title: New 4'-(4-chlorophenyl)-2,2':6',2″-terpyridine ruthenium(II) complexes: Synthesis, characterization, interaction with DNA/BSA and cytotoxicity studies.
abstract: In this study, we have developed a series of new monofunctional Ru(II) complexes of the general formula mer-[Ru(Cl-Ph-tpy)(N-N)Cl]Cl in which Cl-Ph-tpy is 4'-(4-chlorophenyl)-2,2':6',2″-terpyridine, N-N is a bidentate chelating ligand (1,2-diaminoethane (en, 1), 1,2-diaminocyclohexane (dach, 2) or 2,2'-bipyridine (bpy, 3)). All complexes were fully characterized by elemental analysis and spectroscopic techniques (IR, UV-Vis, 1D and 2D NMR). Their chemical behavior in aqueous solution was studied by UV-Vis and NMR spectroscopy showing that all compounds are relatively labile leading to the formation of the corresponding aqua species 1aq-3aq. Their DNA binding ability was evaluated by UV-Vis spectroscopy, fluorescence quenching measurements and viscosity measurements. Competitive studies with ethidium bromide (EB) showed that the complexes can displace DNA-bound EB, suggesting strong competition with EB (Ksv=1.1-2.7×104M-1). These experiments show that the ruthenium complexes interact with DNA via intercalation. The complexes bind to serum protein albumin displaying relatively high binding constants (Ksv=104-105M-1). Compound 3 displayed from high to moderate cytotoxicity against two cancer cell lines HeLa and A549 (with IC50ca. 12.7μM and 53.8μM, respectively), while complexes 1 and 2 showed only moderate cytotoxicity (with IC50ca. 84.8μM and 96.3μM, respectively) against HeLa cells. The cell cycle analysis (by flow cytometry) of HeLa and A549 cells treated with complex 3 shows minor changes on the cell cycle phase distribution.
authors.affiliation: Faculty of Science, University of Kragujevac, R. Domanovića 12, P. O. Box 60, 34000 Kragujevac, Serbia.
authors.forename: Milan M
authors.initials: MM
authors.lastname: Milutinović
authors.affiliation: Faculty of Science, University of Kragujevac, R. Domanovića 12, P. O. Box 60, 34000 Kragujevac, Serbia. Electronic address: anarilak@kg.ac.rs.
authors.forename: Ana
authors.initials: A
authors.lastname: Rilak
authors.affiliation: I.N.N., Dept. of Physical Chemistry, NCSR "Demokritos", 15310, Ag. Paraskevi, Athens, Greece.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Bratsos
authors.affiliation: Department of Physics, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovića 4, 21000 Novi Sad, Serbia.
authors.forename: Olivera
authors.initials: O
authors.lastname: Klisurić
authors.affiliation: University of Novi Sad, Faculty of Sciences, Department of Chemistry, Biochemistry and Environmental Protection, Trg Dositeja Obradovića 3, 21000 Novi Sad, Serbia.
authors.forename: Milan
authors.initials: M
authors.lastname: Vraneš
authors.affiliation: Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia.
authors.forename: Nevenka
authors.initials: N
authors.lastname: Gligorijević
authors.affiliation: Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia.
authors.forename: Siniša
authors.initials: S
authors.lastname: Radulović
authors.affiliation: Faculty of Science, University of Kragujevac, R. Domanovića 12, P. O. Box 60, 34000 Kragujevac, Serbia. Electronic address: bugarcic@kg.ac.rs.
authors.forename: Živadin D
authors.initials: ŽD
authors.lastname: Bugarčić
mesh_terms: D000072283:A549 Cells; D000818:Animals; D002417:Cattle; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D007364:Intercalating Agents / Q000009:adverse effects / Q000138:chemical synthesis* / Q000737:chemistry*; D011485:Protein Binding; D012428:Ruthenium / Q000737:chemistry*; D017975:Ruthenium Compounds / Q000009:adverse effects / Q000138:chemical synthesis* / Q000737:chemistry*; D012710:Serum Albumin, Bovine / Q000737:chemistry / Q000378:metabolism*
chemical_list: D007364:Intercalating Agents; D017975:Ruthenium Compounds; D012710:Serum Albumin, Bovine; D012428:Ruthenium; D004247:DNA
keywords: Albumin; Cytotoxicity; DNA; Meridional; Ru(II) complexes; Substituted terpyridine