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Impact of aromaticity on anticancer activity of polypyridyl ruthenium(II) complexes: synthesis, structure, DNA/protein binding, lipophilicity and anticancer activity.
J Biol Inorg Chem. 2017 Oct; 22(7):1007-1028.JB

Abstract

With the aim of assessing how the aromaticity of the inert chelating ligand can influence the activity of ruthenium(II) polypyridyl complexes, two new monofunctional ruthenium(II) complexes, [Ru(Cl-Ph-tpy)(phen)Cl]Cl (1) and [Ru(Cl-Ph-tpy)(o-bqdi)Cl]Cl (2) (where Cl-Ph-tpy = 4'-(4-chlorophenyl)-2,2':6',2″-terpyridine, phen = 1,10-phenanthroline, o-bqdi = o-benzoquinonediimine), were synthesized. All complexes were fully characterized by elemental analysis and spectroscopic techniques (IR, UV-Vis, 1D and 2D NMR, XRD). Their chemical behavior in aqueous solution was studied by UV-Vis and NMR spectroscopy showing that both compounds are relatively labile leading to the formation of the corresponding aqua species 1a and 2a. 1H NMR spectroscopy studies performed on complexes 1 and 2 demonstrated that after the hydrolysis of the Cl ligand, they are capable to interact with guanine derivatives (i.e., 9-methylguanine (9MeG) and 5'-GMP) through the N7, forming monofunctional adduct. The kinetics and the mechanism of the reaction of complexes 1 and 2 with the biologically more relevant 5'-GMP ligand were studied by UV-Vis spectroscopy. DNA/protein interactions of the complexes have been examined by photophysical studies, which demonstrated a bifunctional binding mode of the complexes with DNA and the complexes strongly quench the fluorescence intensity of bovine serum albumin (BSA) through the mechanism of both static and dynamic quenching. Complexes 1 and 2 strongly induced apoptosis of treated cancer cells with high percentages of apoptotic cells and negligible percentage of necrotic cells. In addition, both ruthenium complexes decreased Bcl-2/Bax ratio causing cytochrome c mitochondrial release, the activation of caspase-3 and induction of apoptosis.

Authors+Show Affiliations

Department of Biochemistry, Faculty of Medical Sciences, University of Kragujevac, Serbia, Svetozara Markovića 69, 34000, Kragujevac, Serbia.Faculty of Science, University of Kragujevac, R. Domanovića 12, P. O. Box 60, 34000, Kragujevac, Serbia. anarilak@kg.ac.rs.Faculty of Science, University of Kragujevac, R. Domanovića 12, P. O. Box 60, 34000, Kragujevac, Serbia.Department of Physical Chemistry, NCSR "Demokritos", I.N.N, 15310 Ag. Paraskevi, Athens, Greece.Elettra, Sincrotrone Trieste, S.S. 14 km 163.5 in Area Science Park, 34149, Basovizza, Trieste, Italy.Department of Biochemistry, Faculty of Medical Sciences, University of Kragujevac, Serbia, Svetozara Markovića 69, 34000, Kragujevac, Serbia.Department of Biochemistry, Faculty of Medical Sciences, University of Kragujevac, Serbia, Svetozara Markovića 69, 34000, Kragujevac, Serbia.Faculty of Science, University of Kragujevac, R. Domanovića 12, P. O. Box 60, 34000, Kragujevac, Serbia. bugarcic@kg.ac.rs.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28695374

Citation

Čanović, Petar, et al. "Impact of Aromaticity On Anticancer Activity of Polypyridyl ruthenium(II) Complexes: Synthesis, Structure, DNA/protein Binding, Lipophilicity and Anticancer Activity." Journal of Biological Inorganic Chemistry : JBIC : a Publication of the Society of Biological Inorganic Chemistry, vol. 22, no. 7, 2017, pp. 1007-1028.
Čanović P, Simović AR, Radisavljević S, et al. Impact of aromaticity on anticancer activity of polypyridyl ruthenium(II) complexes: synthesis, structure, DNA/protein binding, lipophilicity and anticancer activity. J Biol Inorg Chem. 2017;22(7):1007-1028.
Čanović, P., Simović, A. R., Radisavljević, S., Bratsos, I., Demitri, N., Mitrović, M., Zelen, I., & Bugarčić, Ž. D. (2017). Impact of aromaticity on anticancer activity of polypyridyl ruthenium(II) complexes: synthesis, structure, DNA/protein binding, lipophilicity and anticancer activity. Journal of Biological Inorganic Chemistry : JBIC : a Publication of the Society of Biological Inorganic Chemistry, 22(7), 1007-1028. https://doi.org/10.1007/s00775-017-1479-7
Čanović P, et al. Impact of Aromaticity On Anticancer Activity of Polypyridyl ruthenium(II) Complexes: Synthesis, Structure, DNA/protein Binding, Lipophilicity and Anticancer Activity. J Biol Inorg Chem. 2017;22(7):1007-1028. PubMed PMID: 28695374.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Impact of aromaticity on anticancer activity of polypyridyl ruthenium(II) complexes: synthesis, structure, DNA/protein binding, lipophilicity and anticancer activity. AU - Čanović,Petar, AU - Simović,Ana Rilak, AU - Radisavljević,Snežana, AU - Bratsos,Ioannis, AU - Demitri,Nicola, AU - Mitrović,Marina, AU - Zelen,Ivanka, AU - Bugarčić,Živadin D, Y1 - 2017/07/10/ PY - 2017/05/09/received PY - 2017/06/24/accepted PY - 2017/7/12/pubmed PY - 2017/12/16/medline PY - 2017/7/12/entrez KW - Albumin binding KW - Anticancer activity KW - Apoptosis KW - DNA binding KW - Ru complexes SP - 1007 EP - 1028 JF - Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry JO - J. Biol. Inorg. Chem. VL - 22 IS - 7 N2 - With the aim of assessing how the aromaticity of the inert chelating ligand can influence the activity of ruthenium(II) polypyridyl complexes, two new monofunctional ruthenium(II) complexes, [Ru(Cl-Ph-tpy)(phen)Cl]Cl (1) and [Ru(Cl-Ph-tpy)(o-bqdi)Cl]Cl (2) (where Cl-Ph-tpy = 4'-(4-chlorophenyl)-2,2':6',2″-terpyridine, phen = 1,10-phenanthroline, o-bqdi = o-benzoquinonediimine), were synthesized. All complexes were fully characterized by elemental analysis and spectroscopic techniques (IR, UV-Vis, 1D and 2D NMR, XRD). Their chemical behavior in aqueous solution was studied by UV-Vis and NMR spectroscopy showing that both compounds are relatively labile leading to the formation of the corresponding aqua species 1a and 2a. 1H NMR spectroscopy studies performed on complexes 1 and 2 demonstrated that after the hydrolysis of the Cl ligand, they are capable to interact with guanine derivatives (i.e., 9-methylguanine (9MeG) and 5'-GMP) through the N7, forming monofunctional adduct. The kinetics and the mechanism of the reaction of complexes 1 and 2 with the biologically more relevant 5'-GMP ligand were studied by UV-Vis spectroscopy. DNA/protein interactions of the complexes have been examined by photophysical studies, which demonstrated a bifunctional binding mode of the complexes with DNA and the complexes strongly quench the fluorescence intensity of bovine serum albumin (BSA) through the mechanism of both static and dynamic quenching. Complexes 1 and 2 strongly induced apoptosis of treated cancer cells with high percentages of apoptotic cells and negligible percentage of necrotic cells. In addition, both ruthenium complexes decreased Bcl-2/Bax ratio causing cytochrome c mitochondrial release, the activation of caspase-3 and induction of apoptosis. SN - 1432-1327 UR - https://www.unboundmedicine.com/medline/citation/28695374/Impact_of_aromaticity_on_anticancer_activity_of_polypyridyl_ruthenium_II__complexes:_synthesis_structure_DNA/protein_binding_lipophilicity_and_anticancer_activity_ L2 - https://dx.doi.org/10.1007/s00775-017-1479-7 DB - PRIME DP - Unbound Medicine ER -