Novel C-6 fluorinated acyclic side chain pyrimidine derivatives: synthesis, (1)H and (13)C NMR conformational studies, and antiviral and cytostatic evaluations

• Published in: Journal of medicinal chemistry 2007-06, Vol.50 (13), p.3037
• Main Authors: Prekupec, Svjetlana, Makuc, Damjan, Plavec, Janez, Suman, Lidija, Kralj, Marijeta, Pavelić, Kresimir, Balzarini, Jan, Clercq, Erik De, Mintas, Mladen, Raić-Malić, Silvana
• Format: Article
• Language: English
• Subjects: Animals; Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Cell Line; Cell Line, Tumor; Cercopithecus aethiops; Cytostatic Agents - chemical synthesis; Cytostatic Agents - chemistry; Cytostatic Agents - pharmacology; Drug Screening Assays, Antitumor; Humans; Magnetic Resonance Spectroscopy; Mice; Models, Molecular; Molecular Conformation; Molecular Mimicry; Positron-Emission Tomography; Pyrimidine Nucleosides - chemistry; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Structure-Activity Relationship
• ISSN: 0022-2623
• DOI: 10.1021/jm0614329

The synthetic route for introduction of a fluoroalkyl (7-12, 14), fluoroalkenyl (15 and 16), fluorophenylalkyl (17, 19, 20, and 22), and fluorophenylalkenyl (18, 21) side chain at C-6 of the pyrimidine involved the lithiation of the pyrimidine derivatives 3 and 3a and subsequent nucleophilic addition or substitution reactions of the organolithium intermediate thus obtained with various electrophiles. Conformational properties of the novel fluorinated pyrimidine derivatives were assessed by the use of 1D difference NOE enhancements and C-F coupling constants. Compounds 4-22 were evaluated for their antiviral and cytostatic activities. Of all compounds evaluated, the 5-bromopyrimidine derivatives 5 and 6 showed the highest inhibitory activities. Among the series of fluoroalkylated pyrimidines, which is generally more active than the series of fluorophenylalkylated pyrimidines, compounds 8 and 14 displayed moderate cytostatic activities against the tested tumor cell lines. Moreover, compound 8 containing a 2-fluoromethylpropyl side chain expressed some but not highly specific activity against varicella-zoster virus (VZV). From C-6 fluorophenylalkylated pyrimidine derivatives, 17a and 21 showed a slight activity against cytomegalovirus (CMV), VZV, and Coxsackie B4 virus, respectively. Besides, compounds 17a and 21 showed no cytotoxic effect.