Experimental Chemotherapy against<i>Trypanosoma cruzi</i>Infection Using Ruthenium Nitric Oxide Donors

Silva, Jean Jerley N.; Pavanelli, Wander Rogério; Pereira, Juliana da Silva; Silva, João; Franco, Douglas Wagner

doi:10.1128/aac.00104-09

Cited by 51 publications

(41 citation statements)

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“…For example Stasko and Schoenfisch [18] synthesized polypropylenimine (PPI) dendrimers (G3 and G5) functionalized with N-diazeniumdiolates which were able to store $5.6 lmol NO per mg of compound. Following a similar approach, Lu et al [20] synthesized a series of amine PPI dendrimers (G2-G5) functionalized with different surface groups, In this context, this work reports the synthesis and characterization of the complex trans-[Ru(NO)(NH 3 ) 4 Chaga's disease [7,8].…”

Section: (L)]mentioning

confidence: 99%

“…Different compounds have been developed as effective NO donors, such as nitrosothiols, diazeniumdiolates, organic nitrates and nitrites, and also metal nitrosyl complexes [4,5]. These compounds are helpful to better understand the biological functions of NO and some of them exhibited potential therapeutic activities [6][7][8][9][10][11].Among 31]. Dendrimers are attractive molecules for NO transport, once they can provide a scaffold for storing large amounts of NO on a single framework [18].…”

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confidence: 99%

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PAMAM dendrimers functionalized with ruthenium nitrosyl as nitric oxide carriers

Roveda

Papa

Castellano

et al. 2014

Inorganica Chimica Acta

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Section: (L)]mentioning

confidence: 99%

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confidence: 99%

PAMAM dendrimers functionalized with ruthenium nitrosyl as nitric oxide carriers

Roveda

Papa

Castellano

et al. 2014

Inorganica Chimica Acta

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“…This has stimulated the interest in other compounds with more acceptable toxicity, such as ruthenium complexes (32)(33)(34)(35)(36). Effects of ruthenium compounds on some bacteria and parasites have been studied (37)(38)(39)(40)(41)(42)(43)(44)(45)(46). "Classical ruthenium complexes" contain heteroatom ligands (e.g., azole derivatives), and NAMI-A and KP-1019 have been evaluated in phase I clinical trials for cancer treatment (47)(48)(49).…”

mentioning

confidence: 99%

In VitroEffects of Novel Ruthenium Complexes in Neospora caninum and Toxoplasma gondii Tachyzoites

Barna

Debache

Vock

et al. 2013

Antimicrob Agents Chemother

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bUpon the screening of 16 antiproliferative compounds against Toxoplasma gondii and Neospora caninum, two hydrolytically stable ruthenium complexes (compounds 16 and 18) exhibited 50% inhibitory concentrations of 18.7 and 41.1 nM (T. gondii) and 6.7 and 11.3 nM (N. caninum). To achieve parasiticidal activity with compound 16, long-term treatment (22 to 27 days at 80 to 160 nM) was required. Transmission electron microscopy demonstrated the rapid impact on and ultrastructural alterations in both parasites. These preliminary findings suggest that the potential of ruthenium-based compounds should thus be further exploited.T oxoplasma gondii and Neospora caninum are cyst-forming apicomplexan parasites that infect a wide range of hosts. In an immunocompetent host, infection with either parasite does not cause disease (1-3). N. caninum has emerged as one of the most important infectious causes of bovine abortion (4-6). In contrast, T. gondii causes toxoplasmosis in humans and many animal species, either in chronically infected individuals during a decrease in immunoreactivity or if a seronegative mother acquires a primary infection during pregnancy, leading to abortion or serious fetal abnormalities (7-9). Toxoplasmosis treatment is based on only a few chemotherapeutics with considerable adverse effects (10, 11). In Neospora-seropositive cattle, pregnancy and the associated immunomodulation are already sufficient to cause recrudescence, fetal damage, and abortion (2-6). Chemotherapy has been considered a promising option if effective drugs can be identified (12, 13). Several compounds were investigated in vitro (14-16), but only a few were evaluated in small-animal models (14,(17)(18)(19)(20)(21)(22)(23)(24).We have evaluated compounds originally synthesized as anticancer drugs. Currently used metal complexes (25-31) exhibit considerable toxicity. This has stimulated the interest in other compounds with more acceptable toxicity, such as ruthenium complexes (32-36). Effects of ruthenium compounds on some bacteria and parasites have been studied (37-46). "Classical ruthenium complexes" contain heteroatom ligands (e.g., azole derivatives), and NAMI-A and KP-1019 have been evaluated in phase I clinical trials for cancer treatment (47-49). Organometallic complexes are defined by at least one metal-carbon bond. The 6 -arene ruthenium(II) phosphite complexes 5, 6, 12, and 15 to 18 were characterized earlier (50), while [Ru( 6 -p-cymene)(bipyridine)Cl][Cl] 11 was synthesized as shown previously (51). Based on our experiences in the design of selective inhibitors of CYP11B2 (53) and CYP11B1 (54), the pyridine-based compounds 4, 7 to 10, and 14 were from a small in-house library of CYP enzyme inhibitors. 2,2=-Bipyridine 3 was obtained from Joachim W. Heinicke, Ernst Moritz Arndt University of Greifswald, Greifswald, Germany. The cytotoxic lipophilic imidazolium salt 1,3-bis(2,4,6-trimethylphenyl)imidazolium chloride 3 was synthesized as described previously (54-56). The arylimidamide DB745 2 (23) was kindly provided by David Bo...

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“…Organic NO donor molecules have been investigated as anti-T. cruzi agents, but compounds with in vivo efficacy have not been identified (15). In recent years, ruthenium-nitrosyl complexes have been evaluated as anti-T. cruzi agents, demonstrating potent and selective antiparasitic activity, including in T. cruzi-infected mice (16)(17)(18)(19). In addition, this class of complexes exhibited inhibitory activity against the T. cruzi glyceraldehyde 3-phosphate dehydrogenase, suggesting that ruthenium-nitrosyl complexes may have pleiotropic effects (19).…”

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Nitro/Nitrosyl-Ruthenium Complexes Are Potent and Selective Anti-Trypanosoma cruzi Agents Causing Autophagy and Necrotic Parasite Death

Bastos

Barbosa

Silva

et al. 2014

Antimicrob Agents Chemother

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e cis-[RuCl(NO 2 )(dppb)(5,5=-mebipy)] (complex 1), cis-[Ru(NO 2 ) 2 (dppb)(5,5=-mebipy)] (complex 2), ct-[RuCl(NO)(dppb)(5,5=-mebipy)](PF 6 ) 2 (complex 3), and cc-[RuCl(NO)(dppb)(5,5=-mebipy)](PF 6 ) 2 (complex 4), where 5,5=-mebipy is 5,5=-dimethyl-2,2=-bipyridine and dppb is 1,4-bis(diphenylphosphino)butane, were synthesized and characterized. The structure of complex 2 was determined by X-ray crystallography. These complexes exhibited a higher anti-Trypanosoma cruzi activity than benznidazole, the current antiparasitic drug. Complex 3 was the most potent, displaying a 50% effective concentration (EC 50 ) of 2.1 ؎ 0.6 M against trypomastigotes and a 50% inhibitory concentration (IC 50 ) of 1.3 ؎ 0.2 M against amastigotes, while it displayed a 50% cytotoxic concentration (CC 50 ) of 51.4 ؎ 0.2 M in macrophages. It was observed that the nitrosyl complex 3, but not its analog lacking the nitrosyl group, releases nitric oxide into parasite cells. This release has a diminished effect on the trypanosomal protease cruzain but induces substantial parasite autophagy, which is followed by a series of irreversible morphological impairments to the parasites and finally results in cell death by necrosis. In infected mice, orally administered complex 3 (five times at a dose of 75 mol/kg of body weight) reduced blood parasitemia and increased the survival rate of the mice. Combination index analysis of complex 3 indicated that its in vitro activity against trypomastigotes is synergic with benznidazole. In addition, drug combination enhanced efficacy in infected mice, suggesting that ruthenium-nitrosyl complexes are potential constituents for drug combinations.

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Experimental Chemotherapy againstTrypanosoma cruziInfection Using Ruthenium Nitric Oxide Donors

Abstract: The ruthenium NO donors of the group trans-[Ru(NO)(NH

Cited by 51 publications

References 51 publications

PAMAM dendrimers functionalized with ruthenium nitrosyl as nitric oxide carriers

PAMAM dendrimers functionalized with ruthenium nitrosyl as nitric oxide carriers

In VitroEffects of Novel Ruthenium Complexes in Neospora caninum and Toxoplasma gondii Tachyzoites

Nitro/Nitrosyl-Ruthenium Complexes Are Potent and Selective Anti-Trypanosoma cruzi Agents Causing Autophagy and Necrotic Parasite Death

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