Anti-parasitic dinuclear thiolato-bridged arene ruthenium complexes alter the mitochondrial ultrastructure and membrane potential in Trypanosoma brucei bloodstream forms

Jelk, Jennifer; Balmer, Vreni; Stíbal, David; Giannini, Federico; Süß‐Fink, Georg; Bütikofer, Peter; Furrer, Julien; Hemphill, Andrew

doi:10.1016/j.exppara.2019.107753

Cited by 25 publications

(35 citation statements)

References 34 publications

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“…[25] Thus, complex A presents an IC 50 value of 34 nM against the apicomplexan parasite T. gondii cultured in human foreskin fibroblast (HFF) monolayers, [24] while compound B exhibits an IC 50 of 4 nM against T. brucei bloodstream forms. [25] Viability of uninfected HFF cells treated with 2.5 μM of complex A was decreased to 63 %, however complex B did not affect the vitality when applied at the same concentration. [24] In Toxoplasma, Neospora and in Trypanosoma, transmission electron microscopy (TEM) demonstrated that trithiolato diruthenium compounds affected the structural integrity of the mitochondrion after few hours of treatment, and led to a more pronounced destruction of tachyzoites at later timepoints.…”

Section: Introductionmentioning

confidence: 99%

“…[24] In T. brucei, these compounds altered the mitochondrial membrane potential, while other organelles and structural elements of the parasites remained largely unaffected. [25] The intracellular fate of these trithiolato dinuclear ruthenium complexes, and how they exert anticancer and antiparasitic effects, are unknown, and thus investigating their cellular traffic and possible mechanisms of action has become a priority. In vitro/in vivo tracking of organometallic drugs using traceable compounds represents a promising approach.…”

Section: Introductionmentioning

confidence: 99%

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Coumarin‐Tagged Dinuclear Trithiolato‐Bridged Ruthenium(II)⋅Arene Complexes: Photophysical Properties and Antiparasitic Activity

et al. 2020

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The synthesis, characterization, photophysical and biological properties of 13 new conjugate coumarin-diruthenium(II)•arene complexes against Toxoplasma gondii are presented. For all conjugate organometallic unit/coumarins, an almost complete loss of fluorescence efficacy was observed. However, the nature of the fluorophore, the type of bonding, the presence and length of a linker between the coumarin dye and the ruthenium(II) moiety, and the number of dye units influenced their biological properties. The in vitro activity against a trans-genic T. gondii strain grown in human foreskin fibroblasts (HFF) leads to IC 50 values for T. gondii β-gal from 105 to 735 nM. Of note is that nine compounds displayed lower IC 50 than the standard drug pyrimethamine. One compound applied at its IC 50 did not affect B-cell proliferation but had an impact on Tcell proliferation in murine splenocyte cultures. Transmission electron microscopy of T. gondii β-gal-infected HFF showed that treatment predominantly affected the parasites' mitochondrion.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Coumarin‐Tagged Dinuclear Trithiolato‐Bridged Ruthenium(II)⋅Arene Complexes: Photophysical Properties and Antiparasitic Activity

et al. 2020

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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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“…Thiophenols were considered to be too reactive, and the reactions with the starting dimer always led to inseparable mixtures of trithiolato and dithiolato complexes. 47 By using optimised conditions, we were able to obtain the two new dithiophenolato complexes 7 and 8 from the reaction in DCM at 0 °C. Notably, 7 was obtained in quantitative yield and good purity.…”

Section: Synthesis Of the New Dithiophenolato Complexes 7 Andmentioning

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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Anti-parasitic dinuclear thiolato-bridged arene ruthenium complexes alter the mitochondrial ultrastructure and membrane potential in Trypanosoma brucei bloodstream forms

Cited by 25 publications

References 34 publications

Coumarin‐Tagged Dinuclear Trithiolato‐Bridged Ruthenium(II)⋅Arene Complexes: Photophysical Properties and Antiparasitic Activity

Coumarin‐Tagged Dinuclear Trithiolato‐Bridged Ruthenium(II)⋅Arene Complexes: Photophysical Properties and Antiparasitic Activity

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]+

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