Amidine- and Amidoxime-Substituted Heterocycles: Synthesis, Antiproliferative Evaluations and DNA Binding
Silvija Maračić,
Petra Grbčić,
Suresh Shammugam,
Marijana Radić Stojković,
Krešimir Pavelić,
Mirela Sedić,
Sandra Kraljević Pavelić,
Silvana Raić-Malić
Affiliations
Silvija Maračić
Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulićev trg 19, HR-10000 Zagreb, Croatia
Petra Grbčić
Department of Biotechnology, University of Rijeka, Ulica Radmile Matejčić 2, HR-51000 Rijeka, Croatia
Suresh Shammugam
Division of Organic Chemistry and Biochemistry, Laboratory for Biomolecular Interactions and Spectroscopy, Ruđer Bošković Institute, Bijenička 54, HR-10000 Zagreb, Croatia
Marijana Radić Stojković
Division of Organic Chemistry and Biochemistry, Laboratory for Biomolecular Interactions and Spectroscopy, Ruđer Bošković Institute, Bijenička 54, HR-10000 Zagreb, Croatia
Krešimir Pavelić
Faculty of Medicine, Juraj Dobrila University of Pula, HR-52100 Pula, Croatia
Mirela Sedić
Centre for Applied Bioanthropology, Institute for Anthropological Research, Ljudevita Gaja 32, HR-10000 Zagreb, Croatia
Sandra Kraljević Pavelić
Faculty of Health Studies, University of Rijeka, Ulica Viktora Cara Emina 5, HR-51000 Rijeka, Croatia
Silvana Raić-Malić
Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulićev trg 19, HR-10000 Zagreb, Croatia
The novel 1,2,3-triazolyl-appended N- and O-heterocycles containing amidine 4–11 and amidoxime 12–22 moiety were prepared and evaluated for their antiproliferative activities in vitro. Among the series of amidine-substituted heterocycles, aromatic diamidine 5 and coumarine amidine 11 had the most potent growth-inhibitory effect on cervical carcinoma (HeLa), hepatocellular carcinoma (HepG2) and colorectal adenocarcinoma (SW620), with IC50 values in the nM range. Although compound 5 was toxic to non-tumor HFF cells, compound 11 showed certain selectivity. From the amidoxime series, quinoline amidoximes 18 and 20 showed antiproliferative effects on lung adenocarcinoma (A549), HeLa and SW620 cells emphasizing compound 20 that exhibited no cytostatic effect on normal HFF fibroblasts. Results of CD titrations and thermal melting experiments indicated that compounds 5 and 10 most likely bind inside the minor groove of AT-DNA and intercalate into AU-RNA. Compounds 6, 9 and 11 bind to AT-DNA with mixed binding mode, most probably minor groove binding accompanied with aggregate binding along the DNA backbone.
