Recent Advances on Nitrones Design for Stroke Treatment

Marco‐Contelles, José

doi:10.1021/acs.jmedchem.0c00976

Cited by 30 publications

(30 citation statements)

References 82 publications

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“…Consequently, nitrones were initially used because they have extremely potent activity in biological systems, mainly due to their free radical "spin trap" capacity. Subsequent studies have shown that alpha-phenyl-N-tertbutylnitrone(PBN) nitrone, as well as its analogs demonstrated low toxicity and potent pharmacological activity against Parkinson's disease and Alzheimer's (Floyd et al, 2008(Floyd et al, , 2013 and ischemic stroke (Contelles, 2020).…”

Section: Introductionmentioning

confidence: 99%

The Potent Trypanocidal Effect of LQB303, a Novel Redox-Active Phenyl-Tert-Butyl-Nitrone Derivate That Causes Mitochondrial Collapse in Trypanosoma cruzi

et al. 2021

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Chagas disease, which is caused by Trypanosoma cruzi, establishes lifelong infections in humans and other mammals that lead to severe cardiac and gastrointestinal complications despite the competent immune response of the hosts. Furthermore, it is a neglected disease that affects 8 million people worldwide. The scenario is even more frustrating since the main chemotherapy is based on benznidazole, a drug that presents severe side effects and low efficacy in the chronic phase of the disease. Thus, the search for new therapeutic alternatives is urgent. In the present study, we investigated the activity of a novel phenyl-tert-butyl-nitrone (PBN) derivate, LQB303, against T. cruzi. LQB303 presented trypanocidal effect against intracellular [IC50/48 h = 2.6 μM] and extracellular amastigotes [IC50/24 h = 3.3 μM] in vitro, leading to parasite lysis; however, it does not present any toxicity to host cells. Despite emerging evidence that mitochondrial metabolism is essential for amastigotes to grow inside mammalian cells, the mechanism of redox-active molecules that target T. cruzi mitochondrion is still poorly explored. Therefore, we investigated if LQB303 trypanocidal activity was related to the impairment of the mitochondrial function of amastigotes. The investigation showed there was a significant decrease compared to the baseline oxygen consumption rate (OCR) of LQB303-treated extracellular amastigotes of T. cruzi, as well as reduction of “proton leak” (the depletion of proton motive force by the inhibition of F1Fo ATP synthase) and “ETS” (maximal oxygen consumption after uncoupling) oxygen consumption rates. Interestingly, the residual respiration (“ROX”) enhanced about three times in LQB303-treated amastigotes. The spare respiratory capacity ratio (SRC: cell ability to meet new energy demands) and the ATP-linked OCR were also impaired by LQB303 treatment, correlating the trypanocidal activity of LQB303 with the impairment of mitochondrial redox metabolism of amastigotes. Flow cytometric analysis demonstrated a significant reduction of the ΔΨm of treated amastigotes. LQB303 had no significant influence on the OCR of treated mammalian cells, evidencing its specificity against T. cruzi mitochondrial metabolism. Our results suggest a promising trypanocidal activity of LQB303, associated with parasite bioenergetic inefficiency, with no influence on the host energy metabolism, a fact that may point to an attractive alternative therapy for Chagas disease.

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Section: Introductionmentioning

confidence: 99%

The Potent Trypanocidal Effect of LQB303, a Novel Redox-Active Phenyl-Tert-Butyl-Nitrone Derivate That Causes Mitochondrial Collapse in Trypanosoma cruzi

et al. 2021

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“…The formation of stable and persistent nitroxide adducts of free radical reactive species endows nitrones with marked antioxidant properties and support their use as therapeutic agents to treat disorders related to oxidative stress. [1][2][3] The same process promotes the use of nitrones as building blocks for the construction of nitrogenous compounds 4 and as electron paramagnetic resonance (EPR) spin traps. 5 Although natural products containing the nitrone functional group are scarce, 6 antioxidant and pharmacologically active compounds of natural origin can be used as starting materials for the semisynthesis of novel nitrones with high potential for application.…”

Section: Introductionmentioning

confidence: 99%

“…7,8 The nitrone derivatives of ligustrazine, a pyrazine found in the Chinese herb Ligusticum wallichii Franch., have antioxidant and thrombolytic properties and are effective therapeutics for treating ischemic stroke. 3 Another example is the nitrone derived from the water-soluble analogue of vitamin E, Trolox, which shows enhanced radical scavenging and neuroprotective properties. 9 Betalains are non-toxic water-soluble pigments found in plants, fungi and bacteria 10 that have been consumed in foods for millennia.…”

Section: Introductionmentioning

confidence: 99%

Design of an Antioxidant Nitrone Scaffold Based on Plant Pigments

Ac¹,

Rb²,

Lc³

et al. 2021

Preprint

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Nitrones derived from natural antioxidants are emerging as highly specific therapeutics for the treatment of various human diseases, including stroke, neurodegenerative pathologies, and cancer. However, the development of useful pseudo-natural nitrones requires the judicious choice of a secondary metabolite as precursor. Betalains are nitrogen-containing natural pigments that exhibit marked antioxidant and pharmacological properties and, hence, are ideal candidates for the design of multifunctional nitrones. In this work, we describe the semisynthesis and properties of a biocompatible and antioxidant betalain-nitrone named OxiBeet. This bio-based compound is a better radical scavenger than ascorbic acid, gallic acid and most non-phenolic antioxidants and undergoes concerted proton-coupled electron transfer. The autoxidation of OxiBeet gives rise to a persistent nitroxide radical, which was studied by electron paramagnetic resonance spectroscopy. Femtosecond transient absorption spectroscopy reveals that excited state formation is not required for the oxidation of OxiBeet. The results are compared with those obtained using betanin, a natural betalain, and pBeet, the imine analogue of OxiBeet. The findings in this study will enable the development of antioxidant nitrones based on the novel <i>N</i>-oxide 1,7-diazaheptamethinium scaffold and betalain dyes with enhanced hydrolytic stability in aqueous alkaline media.

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“…The formation of stable and persistent nitroxide adducts of free radical reactive species endows nitrones with marked antioxidant potential and supports their use as therapeutic agents to treat disorders related to oxidative stress. [1][2][3] The same process promotes the use of nitrones as building blocks for the construction of nitrogenous compounds 4 and as electron paramagnetic resonance (EPR) spin traps. 5 Although natural products containing the nitrone functional group are scarce, 6 antioxidant and pharmacologically active compounds of natural origin can be used as starting materials for the semisynthesis of novel nitrones that have many potential applications.…”

Section: Introductionmentioning

confidence: 99%

“…7,8 The nitrone derivatives of ligustrazine-a pyrazine found in the Chinese herb Ligusticum wallichii Franch.-have antioxidant and thrombolytic properties and are effective therapeutics for treating ischemic stroke. 3 Another important example is the nitrone derived from the water-soluble analog of vitamin E (Trolox), which shows enhanced radical scavenging and neuroprotective properties. 9 Betalains are non-toxic water-soluble pigments found in plants, fungi, and bacteria 10 that have been consumed for millennia.…”

Section: Introductionmentioning

confidence: 99%

Design of an Antioxidant Nitrone Scaffold Based on Plant Pigments

Pinheiro¹,

Fazzi²,

Esteves³

et al. 2021

Preprint

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<div> <div> <div> <p>Nitrones derived from natural antioxidants are emerging as highly specific therapeutics against various human diseases, including stroke, neurodegenerative pathologies, and cancer. However, the development of useful pseudo-natural nitrones requires the judicious choice of a secondary metabolite as the precursor. Betalains are nitrogen-containing natural pigments that exhibit marked antioxidant capacity and pharmacological properties and, hence, are ideal candidates for designing multifunctional nitrones. In this work, we describe the semisynthesis and properties of a biocompatible, antioxidant betalain-nitrone called OxiBeet. This bio-based compound is a better radical scavenger than ascorbic acid, gallic acid, and most non-phenolic antioxidants and undergoes concerted proton-coupled electron transfer. The autoxidation of OxiBeet produces a persistent nitroxide radical, which, herein, is studied via electron paramagnetic resonance spectroscopy. In addition, femtosecond transient absorption spectroscopy reveals that excited state formation is not required for the oxidation of OxiBeet. The results are compared with those obtained using betanin, a natural betalain, and pBeet, the imine analog of OxiBeet. The findings of this study will enable the development of antioxidant nitrones based on the novel N-oxide 1,7-diazaheptamethinium scaffold and betalain dyes with enhanced hydrolytic stability in aqueous alkaline media. </p> </div> </div> </div>

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Recent Advances on Nitrones Design for Stroke Treatment

Cited by 30 publications

References 82 publications

The Potent Trypanocidal Effect of LQB303, a Novel Redox-Active Phenyl-Tert-Butyl-Nitrone Derivate That Causes Mitochondrial Collapse in Trypanosoma cruzi

The Potent Trypanocidal Effect of LQB303, a Novel Redox-Active Phenyl-Tert-Butyl-Nitrone Derivate That Causes Mitochondrial Collapse in Trypanosoma cruzi

Design of an Antioxidant Nitrone Scaffold Based on Plant Pigments

Design of an Antioxidant Nitrone Scaffold Based on Plant Pigments

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