Novel ruthenium(III) dimers Na2[{trans-RuCl4(Me2SO-S)}2(µ-L)] and [{mer,cis-RuCl3(Me2SO-S)(Me2SO-O)}2(µ-L)] (L = bridging heterocyclic N-donor ligand) closely related to the antimetastatic complex Na[trans-RuCl4(Me2SO-S)(Him)]†

Abstract

The symmetrical dianionic and neutral ruthenium(III) dimers Na₂[{trans-RuCl₄(Me₂SO-S)}₂(µ-L)] 1 and [{mer,cis-RuCl₃(Me₂SO-S)(Me₂SO-O)}₂(µ-L)] 3 (L = pyrazine 1a, 3a; pyrimidine 1b; 4,4′-bipyridine 1c; 1,2-bis(4-pyridyl)ethane 1d; or 1,3-bis(4-pyridyl)propane 1e), which represent unprecedented examples in the general Creutz–Taube family of ruthenium dimers, were developed with the specific aim of assessing their antineoplastic properties. Each ruthenium center in 1 and 3 has a co-ordination environment similar to that of known anionic and neutral monomeric ruthenium(III) complexes endowed with a specific antimetastatic activity against animal model tumors. Beside the synthesis and spectroscopic characterization of the new dimers, and the structural characterization of 1a, 1b, 1c, and 3a, a thorough investigation of their chemical behavior in aqueous solution was made. At 25 °C and pH 7.4 the dianionic species 1a–1e maintain their dimeric structure and undergo rather slow stepwise chloride hydrolysis to yield the relatively inert diaqua species [{mer,cis-RuCl₃(Me₂SO-S)(H₂O)}₂(µ-L)]. At physiological pH dimers 1a–1e are also easily and quantitatively reduced by equivalent amounts of ascorbic acid to the corresponding Ru^II/II dimers which, in turn, undergo stepwise aquation with rates roughly comparable to those of the Ru^III/III species of equal net charge. Since the reduction processes might occur also in vivo, the chemical behavior of the Ru^II/II dimers is relevant to understanding the biological mechanism of action of these compounds and was thus investigated in detail. The neutral dimer 3, which is scarcely soluble in aqueous solution, gives soluble dimeric species upon reduction with ascorbic acid. We found that reduction is accompanied by O to S linkage isomerization and by partial dissociation of the equatorial dmso. Overall, the dimeric structures of the new compounds are quite robust, both in the Ru^III/III and in the Ru^II/II form, and they undergo aquation reactions similar to those of the monomeric analogs. However, while the monomeric species after aquation are either mono- or bi-functional binders, the new dimers might behave as bi- or even tetra-functional binders. Thus, it is likely that their interaction with biological targets might lead to adducts which are not accessible to the mononuclear species.