Synthesis and in vitro antiproliferative evaluation of novel N-alkylated 6-isobutyl- and propyl pyrimidine derivatives

Bioorg Med Chem Lett. 2014 Jul 1;24(13):2913-7. doi: 10.1016/j.bmcl.2014.04.079.

Tatjana Gazivoda Kraljević ¹, Nataša Ilić ², Višnja Stepanić ³, Lana Sappe ², Jasna Petranović ⁴, Sandra Kraljević Pavelić ⁵, Silvana Raić-Malić ⁴

Affiliations

1 Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulićev trg 19, HR-10000 Zagreb, Croatia. Electronic address: tgazivod@fkit.hr.
2 Department of Biotechnology, University of Rijeka, Trg braće Mažuranića 10, HR-51000 Rijeka, Croatia.
3 Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička 54, HR-10002 Zagreb, Croatia.
4 Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulićev trg 19, HR-10000 Zagreb, Croatia.
5 Department of Biotechnology, University of Rijeka, Trg braće Mažuranića 10, HR-51000 Rijeka, Croatia. Electronic address: sandrakp@biotech.uniri.hr.

PMID: 24835982 DOI: 10.1016/j.bmcl.2014.04.079

Abstract

A series of novel N-alkylated C-6-isobutyl- or -propyl pyrimidine derivatives were synthesized and their antiproliferative effect was evaluated on a panel of tumor cell lines including leukemia cell line K562 and normal diploid human fibroblasts. N-methoxymethylated 5-methylpyrimidin-2,4-dione with di(benzyloxy)isobutyl at C-6 (14b) showed the strongest effect on the cell growth at micromolar concentrations. Mechanisms of action for the lipophilic compound 14b predicted in silico, pointed to its Anticancer and antimetastatic potential exerted through inhibition of DNA or RNA polymerases and adhesion molecules. The latter mechanism has been supported in vitro for adherent tumor cell lines.

Keywords

Antiproliferative evaluation; C-6-isobutyl pyrimidine; C-6-propyl pyrimidine; In silico analysis; N-Alkylated pyrimidine derivatives.

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