Investigation of a potential mechanism for the inhibition of SmTGR by Auranofin and its implications for Plasmodium falciparum inhibition

Caroli, Antonia; Simeoni, Silvia; Lepore, Rosalba; Tramontano, Anna; Via, Allegra

doi:10.1016/j.bbrc.2011.12.009

Cited by 34 publications

(30 citation statements)

References 22 publications

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“…In conclusion, the combination of reduced surface area and best shielding of the ruthenium tachyzoites, and after 48 h, they were treated with 100 nM compound 16 for 12 and 36 h, respectively; untreated infected cultures served as a control. Specimens were then processed for TEM as previously described (46,47) and were viewed on a Philips 400T transmission electron microscope operating at 80 kV. (A, B) Numerous tachyzoites enclosed in a parasitophorous vacuole near the vicinity of the host cell nucleus (hcnuc), surrounded by a parasitophorous vacuole membrane (pvm).…”

Section: Fig 4 Effects Of Preincubation Of Extracellular Tachyzoitesmentioning

confidence: 99%

“…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).…”

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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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Section: Fig 4 Effects Of Preincubation Of Extracellular Tachyzoitesmentioning

confidence: 99%

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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“…As such, parasites have evolved specific enzymes that enable them to maintain redox balance; these enzymes are good targets for the treatment of parasitic infections as they are necessary for parasite survival and are often organism specific (Angelucci et al 2009;Caroli et al 2012). Additionally, parasites usually have either TrxR or TGR alone to maintain thiol redox balance, whereas mammals have two independent pathways involving TrxR or glutathione reductase (GR) (Angelucci et al 2009).…”

Section: Anti-parasitic Activity Of Afmentioning

confidence: 99%

“…Deacetylated AF (Fig. 1c) is another metabolite formed in the gastro-intestinal tract (Caroli et al 2012, Tepperman et al 1984 and many in vitro studies do not take into account this first-pass metabolite, which is more lipophilic than AF and could have biological activity that is different from the parent compound (McKeage et al 2000).…”

Section: Introductionmentioning

confidence: 99%

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The biological activity of auranofin: implications for novel treatment of diseases

et al. 2012

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More than 30 years ago, auranofin was developed for the treatment of rheumatoid arthritis as a substitution for the injectable gold compounds aurothiomalate and aurothioglucose. Both the ease of oral administration over intramuscular injections and more potent anti-inflammatory effects in vitro made auranofin seem like an excellent substitute for the traditional injectable gold compounds. Despite efficacy in the treatment of both rheumatoid arthritis and psoriasis, currently, auranofin is seldom used as a treatment for patients with rheumatoid arthritis as more novel anti-rheumatic medications have become available. Despite the decline in its clinical applications, research on auranofin has continued as it shows promise in the treatment of several different diseases. In recent years, advances in technology have allowed researchers to use molecular techniques to identify novel mechanisms of action of auranofin. Additionally, researchers are discovering potential new applications of auranofin. Dual inhibition of inflammatory pathways and thiol redox enzymes by auranofin makes it a new candidate for cancer therapy and treating microbial infections. This review will summarize recently obtained data on the mechanisms of action of auranofin, and potential new applications of auranofin in the treatment of various diseases, including several types of leukaemia, carcinomas, and parasitic, bacterial, and viral infections.

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A Novel Hybrid of Chloroquine and Primaquine Linked by Gold(I): Multitarget and Multiphase Antiplasmodial Agent

et al. 2020

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Plasmodium parasites kill 435 000 people around the world every year due to unavailable vaccines, a limited arsenal of antimalarial drugs, delayed treatment, and the reduced clinical effectiveness of current practices caused by drug resistance. Therefore, there is an urgent need to discover and develop new antiplasmodial candidates. In this work, we present a novel strategy to develop a multitarget metallic hybrid antimalarial agent with possible dual efficacy in both sexual and asexual erythrocytic stages. A hybrid of antimalarial drugs (chloroquine and primaquine) linked by gold(I) was synthesized and characterized by spectroscopic and analytical techniques. The CQPQ‐gold(I) hybrid molecule affects essential parasite targets, it inhibits β‐hematin formation and interacts moderately with the DNA minor groove. Its interaction with PfTrxR was also examined in computational modeling studies. The CQPQ‐gold(I) hybrid displayed an excellent in vitro antimalarial activity against the blood‐stage of Plasmodium falciparum and liver‐stage of Plasmodium berghei and efficacy in vivo against P. berghei, thereby demonstrating its multiple‐stage antiplasmodial activity. This metallic hybrid is a promising chemotherapeutic agent that could act in the treatment, prevention, and transmission of malaria.

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Investigation of a potential mechanism for the inhibition of SmTGR by Auranofin and its implications for Plasmodium falciparum inhibition

Cited by 34 publications

References 22 publications

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

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

The biological activity of auranofin: implications for novel treatment of diseases

A Novel Hybrid of Chloroquine and Primaquine Linked by Gold(I): Multitarget and Multiphase Antiplasmodial Agent

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