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Synthesis, nucleic acid binding and cytotoxicity of oligonuclear ruthenium complexes containing labile ligands

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Abstract

We report the synthesis, nucleic acid binding and cytotoxicity of the complexes [Ru(terpy)(Me2bpy)Cl]+, [Ru(terpy)(phen)Cl]+ and dinuclear [{Ru(terpy)Cl}2(μ-bbn)]2+ {where Me2bpy = 4,4′-dimethyl-2,2′-bipyridine; phen = 1,10-phenanthroline; and bbn = bis[4(4′-methyl-2,2′-bipyridyl)]-1,n-alkane, with n = 7, 10, 12, 14}. The complexes were isolated from the reaction of the [Ru(terpy)Cl3] precursor with the respective bidentate and di-bidentate bridging ligands. The time-course UV–Visible spectroscopy of the reaction of the mono- and dinuclear complexes with guanosine 5-monophosphate (GMP) showed the movement of the metal-to-ligand charge transfer (MLCT) band to lower wavelengths, accompanied by a hypochromism effect. The formation of the aqua complex and phosphate-bound intermediates in the reaction were detected by the time-course 1H NMR and 31P NMR experiments, which also demonstrated that the complex bound to the N7 guanine was the major product. The UV–Visible and 1H NMR studies showed no evidence of the interaction of the complexes with both adenosine 5-monophosphate (AMP) and cytidine 5-monophosphate (CMP). Cytotoxicity studies of these complexes against a murine leukemia L1210 cell line revealed that the dinuclear [{Ru(terpy)Cl}2(μ-bbn)]2+ complexes were significantly more cytotoxic than mononuclear [Ru(terpy)(Me2bpy)Cl]+. The [{Ru(terpy)Cl}2(μ-bb14)]2+ complex appeared to be the most active (IC50 = 4.2 μM).

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Notes

  1. The estimated t1/2 values for the [Ru(terpy)(Me2bpy)Cl]Cl-GMP, [{Ru(terpy)Cl}2(μ-bb7)]-GMP and [{Ru(terpy)Cl}2(μ-bb12)]-GMP reactions were 25, 80 and 92 mins, respectively, calculated on the basis of the changes in the absorbance over time at 500 nm. With the excess amount of the mononucleotides used, it was assumed that there was only a small change in the concentration of the mononucleotides such that the reaction followed pseudo-first-order kinetics. The detailed investigation of the reaction mechanism and kinetics is currently underway.

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Acknowledgments

We acknowledge the financial support of the Australian Research Council. We wish to thank Dr. Carleen Cullinane and Alison Slater (Peter MacCallum Cancer Centre, Melbourne, Australia) for their cooperation and assistance with the cytotoxicity measurements reported in this work.

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Authors and Affiliations

  1. School of Pharmacy and Molecular Sciences, James Cook University, Townsville, QLD, 4811, Australia

    Yanyan Mulyana & Richard Keene

  2. School of Physical, Environmental and Mathematical Sciences, University of New South Wales, Australian Defence Force Academy, Canberra, ACT, 2600, Australia

    Grant Collins

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  1. Yanyan Mulyana
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Correspondence to Richard Keene.

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Dedicated to Len Lindoy—colleague, mentor and friend—on the occasion of his 75th birthday

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Mulyana, Y., Collins, G. & Keene, R. Synthesis, nucleic acid binding and cytotoxicity of oligonuclear ruthenium complexes containing labile ligands. J Incl Phenom Macrocycl Chem 71, 371–379 (2011). https://doi.org/10.1007/s10847-011-0036-1

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