The known paddlewheel, tetrakis(acetato)chloridodiruthenium(II,III), offers a versatile synthetic route to a novel class of antitumor diruthenium(II,III) metallo drugs, where the equatorial ligands are nonsteroidal anti-inflammatory carboxylates. This complex was studied here as a soluble starting prototype model for antitumor analogues to elucidate the reactivity of the [Ru(2)(CH(3)COO)(4)](+) framework. Thermodynamic studies on equilibration reactions for axial substitution of water by chloride and kinetic studies on reactions of the diaqua complexes with the amino acids glycine, cysteine, histidine, and tryptophan were performed. The standard thermodynamic reaction parameters ΔH°, ΔS°, and ΔV° were determined and showed that both of the sequential axial substitution reactions are enthalpy driven. Kinetic rate laws and rate constants were determined for the axial substitution reactions of coordinated water by the amino acids that gave the corresponding aqua(amino acid)-Ru(2) substituted species. The results revealed that the [Ru(2)(CH(3)COO)(4)](+) paddlewheel framework remained stable during the axial ligand substitution reactions and was also mostly preserved in the presence of the amino acids.

The Diruthenium-Ibuprofen compound [Ru2Cl(Ibp)4] (or RuIbp) is known to cause significant inhibition of C6 rat glioma cell proliferation in vitro. RuIbp increased the expression of cell cycle-related proteins such as p21 and p27 and the pro-apoptotic protein Bax, as well as causing a reduction in mitochondrial membrane potential and a modest increase in apoptosis in vitro. The present study extended these findings by (i) investigating the effects of RuIbp on human glioma cell line proliferation in vitro and (ii) investigating the acute and chronic toxicology of the compound in normal Wistar rats. The compound was then tested for its anti-tumour properties by either chronic 14 days intra-peritoneal (IP) administration or chronic Alzet osmotic pump infusion, in the rat C6 orthotopic glioma model in vivo. The IP injection of RuIbp caused a 41 % inhibition of tumour area without significant toxic effects but with an increase in blood neutrophils and monocytes and a decrease in blood lymphocytes. In an attempt to reduce this effect RuIbp was administered by Alzet osmotic pump infusion directly into the tumour at a dose of 15 mg/kg with an infusion rate of 0.5 µL/h for 14 days. The direct infusion of RuIbp caused a 45 % inhibition of tumour area without alterations in differential blood leukocyte counts. These results prove the efficacy of RuIbp in human glioma cell lines in vitro and in an in vivo glioma model and point to its potential as an inhibitor of tumour growth in vivo.

Diruthenium(ii,iii)-tetracarboxylates have shown promising anticancer properties as metallotherapeutics. On the basis of the role that bio-reducing agents may play on the mode of action of ruthenium-based anticancer drugs, we performed detailed kinetic studies on the reaction of ascorbic acid and glutathione with the [Ru2(RCOO)4](+) paddlewheel framework by using the non-drug, diaqua complex ion [Ru2(CH3COO)4(H2O)2](+). In the presence of the reducing agents, the diaqua-Ru2 species first undergo a ligand substitution reaction by which the axially-coordinated water is displaced by the reducing agent. In both cases, this reaction is followed by an intra-molecular electron transfer process during which the metal-metal center is reduced from Ru2(5+) to Ru2(4+) and the reducing agent is oxidized. Product analyses were performed with the application of ESI-MS and (1)H-NMR techniques. Rate and activation parameters are reported for the different reaction steps.