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

Basto, Afonso P.; Anghel, Nicoleta; Rubbiani, Riccardo; Müller, Joachim; Stíbal, David; Giannini, Federico; Süß‐Fink, Georg; Balmer, Vreni; Gasser, Gilles; Furrer, Julien; Hemphill, Andrew

doi:10.1039/c8mt00307f

Cited by 34 publications

(57 citation statements)

References 74 publications

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“…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].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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(1) Background: Neospora caninum is a major cause of abortion in cattle and represents a veterinary health problem of great economic significance. In order to identify novel chemotherapeutic agents for the treatment of neosporosis, the Medicines for Malaria Venture (MMV) Malaria Box, a unique collection of anti-malarial compounds, were screened against N. caninum tachyzoites, and the most efficient compounds were characterized in more detail. (2) Methods: A N. caninum beta-galactosidase reporter strain grown in human foreskin fibroblasts was treated with 390 compounds from the MMV Malaria Box. The IC50s of nine compounds were determined, all of which had been previously been shown to be active against another apicomplexan parasite, Theileria annulata. The effects of three of these compounds on the ultrastructure of N. caninum tachyzoites were further investigated by transmission electron microscopy at different timepoints after initiation of drug treatment. (3) Results: Five MMV Malaria Box compounds exhibited promising IC50s below 0.2 µM. The compound with the lowest IC50, namely 25 nM, was MMV665941. This compound and two others, MMV665807 and MMV009085, specifically induced distinct alterations in the tachyzoites. More specifically, aberrant structural changes were first observed in the parasite mitochondrion, and subsequently progressed to other cytoplasmic compartments of the tachyzoites. The pharmacokinetic (PK) data obtained in mice suggest that treatment with MMV665941 could be potentially useful for further in vivo studies. (4) Conclusions: We have identified five novel compounds with promising activities against N. caninum, the effects of three of these compounds were studies by transmission electron microscopy (TEM). Their modes of action are unknown and require further investigation.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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“…Dinuclear tris(thiolato)-bridged arene complexes are typically obtained from the reaction of the precursor [(arene)MCl(µ2-Cl)2M(arene)Cl] M = Fe, Ru, Rh, Os, Ir with thiolate compounds and represent an interesting class of organometallic compounds. Iron complexes serve as carbon-halogen bond activation reagents, and carbon-halogen bond-cleavage agents, [1][2][3][4] while osmium 5 , iridium, rhodium [6][7][8][9][10][11][12] and especially ruthenium complexes 13,14,[23][24][25][15][16][17][18][19][20][21][22] have in vitro antiproliferative activity against cancer cell lines and several protozoan parasites. Tris(thiolato)-bridged dimolybdenum complexes are also readily available but are synthesised using other strategies such as the direct oxidation of low-valence carbonyl precursors or reductive process from higher-valence derivatives, [26][27][28] which will not be discussed here.…”

Section: Introductionmentioning

confidence: 99%

“…44,46 Dinuclear thiolatobridged arene ruthenium complexes are also promising as antiprotozoal agents, with IC50 values of up to 1.2 nM against T. gondii, N. Caninum and T. Brucei and IC50 values against human foreskin fibroblasts > 800 µM, leading to selectivity indexes > 20'000. 16,17,47 The current synthesis route for obtaining dinuclear cationic trithiolato bridged arene ruthenium complexes of the general formula [(η 6 -p-MeC6H4Pr i )2Ru2(µ2-S-R)3] + with good yields dates back to the early 2000s and involves the reaction of the dimer [(η 6 -p-MeC6H4Pr i )Ru(µ2-Cl)Cl]2 with an excess of the corresponding thiol (see Scheme 1) usually in refluxing ethanol (EtOH). 37 For thiophenolato complexes, depending on the thiophenol used, it is possible to adjust the conditions to direct the synthesis exclusively to the cationic trithiophenolato complex [(η 6 -p-MeC6H4Pr i )2Ru2(µ2-SC6H4-R)3] + , 15 the neutral dithiophenolato complex [(η 6 -p-MeC6H4Pr i )2Ru2(µ2-SC6H4-R)2Cl2], 48 or even the neutral monothiophenolato complex [(η 6 p-MeC6H4Pr i )2Ru2Cl2(µ-Cl)(µ2-SC6H4-R)].…”

Section: Introductionmentioning

confidence: 99%

Synthetic Route of Trithiolato-Bridged Dinuclear Arene Ruthenium(II) Complexes [(η6-P-MeC6H4Pri)2Ru2(μ2-SR)3]+

Primasova¹,

Ninova²,

Furrer³

et al. 2020

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Several dinuclear thiophenolato-bridged arene ruthenium complexes [(η6-p-MeC6H4Pri)2Ru2(μ2-SC6H4-R)3]+ could so far only be obtained with moderate yields using the synthetic route established in the early 2000s. With much less reactive aliphatic thiols or with bulky thiols, the reactions become even less efficient and the desired complexes are obtained with low yields or not at all. We employed density functional theory (DFT) calculations to gain a fundamental understanding of the reaction mechanisms leading to the formation of dithiolato and trithiolato complexes starting from the dichloro(pcymene) ruthenium(II) dimer [(η6-p-MeC6H4Pri)Ru(μ2-Cl)Cl]2. The results of the DFT study enabled us to rationalise experimental results and allowed us, via a modified synthetic route, to synthesise previously unreported and hitherto considered as unrealistic complexes. Our study opens possibilities for the synthesis of so far inaccessible thiolato-bridged dinuclear arene ruthenium(II) complexes but more generally also the synthesis of other thiolato-bridged dinuclear group 8 and 9 metal complexes could be reexamined.

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“…Though it was found that DiRu-1 has the ability to catalyze glutathione (GSH) oxidation, this mechanism can only explain its cytotoxicity to a certain extent. Recently, it was found that, when using inductively coupled plasma mass spectrometry (ICP-MS), 97% of the ruthenium is localized in the mitochondria of treated A2780 cells [9,10,11].…”

Section: Introductionmentioning

confidence: 99%

1H HR-MAS NMR-Based Metabolomics of Cancer Cells in Response to Treatment with the Diruthenium Trithiolato Complex [(p-MeC6H4iPr)2Ru2(SC6H4-p-But)3]+ (DiRu-1)

et al. 2019

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The trithiolato bridged diruthenium complex DiRu-1 [(p-MeC6H4iPr)2Ru2(SC6H4-p-But)3]+ is highly cytotoxic against various cancer cell lines, but its exact mode of action remains unknown. The present 1H HR-MAS NMR-based metabolomic study was performed on ovarian cancer cell line A2780, on its cis-Pt resistant variant A2780cisR, and on the cell line HEK-293 treated with 0.03 µM and 0.015 µM of DiRu-1 corresponding to full and half IC50 doses, respectively, to investigate the mode of action of this ruthenium complex. The resulting changes in the metabolic profile of the cell lines were studied using HR-MAS NMR of cell lysates and a subsequent statistical analysis. We show that DiRu-1 in a 0.03 µM dose has significant impact on the levels of a number of metabolites, such as glutamine, glutamate, glutathione, cysteine, lipid, creatine, lactate, and acetate, especially pronounced in the A2780cisR cell line. The IC50/2 dose shows some significant changes, but full IC50 appears to be necessary to observe the full effect. Overall, the metabolic changes observed suggest that redox homeostasis, the Warburg effect, and the lipid metabolism are affected by DiRu-1.

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

Abstract: Dinuclear ruthenium complexes inhibit N. caninum and specifically target the parasite mitochondria.

Cited by 34 publications

References 74 publications

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

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

Synthetic Route of Trithiolato-Bridged Dinuclear Arene Ruthenium(II) Complexes [(η6-P-MeC6H4Pri)2Ru2(μ2-SR)3]+

1H HR-MAS NMR-Based Metabolomics of Cancer Cells in Response to Treatment with the Diruthenium Trithiolato Complex [(p-MeC6H4iPr)2Ru2(SC6H4-p-But)3]+ (DiRu-1)

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