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Tuning the cytotoxic properties of new ruthenium(III) and ruthenium(II) complexes with a modified bis(arylimino)pyridine Schiff base ligand using bidentate pyridine-based ligands

  • Ariadna Garza-Ortiz
  • Palanisamy Uma Maheswari
  • Martin Lutz
  • Maxime A. Siegler
  • Jan Reedijk
Original Paper
Part of the following topical collections:
  1. Topical issue in honor of Ivano Bertini

Abstract

Synthesis, spectroscopy, characterization, structures, and cytotoxicity studies of 2,6-bis(2,6-diisopropylphenyliminomethyl)pyridine (LLL) ruthenium compounds are described. The starting compound [RuCl3(LLL)] has been fully characterized using IR spectroscopy, UV–vis spectroscopy, electrospray ionization mass spectrometry, and NMR spectroscopy. In addition, the crystal structure of the ligand LLL has been determined using single-crystal X-ray diffraction. With the ruthenium(III) trichloride compound as starting material, a new family of Ru(II) complexes with a number of neutral and charged bidentate co-ligands have been synthesized and used for characterization and cytotoxicity studies. The synthesis of the corresponding [RuIILLL(LL)Cl]+/0 complexes with co-ligands— LL is 1,10-phenanthroline, 2,2′-bipyridyl, 2-(phenylazo)pyridine, 2-(phenylazo)-3-methylpyridine, 2-(tolylazo)pyridine, or the anionic 2-picolinate—is reported. Analytical, spectroscopic (IR spectroscopy, UV–vis spectroscopy, 1H NMR spectroscopy, and electrospray ionization mass spectrometry), and structural characterization of the new compounds is described. Crystal structure analyses of two Ru(II) compounds show a slightly distorted octahedral Ru(II) geometry with tridentate LLL coordinated in a planar meridional fashion, and the chelating co-ligand (LL) and a chloride ion complete the octahedron. The co-ligand plays a significant role in modulating the physicochemical and cytotoxic properties of these new ruthenium complexes. The in vitro cytotoxicity of these new Ru(II) complexes (half-maximal inhibitory concentration, IC50, of 0.5–1.5 μM), in comparison with the parent Ru(III) compound (half-maximal inhibitory concentration of 3.9–4.3 μM) is higher for several of the human cancer cell lines tested. The cytotoxic activity of some of the new ruthenium compounds is even higher than that of cisplatin in the same cancer cell lines. The cytotoxicity of these new anticancer compounds is discussed in the light of structure-based activity relationships, and a possible mechanism of action is suggested.

Graphical abstract

Synthesis, spectroscopy, structures, and cytotoxicity studies of new Ru(III) and Ru(II) compounds with a substituted bis(arylimino)pyridine ligand and bidentate co-ligands are reported. The co-ligands play a significant role in modulating the physicochemical and cytotoxic properties. The in vitro cytotoxicity data are discussed in the light of structure-based activity relationships (SARs).

Highlights:
  1. (a)

    The synthesis, structure, and spectroscopic characterization of 2,6-bis(2,6-diisopropylphenyliminomethyl)pyridine, a tridentate Schiff base ligand, are reported.

     
  2. (b)

    A new Ru(III) complex with a bis(arylimino)pyridine Schiff base ligand has been synthesized and characterized spectroscopically.

     
  3. (c)

    A family of Ru(II) compounds with a bis(arylimino)pyridine Schiff base ligand as a primary ligand and bidentate pyridine-based co-ligands are reported.

     
  4. (d)

    The cytotoxic activity of Ru(II) and Ru(III) compounds has been studied systematically.

     

Keywords

Ruthenium Bis(arylimino)pyridine derivatives 2,6-Bis(2,6-diisopropylphenyliminomethyl)pyridine Co-ligand Cytotoxic properties 

Abbreviations

azpy

2-(Phenylazo)pyridine

bpy

2,2′-Bipyridyl

DMF

Dimethylformamide

ESI

Electrospray ionization

IC50

Half-maximal inhibitory concentration

IR

Infrared

LLL

2,6-Bis(2,6-diisopropylphenyliminomethyl)pyridine

3mazpy

2-(Phenylazo)-3-methylpyridine

MS

Mass spectrometry

NMR

Nuclear magnetic resonance

phen

1,10-Phenanthroline

pic

2-Picolinic acid

[RuCl3(LLL)]

Trichlorido(2,6-bis(2,6-diisopropylphenyliminomethyl)pyridine)ruthenium(III)

RuLLL-azpy

Chlorido(2-(phenylazo)pyridine)(2,6-bis(2,6-diisopropylphenyliminomethyl)pyridine)ruthenium(II) perchlorate

RuLLL-bpy

Chlorido(2,2′-bipyridyl)(2,6-bis(2,6-diisopropylphenyliminomethyl)pyridine)ruthenium(II) perchlorate

RuLLL-3mazpy

Chlorido(2-(phenylazo)-3-methylpyridine)(2,6-bis(2,6-diisopropylphenyliminomethyl)pyridine)ruthenium(II) perchlorate

RuLLL-phen

Chlorido(1,10-phenanthroline)(2,6-bis(2,6-diisopropylphenyliminomethyl)pyridine)ruthenium(II) perchlorate

RuLLL-pic

Chlorido(2-picolinate)(2,6-bis(2,6-diisopropylphenyliminomethyl)pyridine)ruthenium(II)

RuLLL-tazpy

Chlorido(2-(tolylazo)pyridine)(2,6-bis(2,6-diisopropylphenyliminomethyl)pyridine)ruthenium(II) perchlorate

SRB

Sulforhodamine B

tazpy

2-(Tolylazo)pyridine

Terpy

2,2′:6′,2-Terpyridine

UV–vis

UV–visible

Notes

Acknowledgments

The authors thank Johnson Matthey (Reading, UK) for the generous loan of RuCl3·3H2O. This work was supported in part (A.G.-O., J.R., M.A.S., M.L.) by the Council for the Chemical Sciences of the Netherlands Organization for Scientific Research (CW-NWO) and in part by CONACYT (National Council of Science and Technology) as a doctoral fellowship to A.G.-O. We thank A.W.M. Lefeber for assistance with the NMR experiments, and Jos van Brussel, John A.P.P. van Dijk, and Jopie A. Erkelens-Duijndam for technical assistance with the syntheses and analyses. The in vitro cytotoxicity experiments were performed by P.F. van Cuijk in the Laboratory of Translational Pharmacology, Department of Medical Oncology. Erasmus Medical Center, Rotterdam, The Netherlands, under the supervision of E.A.C. Wiemer and G. Stoter. A.G.-O. expresses gratitude to the Universidad Autónoma Metropolitana-Xochimilco for a postdoctoral fellowship.

Supplementary material

775_2013_1083_MOESM1_ESM.pdf (243 kb)
Supplementary material 1 (PDF 243 kb)

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Copyright information

© SBIC 2014

Authors and Affiliations

  • Ariadna Garza-Ortiz
    • 1
    • 4
  • Palanisamy Uma Maheswari
    • 1
    • 5
  • Martin Lutz
    • 2
  • Maxime A. Siegler
    • 2
  • Jan Reedijk
    • 1
    • 3
  1. 1.Gorlaeus Laboratories, Leiden Institute of ChemistryLeiden UniversityLeidenThe Netherlands
  2. 2.Crystal and Structural Chemistry, Bijvoet Center for Biomolecular ResearchUtrecht UniversityUtrechtThe Netherlands
  3. 3.Department of Chemistry, College of ScienceKing Saud UniversityRiyadhSaudi Arabia
  4. 4.Departamento de Sistemas BiológicosUniversidad Autónoma Metropolitana-Unidad XochimilcoCoyoacánMexico
  5. 5.Department of ChemistryNational Institute of TechnologyTiruchirappalliIndia

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