Gazivoda Kraljević Tatjana, Ilić Nataša, Stepanić Višnja, Sappe Lana, Petranović Jasna, Kraljević Pavelić Sandra, Raić-Malić Silvana
Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulićev trg 19, HR-10000 Zagreb, Croatia.
Department of Biotechnology, University of Rijeka, Trg braće Mažuranića 10, HR-51000 Rijeka, Croatia.
Bioorg Med Chem Lett. 2014 Jul 1;24(13):2913-7. doi: 10.1016/j.bmcl.2014.04.079. Epub 2014 Apr 30.
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.
合成了一系列新型的N-烷基化C-6-异丁基或-丙基嘧啶衍生物，并在包括白血病细胞系K562和正常二倍体人成纤维细胞在内的一组肿瘤细胞系上评估了它们的抗增殖作用。在C-6位带有二（苄氧基）异丁基的N-甲氧基甲基化5-甲基嘧啶-2,4-二酮（14b）在微摩尔浓度下对细胞生长显示出最强的作用。通过计算机模拟预测的亲脂性化合物14b的作用机制表明，其抗癌和抗转移潜力是通过抑制DNA或RNA聚合酶以及粘附分子来发挥的。后一种机制已在体外对贴壁肿瘤细胞系得到了支持。
