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
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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.

Graphical Abstract

Keywords

Ru complexes DNA binding Albumin binding Anticancer activity Apoptosis 

Abbreviations

Cl-Ph-tpy

4′-(4-chlorophenyl)-2,2′:6′,2″-terpyridine

Phen

1,10-phenanthroline

o-bqdi

o-benzoquinonediimine

9MeG

9-methylguanine

5′-GMP

guanosine-5′-monophosphate

BSA

Bovine serum albumin

en

1,2-diaminoethane

dach

1,2-diaminocyclohexane

bpy

2,2′-bipyridine

DNA

Deoxyribonucleic acid

tpy

2,2′:6′,2″-terpyridine

Cl-tpy

4′-chloro-2,2′:6′,2″-terpyridine

Cl-Ph-tpy

4′-(4-chlorophenyl)-2,2′:6′,2″-terpyridine

CT DNA

Calf thymus DNA

HT DNA

Herring testes DNA

HSA

Human serum albumin

Tf

Serum transferrin

dmpda

4,5-dimethyl-o-phenylenediamine

s-bqdi

Semi-o-benzoquinonediimine

EB

Ethidium bromide

A549

Human lung carcinoma

MCF-7

Breast carcinoma

HeLa

Epithelial cervical carcinoma

Hs294T

Melanoma

MRC-5

Human fetal lung fibroblast cells

PI

Propidium iodide

Et3N

Triethylamine

PBS

Phosphate buffered saline

FITC

V–fluorescein isothiocyanate

7-AAD

7-amino-actinomycin D

RNA

Ribonucleic acid

Bax

Active proapoptotic protein

Bcl-2

Antiapoptotic protein

Guo

Guanosine

Tu

Thiourea

L-Cys

l-Cysteine

L-Met

l-Methionine

Pz

Pyrazole

Tz

1,2,4-triazole

Py

Pyridine

SAR

Structure–activity relationship

QSAR

Quantitative structure–activity relationship

Supplementary material

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

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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