Can nucleotides prevent Cu-induced oxidative damage?

Baruch-Suchodolsky, Rozena; Fischer, Bilha

doi:10.1016/j.jinorgbio.2007.11.023

Cited by 9 publications

(27 citation statements)

References 66 publications

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“…IC 50 values of ADP-β-S and ADP were 85 and 250 µM, respectively vs. DTPA, Trolox, and citrate, 90, 150 and 300 µM, respectively. Our findings here and our previous results support the assumption that a sulfur atom replacing oxygen in the phosphate moiety improves the antioxidant activity of the molecule due to improved affinity to Fe(II) 17,29 and improved chemical and metabolic stability of the compounds. [30][31][32] Inhibition of ROS production in PC12 cells under oxidizing conditions by thiophosphate analogues 6-11 Previously we studied the modulation of Fe(II)-induced oxidative stress in PC12 cells by nucleotides and dinucleotides, using DCFH-DA, 19 a radical sensitive indicator.…”

Section: Evaluation Of the Relative Binding Of Fe(ii) Ions To Nucleotsupporting

confidence: 91%

“…We found that certain natural and synthetic adenine nucleotides at sub-millimolar concentrations prevented OH radical production from H 2 O 2 in the presence of Cu(I)/Fe(II) ions better than standard antioxidants. 16,17 specifically, 3 proved a 100-and 20-times more active antioxidant at Fe(II)/H 2 O 2 system than 1 and the potent antioxidant Trolox, 16 respectively. Furthermore, we identified 3 as a highly promising antioxidant and neuroprotective agent in PC12 cells and primary neurons exposed to oxidative stress, 19 which was significantly more potent than 5 and GDP-β-S.…”

Section: Introductionmentioning

confidence: 95%

“…Specifically, purine nucleotide analogues are natural metal-ion chelators binding metal-ions by the purine ring N7 nitrogen atom, and / or the 5'-phosphate chain. [16][17][18] Recently, we have studied natural nucleotides and the corresponding phosphorothioate analogues, as well as inorganic phosphates as inhibitors of Fenton reaction. We found that certain natural and synthetic adenine nucleotides at sub-millimolar concentrations prevented OH radical production from H 2 O 2 in the presence of Cu(I)/Fe(II) ions better than standard antioxidants.…”

Section: Introductionmentioning

confidence: 99%

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Identification of Highly Promising Antioxidants/Neuroprotectants Based on Nucleoside 5′-Phosphorothioate Scaffold. Synthesis, Activity, and Mechanisms of Action

et al. 2015

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With a view to identify novel and biocompatible neuroprotectants, we designed nucleoside 5'-thiophosphate analogues, 6-11. We identified 2-SMe-ADP(α-S), 7A, as a most promising neuroprotectant. 7A reduced ROS production in PC12 cells under oxidizing conditions, IC50 of 0.08 vs 21 μM for ADP. Furthermore, 7A rescued primary neurons subjected to oxidation, EC50 of 0.04 vs 19 μM for ADP. 7A is a most potent P2Y1-R agonist, EC50 of 0.0026 μM. Activity of 7A in cells involved P2Y1/12-R as indicated by blocking P2Y12-R or P2Y1-R. Compound 7A inhibited Fenton reaction better than EDTA, IC50 of 37 vs 54 μM, due to radical scavenging, IC50 of 12.5 vs 30 μM for ADP, and Fe(II)-chelation, IC50 of 80 vs >200 μM for ADP (ferrozine assay). In addition, 7A was stable in human blood serum, t1/2 of 15 vs 1.5 h for ADP, and resisted hydrolysis by NPP1/3, 2-fold vs ADP. Hence, we propose 7A as a highly promising neuroprotectant.

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Section: Evaluation Of the Relative Binding Of Fe(ii) Ions To Nucleotsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

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Identification of Highly Promising Antioxidants/Neuroprotectants Based on Nucleoside 5′-Phosphorothioate Scaffold. Synthesis, Activity, and Mechanisms of Action

et al. 2015

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“…44 The inhibition of radical production by chelators 6 and 7 (expressed in IC 50 and IC 90 values, Table 1) was compared to the inhibitory effect of common antioxidants including ascorbic acid, glutathione and the metal-ion chelator EDTA. Based on our previous reports 44,45 we expected compounds 6 and 7 to be more potent inhibitors than ADP and ATP since the formers bear a sulfur substitution at the P β /P γ position. Thiophosphate, unlike phosphate, is a soft ligand that binds preferably soft and borderline metal-ions.…”

Section: Esr Oh Radical Assaymentioning

confidence: 99%

“…ATP, ADP, 4, and thiophosphate, 5) proved potent antioxidants in Cu + /Cu 2+ -H 2 O 2 systems. 44,45 Modification of a nucleotide by a terminal thiophosphate moiety resulted in significantly enhanced antioxidant activity as compared to that of the corresponding parent compound (e.g. 3, and ADP-β-S, 6).…”

Section: Introductionmentioning

confidence: 99%

Nucleoside-5′-phosphorothioate analogues are biocompatible antioxidants dissolving efficiently amyloid beta–metal ion aggregates

et al. 2012

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Amyloid beta (Aβ) peptide is known to precipitate and form aggregates with zinc and copper ions in vitro and, in vivo in Alzheimer's disease (AD) patients. Metal-ion-chelation was suggested as therapy for the metal-ion-induced Aβ aggregation, metal-ion overload, and oxidative stress. In a quest for biocompatible metal-ion chelators potentially useful for AD therapy, we tested a series of nucleoside 5'-phosphorothioate derivatives as re-solubilization agents of Cu(+)/Cu(2+)/Zn(2+)-induced Aβ-aggregates, and inhibitors of Fenton reaction in Cu(+) or Fe(2+)/H(2)O(2) system. The most promising chelator in this series was found to be APCPP-γ-S. This nucleotide was found to be more efficient than EDTA in re-solubilization of Aβ(40)-Cu(2+) aggregates as observed by the lower diameter, d(H), (86 vs. 64 nm, respectively) obtained in dynamic light scattering measurements. Likewise, APCPP-γ-S dissolved Aβ(40)-Cu(+) and Aβ(42)-Cu(2+)/Zn(2+) aggregates, as monitored by (1)H-NMR and turbidity assays, respectively. Furthermore, addition of APCPP-γ-S to nine-day old Aβ(40)-Cu(2+)/Zn(2+) aggregates, resulted in size reduction as observed by transition electron microscopy (diameter reduction from 2.5 to 0.1 μm for Aβ(40)-Cu(2+) aggregates). APCPP-γ-S proved to be more efficient than ascorbic acid and GSH in reducing OH radical production in Fe(2+)/H(2)O(2) system (IC(50) values 85, 216 and, 92 μM, respectively). Therefore, we propose APCPP-γ-S as a potential AD therapy capable of both reducing OH radical production and re-solubilization of Aβ(40/42)-M(n+) aggregates.

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Oligonucleotides are potent antioxidants acting primarily through metal ion chelation

et al. 2010

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We report on a rather unknown feature of oligonucleotides, namely, their potent antioxidant activity. Previously, we showed that nucleotides are potent antioxidants in Fe(II)/Cu(I/II)-H(2)O(2) systems. Here, we explored the potential of 2'-deoxyoligonucleotides as inhibitors of the Fe(II)/Cu(I/II)-induced *OH formation from H(2)O(2). The oligonucleotides [d(A)(5,7,20); d(T)(20); (2'-OMe-A)(5)] proved to be highly potent antioxidants with IC(50) values of 5-17 or 48-85 microM in inhibiting Fe(II)/Cu(I)- or Cu(II)-induced H(2)O(2) decomposition, respectively, thus representing a 40-215-fold increase in potency as compared with Trolox, a standard antioxidant. The antioxidant activity is only weakly dependent on the oligonucleotides' length or base identity. We analyzed by matrix-assisted laser desorption/ionization time of flight mass spectrometry and (1)H-NMR spectroscopy the composition of the d(A)(5) solution exposed to the aforementioned oxidative conditions for 4 min or 24 h. We concluded that the primary (rapid) inhibition mechanism by oligonucleotides is metal ion chelation and the secondary (slow) mechanism is radical scavenging. We characterized the Cu(I)-d(A)(5) and Cu(II)-d(A)(7) complexes by (1)H-NMR and (31)P-NMR or frozen-solution ESR spectroscopy, respectively. Cu(I) is probably coordinated to d(A)(5) via N1 and N7 of two adenine residues and possibly also via two phosphate/bridging water molecules. The ESR data suggest Cu(II) chelation through two nitrogen atoms of the adenine bases and two oxygen atoms (phosphates or water molecules). We conclude that oligonucleotides at micromolar concentrations prevent Fe(II)/Cu(I/II)-induced oxidative damage, primarily through metal ion chelation. Furthermore, we propose the use of a short, metabolically stable oligonucleotide, (2'-OMe-A)(5), as a highly potent and relatively long lived (t(1/2) approximately 20 h) antioxidant.

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Can nucleotides prevent Cu-induced oxidative damage?

Cited by 9 publications

References 66 publications

Identification of Highly Promising Antioxidants/Neuroprotectants Based on Nucleoside 5′-Phosphorothioate Scaffold. Synthesis, Activity, and Mechanisms of Action

Identification of Highly Promising Antioxidants/Neuroprotectants Based on Nucleoside 5′-Phosphorothioate Scaffold. Synthesis, Activity, and Mechanisms of Action

Nucleoside-5′-phosphorothioate analogues are biocompatible antioxidants dissolving efficiently amyloid beta–metal ion aggregates

Oligonucleotides are potent antioxidants acting primarily through metal ion chelation

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