Characterization of the Activities of Dinuclear Thiolato-Bridged Arene Ruthenium Complexes against Toxoplasma gondii

Abstract

The effects of 18 dinuclear thiolato-bridged arene ruthenium complexes (1 monohiolato compound, 4 dithiolato compounds, and 13 trithiolato compounds), originally designed as anticancer agents, on the apicomplexan parasite grown in human foreskin fibroblast (HFF) host cells were studied. Some trithiolato compounds exhibited antiparasitic efficacy at concentrations of 250 nM and below. Among those, complex 1 and complex 2 inhibited proliferation with 50% inhibitory concentrations (ICs) of 34 and 62 nM, respectively, and they did not affect HFFs at dosages of 200 μM or above, resulting in selectivity indices of >23,000. The ICs of complex 9 were 1.2 nM for and above 5 μM for HFFs. Transmission electron microscopy detected ultrastructural alterations in the matrix of the parasite mitochondria at the early stages of treatment, followed by a more pronounced destruction of tachyzoites. However, none of the three compounds applied at 250 nM for 15 days was parasiticidal. By affinity chromatography using complex 9 coupled to epoxy-activated Sepharose followed by mass spectrometry, translation elongation factor 1α and two ribosomal proteins, RPS18 and RPL27, were identified to be potential binding proteins. In conclusion, organometallic ruthenium complexes exhibit promising activities against , and the potential mechanisms of action of these compounds as well as their prospective applications for the treatment of toxoplasmosis are discussed.

Encapsulation of the Dinuclear Trithiolato‐Bridged Arene Ruthenium Complex Diruthenium‐1 in an Apoferritin Nanocage: Structure and Cytotoxicity

“…These findings suggest that DiRu‐1 is trapped within the cage and that only weak interactions (such as long‐range electrostatic interactions) between DiRu‐1 and AFt are present. This result is in line with the low reactivity of DiRu‐1 toward model proteins, i.e., hen egg white lysozyme and bovine pancreatic ribonuclease (unpublished data), and with published data indicating that DiRu‐1 is inert toward all the amino acids, with the exception of cysteines, for which DiRu‐1 promotes oxidation of the sulfur atom . Similar results were obtained with three hexacationic arene ruthenium metallaprisms and several human proteins.…”

“…Dinuclear trithiolato complexes [(arene) 2 Ru 2 (SR) 3 ] + are also promising antiparasitic compounds, as they are able to inhibit the apicomplexan parasite Toxoplasma gondii grown in human foreskin fibroblast host cells . Interestingly, DiRu‐1 and in general dinuclear trithiolato complexes [(arene) 2 Ru 2 (SR) 3 ] + are very stable in aqueous solution and are inert toward ligand substitution . The results of the recent in vivo study suggest that increasing the aqueous solubility of DiRu‐1 and its selectivity for cancer cells could significantly increase the efficacy of this promising ruthenium‐based anticancer agent .…”

Targeting of the mitochondrion by dinuclear thiolato-bridged arene ruthenium complexes in cancer cells and in the apicomplexan parasite Neospora caninum

“…26,27 Some other mononuclear ruthenium complexes were shown to exhibit promising in vitro activities against T. gondii and N. caninum, 28,29 and we have recently reported on the activity of a panel of dinuclear thiolato-bridged arene ruthenium complexes against T. gondii tachyzoites. 30 Some of these compounds efficiently inhibited host cell invasion, and had an IC 50 in the low nanomolar range, low host cell toxicity, and exposure of parasites to these compounds led to distinct alterations in the parasite mitochondrion. 30 Neospora caninum is an apicomplexan, which belongs to the family Sarcocystidae.…”

In Vitro Activities of MMV Malaria Box Compounds against the Apicomplexan Parasite Neospora caninum, the Causative Agent of Neosporosis in Animals

“…For instance, endochin-like quinolones affect the ultrastructure of mitochondria-as evidenced by digestive vacuoles containing mitochondrial fragments-but not of other organelles in N. caninum tachyzoites [24]. In addition, organometallic ruthenium complexes were shown to primarily act on mitochondria in Toxoplasma gondii [25], N. caninum [26], and in the extracellular protozoan parasite Trypanosoma brucei [27].…”