Effective inhibition of copper-catalyzed production of hydroxyl radicals by deferiprone

Timoshnikov, Viktor A.; Kobzeva, T. V.; Selyutina, Olga Yu.; Polyakov, Nikolay E.; Kontoghiorghes, George J.

doi:10.1007/s00775-019-01650-9

Cited by 23 publications

(34 citation statements)

References 73 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The formation of •OH radicals in the systems under study was proved by the detection of the corresponding TMIO-OH spin adduct with HFC constants: a(N) = 14.07 G, a(H) = 16.08 G (Figure 4) [39,40,55,64]. It was found that the signal from •OH spin adducts increased after addition of ascorbic The TMIO spin trap provides more distinguishable individual spectra with the •OH radical than the widely used DMPO spin trap [55][56][57].…”

Section: Epr Spin Trapping Study Of the Hydroxyl Radicals Production mentioning

confidence: 97%

“…The formation of •OH radicals in the systems under study was proved by the detection of the corresponding TMIO-OH spin adduct with HFC constants: a(N) = 14.07 G, a(H) = 16.08 G (Figure 4) [39,40,55,64]. It was found that the signal from •OH spin adducts increased after addition of ascorbic acid to the solution in the absence of L1, as well as in the presence of low concentrations of L1 (L1:Fe = 0 or 1:1, see Figure 4a,b).…”

Section: Epr Spin Trapping Study Of the Hydroxyl Radicals Production mentioning

confidence: 97%

“…It has been shown that the reaction proceeds on a millisecond time scale with the subsequent formation of the oxidation product of ascorbic acid, namely dehydroascorbic acid (DHA) (see Scheme 1). These and other researchers pointed to the rapid reduction of Fe 3+ via intramolecular electron transfer with simultaneous production of the ascorbyl radical (AscH • ) [38][39][40]47].…”

Section: Introductionmentioning

confidence: 98%

“…In this regard, numerous studies have been conducted to elucidate the redox activity of iron in chelate complexes [35][36][37][38][39]. As an example, we recently demonstrated the inhibition of iron-and copper-induced hydroxyl radical production by the water-soluble chelator deferiprone (L1, Figure 1) [39,40]. L1 is an effective iron-chelating drug developed for the treatment of iron overload toxicity in thalassaemia and other iron-related toxicity conditions.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Redox Interactions of Vitamin C and Iron: Inhibition of the Pro-Oxidant Activity by Deferiprone

Timoshnikov

Kobzeva

Polyakov

et al. 2020

IJMS

View full text Add to dashboard Cite

Ascorbic acid (AscH2) is one of the most important vitamins found in the human diet, with many biological functions including antioxidant, chelating, and coenzyme activities. Ascorbic acid is also widely used in medical practice especially for increasing iron absorption and as an adjuvant therapeutic in iron chelation therapy, but its mode of action and implications in iron metabolism and toxicity are not yet clear. In this study, we used UV–Vis spectrophotometry, NMR spectroscopy, and EPR spin trapping spectroscopy to investigate the antioxidant/pro-oxidant effects of ascorbic acid in reactions involving iron and the iron chelator deferiprone (L1). The experiments were carried out in a weak acidic (pH from 3 to 5) and neutral (pH 7.4) medium. Ascorbic acid exhibits predominantly pro-oxidant activity by reducing Fe3+ to Fe2+, followed by the formation of dehydroascorbic acid. As a result, ascorbic acid accelerates the redox cycle Fe3+ ↔ Fe2+ in the Fenton reaction, which leads to a significant increase in the yield of toxic hydroxyl radicals. The analysis of the experimental data suggests that despite a much lower stability constant of the iron–ascorbate complex compared to the FeL13 complex, ascorbic acid at high concentrations is able to substitute L1 in the FeL13 chelate complex resulting in the formation of mixed L12AscFe complex. This mixed chelate complex is redox stable at neutral pH = 7.4, but decomposes at pH = 4–5 during several minutes at sub-millimolar concentrations of ascorbic acid. The proposed mechanisms play a significant role in understanding the mechanism of action, pharmacological, therapeutic, and toxic effects of the interaction of ascorbic acid, iron, and L1.

show abstract

Section: Epr Spin Trapping Study Of the Hydroxyl Radicals Production mentioning

confidence: 97%

“…The formation of •OH radicals in the systems under study was proved by the detection of the corresponding TMIO-OH spin adduct with HFC constants: a(N) = 14.07 G, a(H) = 16.08 G (Figure 4) [39,40,55,64]. It was found that the signal from •OH spin adducts increased after addition of ascorbic acid to the solution in the absence of L1, as well as in the presence of low concentrations of L1 (L1:Fe = 0 or 1:1, see Figure 4a,b).…”

Section: Epr Spin Trapping Study Of the Hydroxyl Radicals Production mentioning

confidence: 97%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Redox Interactions of Vitamin C and Iron: Inhibition of the Pro-Oxidant Activity by Deferiprone

Timoshnikov

Kobzeva

Polyakov

et al. 2020

IJMS

View full text Add to dashboard Cite

show abstract

“…For instance, deferiprone has been widely used for the treatment of systemic iron-related diseases and for neurological pathologies, including PD [72], due to its low molecular weight and ability to cross the blood-brain barrier. Different studies demonstrated deferiprone's ability to chelate not only iron but also copper, aluminum and zinc [73], reducing their free radical catalytic activity [74]. Moreover, multifunctional iron/copper chelating agents have been evaluated even if their clinical translation has not yet progressed [75].…”

Section: Parkinson's Diseasementioning

confidence: 99%

Current Biomedical Use of Copper Chelation Therapy

Baldari

Rocco

Toietta

2020

IJMS

103

View full text Add to dashboard Cite

Copper is an essential microelement that plays an important role in a wide variety of biological processes. Copper concentration has to be finely regulated, as any imbalance in its homeostasis can induce abnormalities. In particular, excess copper plays an important role in the etiopathogenesis of the genetic disease Wilson’s syndrome, in neurological and neurodegenerative pathologies such as Alzheimer’s and Parkinson’s diseases, in idiopathic pulmonary fibrosis, in diabetes, and in several forms of cancer. Copper chelating agents are among the most promising tools to keep copper concentration at physiological levels. In this review, we focus on the most relevant compounds experimentally and clinically evaluated for their ability to counteract copper homeostasis deregulation. In particular, we provide a general overview of the main disorders characterized by a pathological increase in copper levels, summarizing the principal copper chelating therapies adopted in clinical trials.

show abstract

A Mitochondrion‐Localized Two‐Photon Photosensitizer Generating Carbon Radicals Against Hypoxic Tumors

et al. 2020

View full text Add to dashboard Cite

The efficacy of photodynamic therapyi st ypically reliant on the local concentration and diffusion of oxygen. Due to the hypoxic microenvironment found in solid tumors, oxygen-independent photosensitizers are in great demand for cancer therapy. We herein report an iridium(III) anthraquinone complex as am itochondrion-localized carbon-radical initiator.I ts emission is turned on under hypoxic conditions after reduction by reductase.F urthermore,i ts two-photon excitation properties (l ex = 730 nm) are highly desirable for imaging.U pon irradiation, the reduced form of the complex generates carbon radicals,l eading to al oss of mitochondrial membrane potential and cell death (IC 50 light = 2.1 mm,IC 50 dark = 58.2 mm,P I= 27.7). The efficacy of the complex as aP DT agent was also demonstrated under hypoxic conditions in vivo. To the best of our knowledge,i ti st he first metal-complexbased theranostic agent which can generate carbon radicals for oxygen-independent two-photon photodynamic therapy.

show abstract

Effective inhibition of copper-catalyzed production of hydroxyl radicals by deferiprone

Cited by 23 publications

References 73 publications

Redox Interactions of Vitamin C and Iron: Inhibition of the Pro-Oxidant Activity by Deferiprone

Redox Interactions of Vitamin C and Iron: Inhibition of the Pro-Oxidant Activity by Deferiprone

Current Biomedical Use of Copper Chelation Therapy

A Mitochondrion‐Localized Two‐Photon Photosensitizer Generating Carbon Radicals Against Hypoxic Tumors

Contact Info

Product

Resources

About