania 15282.
Donkor
I O
IO
Kisliuk
R L
RL
Gaumont
Y
Y
Thorndike
J
J
D002460:Cell Line; D055598:Chemical Phenomena; D002621:Chemistry; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy; D013237:Stereoisomerism; D013763:Tetrahydrofolates / Q000138:chemical synthesis* / Q000494:pharmacology; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*
D013763:Tetrahydrofolates; C067393:5,11-methylenetetrahydro-5-deazahomofolic acid; D013940:Thymidylate Synthase