Abstract
The synthetic route for introduction of fluorophenylalkyl (compounds 5, 7, 14 and 15) and fluorophenylalkenyl (compounds 4E and 13) side chains at C-6 of the pyrimidine nucleus involved the lithiation of the pyrimidine derivatives 1, 2 and 11 and subsequent nucleophilic addition or substitution reactions of the organolithium intermediate thus obtained with 2-fluorophenylacetone, 4-fluoroacetophenone or ethyl 4-fluorobenzoate as electrophiles. The structures of novel compounds were confirmed by 1H-, 19F- and 13C-NMR and MS. Compounds 8 and 10 containing unsaturated fluorophenylalkyl side chains showed better inhibitory effect than their saturated fluorophenylalkylated pyrimidine counterparts 7 and 9. A conformational study based on NOE enhancements showed the importance of the double bond and substitution in the side chain for the conformational preferences in relation to inhibitory activity. Among all tested compounds, C-5 furyl (12) and phenyl (13 and 15) substituted pyrimidine derivatives showed significant cytostatic activities against all tested tumor cell lines.
Highlights
The application of fluorine-containing compounds in the pharmaceutical and agrochemical fields has a very short history [1,2]
We have reported the synthesis and biological results of a new type of C-6 fluoroalkylated and fluorophenylalkylated pyrimidine derivatives as model compounds for development of tracer molecules in positron-emission tomography (PET) [10]
In this study we present the syntheses and antitumoral evaluations of C-6 fluorophenylalkyl (6, 9, 14 and 15), fluorophenylalkenyl (4, 8, 10 and 13) and 5-furyl-6-methyl (12)
Summary
The application of fluorine-containing compounds in the pharmaceutical and agrochemical fields has a very short history [1,2]. Fluorine affects the biological activity of compounds in a number of important ways. A great number of C-5 and C-6 substituted pyrimidine nucleosides have been prepared in view of their various biological activities [8]. For this reason, the development of synthetic methods for fluorine-containing heterocyclic compounds has been an important field in both organofluorine chemistry and organic synthesis. We have reported the synthesis and biological results of a new type of C-6 fluoroalkylated and fluorophenylalkylated pyrimidine derivatives as model compounds for development of tracer molecules in positron-emission tomography (PET) [10].
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