title: Synthesis, cytostatic activity and ADME properties of C-5 substituted and N-acyclic pyrimidine derivatives.
abstract: The synthesis of the novel 5-alkyl pyrimidine derivatives, 5,6-dihydrofuro[2,3-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.
authors: Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulićev trg 19, HR-10000 Zagreb, Croatia.
authors: Tatjana Gazivoda
authors: TG
authors: Kraljević
authors: Mateja
authors: M
authors: Klika
authors: Marijeta
authors: M
authors: Kralj
authors: Irena
authors: I
authors: Martin-Kleiner
authors: Stella
authors: S
authors: Jurmanović
authors: Astrid
authors: A
authors: Milić
authors: Jasna
authors: J
authors: Padovan
authors: Silvana
authors: S
authors: Raić-Malić
mesh_terms: D000477:Alkylating Agents / Q000494:pharmacology; D000818:Animals; D002455:Cell Division; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002626:Chemistry, Pharmaceutical / Q000379:methods; D054697:Cytostatic Agents / Q000494:pharmacology; D004247:DNA / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D016195:G2 Phase; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008956:Models, Chemical; D010539:Permeability; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry; D051381:Rats
chemical_list: D000477:Alkylating Agents; D054697:Cytostatic Agents; D011743:Pyrimidines; D004247:DNA