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. 2009 Nov 27;14(12):4866-79.
doi: 10.3390/molecules14124866.

Synthesis, structural studies and antitumoral evaluation of C-6 alkyl and alkenyl side chain pyrimidine derivatives

Svjetlana Kristafor  1 , Tatjana Gazivoda Kraljević, Damjan Makuc, Janez Plavec, Lidija Suman, Marijeta Kralj, Silvana Raić-Malić
Affiliations

Synthesis, structural studies and antitumoral evaluation of C-6 alkyl and alkenyl side chain pyrimidine derivatives

Svjetlana Kristafor et al. Molecules. .

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 (1)H-, (19)F- and (13)C-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.

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Figures

Scheme 1
Scheme 1
Synthesis of C-6 alkyl and alkenyl side chain pyrimidine derivatives (4-10).
Scheme 2
Scheme 2
Synthesis of 5-phenylpyrimidine derivatives with C-6 fluorophenylalkyl side chain (13-15).
Figure 1
Figure 1
Dose-response profiles for compounds 12 and 15. PG = percentage of growth.
Figure 2
Figure 2
Cell cycle analysis of HCT 116 cells treated with 1, 5 and 10 μM compounds 12 and 15, 24 h (A and C, respectively), or 48 h (B and D, respectively). The histograms show percentages of live cells in G0/G1, S or G2/M phase, along with the number of dead (subG1) cells, where subG1 population is expressed as a percentage of total number of measured cells/counts.
Figure 3
Figure 3
The key NOE enhancements and configuration along C1'=C2' double bond for a) 4E, b) 8 and c) 10 in DMSO-d6 solution.
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