Synthesis and in vitro antiproliferative evaluation of novel N-alkylated 6-isobutyl- and propyl pyrimidine derivatives.
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.
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.
Tatjana
T
Gazivoda Kraljević
Department of Biotechnology, University of Rijeka, Trg braće Mažuranića 10, HR-51000 Rijeka, Croatia.
Nataša
N
Ilić
Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička 54, HR-10002 Zagreb, Croatia.
Višnja
V
Stepanić
Department of Biotechnology, University of Rijeka, Trg braće Mažuranića 10, HR-51000 Rijeka, Croatia.
Lana
L
Sappe
Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulićev trg 19, HR-10000 Zagreb, Croatia.
Jasna
J
Petranović
Department of Biotechnology, University of Rijeka, Trg braće Mažuranića 10, HR-51000 Rijeka, Croatia. Electronic address: sandrakp@biotech.uniri.hr.
Sandra
S
Kraljević Pavelić
Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulićev trg 19, HR-10000 Zagreb, Croatia.
Silvana
S
Raić-Malić
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005347:Fibroblasts / Q000187:drug effects*; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D020014:K562 Cells; D061986:MCF-7 Cells; D015394:Molecular Structure; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D011743:Pyrimidines
Antiproliferative evaluation; C-6-isobutyl pyrimidine; C-6-propyl pyrimidine; In silico analysis; N-Alkylated pyrimidine derivatives