Synthesis, antifolate, and antitumor activities of classical and nonclassical 2-amino-4-oxo-5-substituted-pyrrolo[2,3-d]pyrimidines

A. Gangjee, A. Vidwans, E. Elzein, J. J. McGuire, Sherry Queener, R. L. Kisliuk

Research output: Contribution to journalArticle

66 Citations (Scopus)

Abstract

Classical and nonclassical isosteric C8-N9 bridged analogues of the multitargeted antifolate LY231514 were synthesized as inhibitors of thymidylate synthase (TS), dihydrofolate reductase (DHFR), and as antitumor and antiopportunistic infection agents. The syntheses of the analogues were accomplished by reductive amination of the appropriate anilines with 2-amino-4-oxo-5-cyanopyrrolo[2,3-d]pyrimidine (28) followed by saponification of the ethyl esters, for the classical analogue 6. The N9-methyl analogues were obtained from the N9-H precursors by reductive methylation. In general, the nonclassical compounds 7-17 were similar in potency to TMP against Toxoplasma gondii DHFR, with selectivity ratios greater than 38 and 21 for 11 and 16, respectively. These compounds were poor inhibitors of Pneumocystis carinii DHFR and rat liver DHFR. The nonclassical analogues were also inactive against TS. The classical analogue 6 was a marginal inhibitor of isolated human TS (IC50 = 46 μM) and of human DHFR (IC50 = 10 μM), however, it was a potent inhibitor of the growth of two human head and neck squamous cell carcinoma cell lines and of CCRF-CEM human lymphoblastic leukemia cells in culture and was similar to LY231514 against ZR-75-1 human breast carcinoma cell line. Evaluation of 6 against MTX-resistant sublines indicated that DHFR is not the major target of 6. Metabolite protection studies of the growth inhibitory activity of 6 suggest that TS is a major target of this drug and that polyglutamyl forms of 6 may serve as the intracellular TS inhibitors. These studies also suggest that 6 has a site of action in addition to sites in the folate pathway.

Original languageEnglish
Pages (from-to)1993-2003
Number of pages11
JournalJournal of Medicinal Chemistry
Volume44
Issue number12
DOIs
StatePublished - Jun 7 2001

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Folic Acid Antagonists
Tetrahydrofolate Dehydrogenase
Thymidylate Synthase
Pemetrexed
Inhibitory Concentration 50
Aniline Compounds
Cells
Thymidine Monophosphate
Saponification
Amination
Pneumocystis carinii
Cell Line
Growth Inhibitors
Methylation
Toxoplasma
Metabolites
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Folic Acid
Liver
Rats

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Synthesis, antifolate, and antitumor activities of classical and nonclassical 2-amino-4-oxo-5-substituted-pyrrolo[2,3-d]pyrimidines. / Gangjee, A.; Vidwans, A.; Elzein, E.; McGuire, J. J.; Queener, Sherry; Kisliuk, R. L.

In: Journal of Medicinal Chemistry, Vol. 44, No. 12, 07.06.2001, p. 1993-2003.

Research output: Contribution to journalArticle

Gangjee, A. ; Vidwans, A. ; Elzein, E. ; McGuire, J. J. ; Queener, Sherry ; Kisliuk, R. L. / Synthesis, antifolate, and antitumor activities of classical and nonclassical 2-amino-4-oxo-5-substituted-pyrrolo[2,3-d]pyrimidines. In: Journal of Medicinal Chemistry. 2001 ; Vol. 44, No. 12. pp. 1993-2003.
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AU - Queener, Sherry

AU - Kisliuk, R. L.

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AB - Classical and nonclassical isosteric C8-N9 bridged analogues of the multitargeted antifolate LY231514 were synthesized as inhibitors of thymidylate synthase (TS), dihydrofolate reductase (DHFR), and as antitumor and antiopportunistic infection agents. The syntheses of the analogues were accomplished by reductive amination of the appropriate anilines with 2-amino-4-oxo-5-cyanopyrrolo[2,3-d]pyrimidine (28) followed by saponification of the ethyl esters, for the classical analogue 6. The N9-methyl analogues were obtained from the N9-H precursors by reductive methylation. In general, the nonclassical compounds 7-17 were similar in potency to TMP against Toxoplasma gondii DHFR, with selectivity ratios greater than 38 and 21 for 11 and 16, respectively. These compounds were poor inhibitors of Pneumocystis carinii DHFR and rat liver DHFR. The nonclassical analogues were also inactive against TS. The classical analogue 6 was a marginal inhibitor of isolated human TS (IC50 = 46 μM) and of human DHFR (IC50 = 10 μM), however, it was a potent inhibitor of the growth of two human head and neck squamous cell carcinoma cell lines and of CCRF-CEM human lymphoblastic leukemia cells in culture and was similar to LY231514 against ZR-75-1 human breast carcinoma cell line. Evaluation of 6 against MTX-resistant sublines indicated that DHFR is not the major target of 6. Metabolite protection studies of the growth inhibitory activity of 6 suggest that TS is a major target of this drug and that polyglutamyl forms of 6 may serve as the intracellular TS inhibitors. These studies also suggest that 6 has a site of action in addition to sites in the folate pathway.

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