Synthesis, cytostatic activity and ADME properties of C-5 substituted and N-acyclic pyrimidine derivatives |
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| Authors: | Kraljević Tatjana Gazivoda Klika Mateja Kralj Marijeta Martin-Kleiner Irena Jurmanović Stella Milić Astrid Padovan Jasna Raić-Malić Silvana |
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| Institution: | 1. Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Maruli?ev trg 19, HR-10000 Zagreb, Croatia;2. Division of Molecular Medicine, Ru?er Bo?kovi? Institute, Bijeni?ka 54, HR-10001 Zagreb, Croatia;3. Galapagos Research Centre Zagreb Ltd, Prilaz baruna Filipovi?a 29, HR-10000 Zagreb, Croatia |
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| Abstract: | The synthesis of the novel 5-alkyl pyrimidine derivatives, 5,6-dihydrofuro2,3-d]pyrimidines and 5-alkyl N-methoxymethyl pyrimidine derivatives and evaluation of their cytostatic activities are described. The mechanism of antiproliferative effect of 5-(2-chloroethyl)-substituted pyrimidine 3 that exerted the pronounced cytostatic activity was studied in further details on colon carcinoma (HCT116) cells. The cell cycle perturbation analysis demonstrated severe DNA damage (G2/M arrest) pointing to a potential DNA alkylating ability of 3. Preliminary ADME data of 3 and its 6-methylated structural congener (6-Me-3) showed their high permeability and good metabolic stability. |
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