Synthesis and Biological Activity of 5, 11-Methylenetetrahydro-5-deazahomofolic Acid

Aleem Gangjee, Isaac Donkor, Roy L. Kisliuk, Yvette Gaumont, Janet Thorndike

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

The synthesis of 5, 11-methylene-5-deazatetrahydrohomofolate (5), a stable, semirigid mimic of 5,10-methylene- tetrahydrofolate (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.

Original languageEnglish (US)
Pages (from-to)611-616
Number of pages6
JournalJournal of Medicinal Chemistry
Volume34
Issue number2
DOIs
StatePublished - Feb 1 1991
Externally publishedYes

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Lactobacillus casei
Thymidylate Synthase
Hydroxymethyl and Formyl Transferases
Naphthyridines
Lactams
Growth Inhibitors
Halogenation
Glutamic Acid
Lymphoma
5,11-methylenetetrahydro-5-deazahomofolic acid
5,6,7,8-tetrahydrofolic acid
2,4,6-triaminopyrimidine
glycinamide ribonucleotide

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

Synthesis and Biological Activity of 5, 11-Methylenetetrahydro-5-deazahomofolic Acid. / Gangjee, Aleem; Donkor, Isaac; Kisliuk, Roy L.; Gaumont, Yvette; Thorndike, Janet.

In: Journal of Medicinal Chemistry, Vol. 34, No. 2, 01.02.1991, p. 611-616.

Research output: Contribution to journalArticle

Gangjee, Aleem ; Donkor, Isaac ; Kisliuk, Roy L. ; Gaumont, Yvette ; Thorndike, Janet. / Synthesis and Biological Activity of 5, 11-Methylenetetrahydro-5-deazahomofolic Acid. In: Journal of Medicinal Chemistry. 1991 ; Vol. 34, No. 2. pp. 611-616.
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