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Synthesis, Structural Studies and Antitumoral Evaluation of C-6 Alkyl and Alkenyl Side Chain Pyrimidine Derivatives S
Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulićev trg 20, P.O. Box 177, HR-10000 Zagreb, Croatia
Slovenian NMR Centre, National Institute of Chemistry, Hajdrihova 19, P.O. Box 660, SI-1001 Ljubljana, Slovenia
Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička 54, P.O. Box 1016, HR-10001, Zagreb, Croatia
* Author to whom correspondence should be addressed.
Received: 30 September 2009; in revised form: 19 November 2009 / Accepted: 25 November 2009 / Published: 27 November 2009
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.
Keywords: C-6 alkyl and alkenyl pyrimidine derivatives; NMR conformational analysis; cytostatic activity evaluations
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Krištafor, S.; Gazivoda Kraljević, T.; Makuc, D.; Plavec, J.; Šuman, L.; Kralj, M.; Raić-Malić, S. Synthesis, Structural Studies and Antitumoral Evaluation of C-6 Alkyl and Alkenyl Side Chain Pyrimidine Derivatives S. Molecules 2009, 14, 4866-4879.
Krištafor S, Gazivoda Kraljević T, Makuc D, Plavec J, Šuman L, Kralj M, Raić-Malić S. Synthesis, Structural Studies and Antitumoral Evaluation of C-6 Alkyl and Alkenyl Side Chain Pyrimidine Derivatives S. Molecules. 2009; 14(12):4866-4879.
Krištafor, Svjetlana; Gazivoda Kraljević, Tatjana; Makuc, Damjan; Plavec, Janez; Šuman, Lidija; Kralj, Marijeta; Raić-Malić, Silvana. 2009. "Synthesis, Structural Studies and Antitumoral Evaluation of C-6 Alkyl and Alkenyl Side Chain Pyrimidine Derivatives S." Molecules 14, no. 12: 4866-4879.