JBIC Journal of Biological Inorganic Chemistry

, Volume 22, Issue 7, pp 1007–1028 | Cite as

Impact of aromaticity on anticancer activity of polypyridyl ruthenium(II) complexes: synthesis, structure, DNA/protein binding, lipophilicity and anticancer activity

  • Petar Čanović
  • Ana Rilak Simović
  • Snežana Radisavljević
  • Ioannis Bratsos
  • Nicola Demitri
  • Marina Mitrović
  • Ivanka Zelen
  • Živadin D. Bugarčić
Original Paper


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.

Graphical Abstract


Ru complexes DNA binding Albumin binding Anticancer activity Apoptosis 













Bovine serum albumin








Deoxyribonucleic acid








Calf thymus DNA


Herring testes DNA


Human serum albumin


Serum transferrin






Ethidium bromide


Human lung carcinoma


Breast carcinoma


Epithelial cervical carcinoma




Human fetal lung fibroblast cells


Propidium iodide




Phosphate buffered saline


V–fluorescein isothiocyanate


7-amino-actinomycin D


Ribonucleic acid


Active proapoptotic protein


Antiapoptotic protein
















Structure–activity relationship


Quantitative structure–activity relationship



The authors gratefully acknowledge financial support from the Ministry of Education and Science of the Republic of Serbia (Project Number No. 172011). I.B. wishes to thank Dr. Dionisios Vourloumis for hosting him at his lab (Chemical Biology Lab, I.N.N., NCSR “Demokritos”) and providing access to the NMR facilities.

Supplementary material

775_2017_1479_MOESM1_ESM.pdf (3.1 mb)
Supplementary material 1 (PDF 3126 kb)


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Copyright information

© SBIC 2017

Authors and Affiliations

  • Petar Čanović
    • 1
  • Ana Rilak Simović
    • 2
  • Snežana Radisavljević
    • 2
  • Ioannis Bratsos
    • 3
  • Nicola Demitri
    • 4
  • Marina Mitrović
    • 1
  • Ivanka Zelen
    • 1
  • Živadin D. Bugarčić
    • 2
  1. 1.Department of Biochemistry, Faculty of Medical SciencesUniversity of Kragujevac, SerbiaKragujevacSerbia
  2. 2.Faculty of ScienceUniversity of KragujevacKragujevacSerbia
  3. 3.Department of Physical Chemistry, NCSR “Demokritos”I.N.NAthensGreece
  4. 4.Elettra, Sincrotrone TriesteBasovizzaItaly

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