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Structure-dependent in vitro cytotoxicity of the isomeric complexes [Ru(L)2Cl2] (L=o-tolylazopyridine and 4-methyl-2-phenylazopyridine) in comparison to [Ru(azpy)2Cl2]

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Abstract

The dichlorobis(2-phenylazopyridine)ruthenium(II) complexes, [Ru(azpy)2Cl2], are under renewed investigation due to their potential anticancer activity. The three most common isomers α-, β- and γ-[RuL2Cl2] with L=o-tolylazopyridine (tazpy) and 4-methyl-2-phenylazopyridine (mazpy) (α indicating the coordinating Cl, N(pyridine) and Nazo atoms in mutual cis, trans, cis positions, β indicating the coordinating Cl, N(pyridine) and Nazo atoms in mutual cis, cis, cis positions, and γ indicating the coordinating Cl, N(pyridine) and Nazo atoms in mutual trans, cis, cis positions) are synthesized and characterized by NMR spectroscopy. The molecular structures of γ-[Ru(tazpy)2Cl2] and α-[Ru(mazpy)2Cl2] are determined by X-ray diffraction analysis. The IC50 values of the geometrically isomeric [Ru(tazpy)2Cl2] and [Ru(mazpy)2Cl2] complexes compared with those of the parent [Ru(azpy)2Cl2] complexes are determined in a series of human tumour cell lines (MCF-7, EVSA-T, WIDR, IGROV, M19, A498 and H266). These data unambiguously show for all complexes the following trend: the α isomer shows a very high cytotoxicity, whereas the β isomer is a factor 10 less cytotoxic. The γ isomers of [Ru(tazpy)2Cl2] and [Ru(mazpy)2Cl2] display a very high cytotoxicity comparable to that of the γ isomer of the parent compound [Ru(azpy)2Cl2] and to that of the α isomer. These biological data are of the utmost importance for a better understanding of the structure–activity relationships for the isomeric [RuL2Cl2] complexes.

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Notes

  1. In the C2, symmetric γ and α isomers of the [Ru(azpy)2Cl2] complexes, the two azpy ligands are equivalent. Therefore, it is not clear beforehand whether an NOE is an (intramolecular) inter- or intraligand NOE cross-peak. However, the NOE H6–H(o) in the α isomer of α-[Ru(azpy)2Cl2] is definitely an interligand one, for example. Obviously from the distance H6–H(o) within one azpy ligand of α-[Ru(azpy)2Cl2], as derived from the X-ray structure [35] (on average 6.31 Å), it is clear that no intraligand NOE can be expected. The interligand H6–H(o) distance, as shown in the X-ray structure, is on average 4.14 Å, predicting the interligand NOE. Moreover, in asymmetric α-isomeric azpy complexes [37], like α-[Ru(azpy)2(9-Egua)(H2O)](PF6)2 or α-[Ru(azpy)2Cl(NO3)] (unpublished data), the interligand H6–o’ and H6’–o (prime denoting the other azpy ligand) are observed and not, for example, the intraligand H6–o NOE.

Abbreviations

AAS:

atomic absorption spectroscopy

azpy:

2-phenylazopyridine

COSY:

correlation spectroscopy

mazpy:

4-methyl-2-phenylazopyridine

MTT:

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide

NOESY:

nuclear Overhauser-effect spectroscopy

PBS:

phosphate-buffered saline

tazpy:

o-tolylazopyridine

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Acknowledgements

This work was supported by the Council for Chemical Sciences of the Netherlands Organisation for Scientific Research (CW-NWO). We thank Johnson Matthey Chemicals (Reading, UK) for a generous loan of RuCl3·3H2O. Additional support from COST Action D20, allowing regular research exchanges to partner laboratories inside EU countries, is gratefully acknowledged. Marina Bacac is grateful to the Callerio Foundation for providing a three-year fellowship grant.

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Authors and Affiliations

  1. Leiden Institute of Chemistry, Gorlaeus Laboratories, Leiden University, P.O. Box 9502, 2300 RA , Leiden, The Netherlands

    Anna C. G. Hotze, Sabrine E. Caspers, Jaap G. Haasnoot & Jan Reedijk

  2. Pharmachemie BV, P.O. Box 552, 2003 RN , Haarlem, The Netherlands

    Dick de Vos

  3. Bijvoet Center for Biomolecular Research, Crystal and Structural Chemistry, Utrecht University, Padualaan 8, 3584 CH , Utrecht, The Netherlands

    Huub Kooijman & Anthony L. Spek

  4. Department of Biomedical Sciences, University of Trieste, via L. Giorgieri 7, 34127 , Trieste, Italy

    Anna Flamigni, Marina Bacac & Gianni Sava

  5. Callerio Foundation Onlus, via A. Fleming 22–31, 34127 , Trieste, Italy

    Marina Bacac & Gianni Sava

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  1. Anna C. G. Hotze
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  2. Sabrine E. Caspers
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  9. Jaap G. Haasnoot
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  10. Jan Reedijk
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Correspondence to Jan Reedijk.

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Hotze, A.C.G., Caspers, S.E., de Vos, D. et al. Structure-dependent in vitro cytotoxicity of the isomeric complexes [Ru(L)2Cl2] (L=o-tolylazopyridine and 4-methyl-2-phenylazopyridine) in comparison to [Ru(azpy)2Cl2]. J Biol Inorg Chem 9, 354–364 (2004). https://doi.org/10.1007/s00775-004-0531-6

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