Synthesis and Evaluation of 6-(Dibromomethyl)-5-nitropyrimidines as Potential Antitumor Agents

• Published in: Journal of medicinal chemistry 1997-02, Vol.40 (5), p.766-770
• Main Authors: Thompson, M. Daniel, Cupps, Thomas L, Wise, Dean S, Wotring, Linda L, Townsend, Leroy B
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Biological and medical sciences; Cell Division - drug effects; Drug Screening Assays, Antitumor; General aspects; Humans; Magnetic Resonance Spectroscopy; Medical sciences; Mice; Molecular Structure; Neoplasms, Experimental - drug therapy; Pharmacology. Drug treatments; Purine Nucleosides - chemical synthesis; Purine Nucleosides - chemistry; Purine Nucleosides - pharmacology; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Ribonucleosides - chemical synthesis; Ribonucleosides - chemistry; Ribonucleosides - pharmacology; Structure-Activity Relationship; Tumor Cells, Cultured
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm9605546

A series of 2,4,6-trisubstituted-5-nitropyrimidines have been prepared and evaluated for inhibition of proliferation of L1210 and H.Ep.2 cells in vitro. The most potent compound was 6-(dibromomethyl)-2-methoxy-4-morpholino-5-nitropyrimidine (11) (L1210, IC50 = 0.32 μM; H.Ep.2, IC50 = 1.6 μM). Of the 6-substituents incorporated, only CHBr2, CH2Br, and CHO were compatible with antiproliferative activity, while a wider variety of 4-substituents were tolerated. At concentrations near the IC50 for antiproliferative activity, a delayed resumption of cell proliferation in L1210 cultures indicated that the activity of the compounds was short-lived and suggested they might act by an alkylation mechanism.