Antimetastatic properties and DNA interactions of the novel class of dimeric Ru(III) compounds Na2[{trans-RuCl4(Me2SO)}2(μ-L)] (L=ditopic, non-chelating aromatic N-ligand). A preliminary investigation
Introduction
We recently reported the synthesis and characterization of novel dianionic Ru(III) dimers of formula Na2[{trans-RuCl4(Me2SO)}2(μ-L)] (Fig. 1), in which the two trans-RuCl4(Me2SO) units are bridged by a ditopic non-chelating aromatic N-ligand, such as pyrazine [1], [2]. Each half of these dimers maintains essentially the same coordination sphere (four trans chlorides, one S-bonded dimethyl sulfoxide and one heterocyclic N-ligand) that characterizes the mononuclear compound Na[trans-RuCl4(Me2SO)(Im)] (NAMI, Im=imidazole), whose selective antimetastatic properties against animal tumor models have been repeatedly reported by us [3], [4], [5]. The imidazolium salt of NAMI, NAMI-A, which has improved characteristics of stability in the solid state and a similar antineoplastic activity compared to NAMI [6], [7], [8], [9], [10], [11], is currently being tested in clinical phase I as an antimetastatic drug.
The new dimeric compounds were developed with the specific aim of assessing their antitumor properties. By virtue of the structural analogies, they might maintain the antineoplastic activity of the closely related mononuclear species but with some different, and possibly enhanced, selectivity and/or specificity. In fact, although the mechanism of action of NAMI-A has not yet been elucidated, DNA and/or proteins are among its most likely biological targets. The general dinuclear structure of the novel compounds might allow DNA intrastrand and interstrand cross-links, protein cross-links, as well as ternary complex formation of DNA-protein cross-links that are unavailable to the mononuclear analogs. The precedents in the field of platinum drugs, in which the dimers and trimers developed by Farrell et al. [12], [13] show remarkable activity also against tumor lines resistant to cisplatin, seemed particularly encouraging.
We report here some preliminary results on the antineoplastic activity against animal tumor models and on the in vitro interactions with DNA for four dimers of formula Na2[{trans-RuCl4(Me2SO)}2(μ-L)], with L=pyrazine (pyz, 1), pyrimidine (pym, 2), 4,4′-bipyridine (bipy, 3), and 1,2-bis(4-pyridine)ethane (etbipy, 4).
Section snippets
Materials and methods
The synthesis of dimers 1–4 was performed according to published procedures [1], [2].
Synthesis and chemical behavior
The synthesis, structural characterization and thorough chemical behavior in physiological solution of the new dimers have been recently described by us elsewhere [1], [2]. For the sake of clarity, we report here a brief summary of those aspects which might be relevant to the evaluation of the biological properties described below.
The dimers are synthesized in good yield by treatment of the precursor Na[trans-RuCl4(Me2SO)2] with 0.5 equivalent of the bridging ligand. The complexes usually
Discussion
Although the nature of the biological target(s) of the antimetastatic NAMI-A is yet unknown, we have shown that mononuclear Ru(III) complexes, including NAMI-A, after hydrolysis of at least one chloride are capable of binding DNA [14] and also proteins such as transferrin [15] and albumine [16] in vitro; moreover, they were recently proved capable of inducing DNA-protein cross-links in isolated nuclei [17]. Thus, in vivo, the mononuclear Ru(III) complexes behave, very likely, as either
Acknowledgements
This work was supported by Italian MURST in the frame of the Project ‘Pharmacological and Diagnostic Properties of Metal Complexes’ (coordinator Professor G. Natile), by Polytech s.r.l. (Science Park of Trieste), and by EU COST Action D8 (Project D8/96/0017). We thank Johnson Matthey for the generous loan of hydrated RuCl3.
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