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The synthetic route for introduction of a fluoroalkyl (7-12, 14), fluoroalkenyl (16 and 17), fluorophenylalkyl (18, 20, 21 and 23) and fluorophenylalkenyl (19, 22) 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 (Figure).1 Conformational properties of the novel fluorinated pyrimidine derivatives were assessed by the use of 1D difference NOE enhancements and C-F coupling constants. The novel compounds 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 that is generally more active than the series of fluorophenylalkylated pyrimidines, compounds 8 and 14 displayed moderate cytostatic activities against the tested tumor cell lines. Compounds 6, 8 and 15a are worth considering for further development because they afforded a limited specific activity against varicella zoster virus (VZV) and cytomegalovirus (CMV) at a 10-fold lower concentration than that required for cytotoxicity. 1. Raić-Malić, S., et al., Nucl. Nucl. & Nucl. Acids 2004, 23, 1707 ; Johayem, A., Raić-Malić, S., et al., Chemistry&Biodiversity 2006, 3, 274 ; Prekupec, S., Raić-Malić, S., et al., Antiviral Chem. & Chemother. 2005, 16, 327. |
