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Reactivities of substituted α-phenyl-N-tert-butyl nitrones.

Rosselin M, Choteau F, Zéamari K, Nash KM, Das A, Lauricella R, Lojou E, Tuccio B, Villamena FA, Durand G - J. Org. Chem. (2014)

Bottom Line: The effect of N-tert-butyl substitution on the charge density and electron density localization of the nitronyl carbon as well as on the free energies of nitrone reactivity with O2(•-) and HO2(•) were computationally rationalized at the PCM/B3LYP/6-31+G**//B3LYP/6-31G* level of theory.Finally, the substituent effect was investigated in cell cultures exposed to hydrogen peroxide and a correlation between the cell viability and the oxidation potential of the nitrones was observed.Through a combination of computational methodologies and experimental methods, new insights into the reactivity of free radicals with nitrone derivatives have been proposed.

View Article: PubMed Central - PubMed

Affiliation: Avignon Université , Equipe Chimie Bioorganique et Systèmes Amphiphiles, 33 rue Louis Pasteur, F-84000 Avignon, France.

ABSTRACT
In this work, a series of α-phenyl-N-tert-butyl nitrones bearing one, two, or three substituents on the tert-butyl group was synthesized. Cyclic voltammetry (CV) was used to investigate their electrochemical properties and showed a more pronounced substituent effect for oxidation than for reduction. Rate constants of superoxide radical (O2(•-)) reactions with nitrones were determined using a UV-vis stopped-flow method, and phenyl radical (Ph(•)) trapping rate constants were measured by EPR spectroscopy. The effect of N-tert-butyl substitution on the charge density and electron density localization of the nitronyl carbon as well as on the free energies of nitrone reactivity with O2(•-) and HO2(•) were computationally rationalized at the PCM/B3LYP/6-31+G**//B3LYP/6-31G* level of theory. Theoretical and experimental data showed that the rates of the reaction correlate with the nitronyl carbon charge density, suggesting a nucleophilic nature of O2(•-) and Ph(•) addition to the nitronyl carbon atom. Finally, the substituent effect was investigated in cell cultures exposed to hydrogen peroxide and a correlation between the cell viability and the oxidation potential of the nitrones was observed. Through a combination of computational methodologies and experimental methods, new insights into the reactivity of free radicals with nitrone derivatives have been proposed.

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Cytoprotectivity of PBN derivatives at 10 and50 μM on bovineaortic endothelial cells against 1 mM H2O2 after2 h of incubation.
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fig6: Cytoprotectivity of PBN derivatives at 10 and50 μM on bovineaortic endothelial cells against 1 mM H2O2 after2 h of incubation.

Mentions: Cytoprotective propertiesof nitrones against H2O2-induced cell deathwas investigated in vitro using bovine aortic endothelial cells (BAEC).BAEC were preincubated with varying concentrations (10–50 μM)of nitrone derivatives 1, 2, and 6–8 (i.e., PBN-CH2OH, PBN-CH2OAc, PBN-CH2OCONHMe, PBN-CH2NHAc, and PBN-(CH2OH)2) and were challenged for 2 h with H2O2 (1 mM). Extent of cytoprotection was measured using[3-(4,5-dimethylthiazol-2-yl)-2–5-diphenyltetrazolium-bromide](MTT) assay. Our results are presented in Figure 6 and show that at 10 μM nitrones 2 and 7 exhibited the highest cytoprotection against H2O2-induced toxicity. At 50 μM, the protection affordedby the nitrones was more pronounced for PBN and compounds 1, 7 and 8 while for compounds 2 the protection remained similar. A significant decrease of cellviability for compound 6 was noted which was even lowerthan that of the control and may indicate a slight toxicity due tothe carbamate substituent.


Reactivities of substituted α-phenyl-N-tert-butyl nitrones.

Rosselin M, Choteau F, Zéamari K, Nash KM, Das A, Lauricella R, Lojou E, Tuccio B, Villamena FA, Durand G - J. Org. Chem. (2014)

Cytoprotectivity of PBN derivatives at 10 and50 μM on bovineaortic endothelial cells against 1 mM H2O2 after2 h of incubation.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4216227&req=5

fig6: Cytoprotectivity of PBN derivatives at 10 and50 μM on bovineaortic endothelial cells against 1 mM H2O2 after2 h of incubation.
Mentions: Cytoprotective propertiesof nitrones against H2O2-induced cell deathwas investigated in vitro using bovine aortic endothelial cells (BAEC).BAEC were preincubated with varying concentrations (10–50 μM)of nitrone derivatives 1, 2, and 6–8 (i.e., PBN-CH2OH, PBN-CH2OAc, PBN-CH2OCONHMe, PBN-CH2NHAc, and PBN-(CH2OH)2) and were challenged for 2 h with H2O2 (1 mM). Extent of cytoprotection was measured using[3-(4,5-dimethylthiazol-2-yl)-2–5-diphenyltetrazolium-bromide](MTT) assay. Our results are presented in Figure 6 and show that at 10 μM nitrones 2 and 7 exhibited the highest cytoprotection against H2O2-induced toxicity. At 50 μM, the protection affordedby the nitrones was more pronounced for PBN and compounds 1, 7 and 8 while for compounds 2 the protection remained similar. A significant decrease of cellviability for compound 6 was noted which was even lowerthan that of the control and may indicate a slight toxicity due tothe carbamate substituent.

Bottom Line: The effect of N-tert-butyl substitution on the charge density and electron density localization of the nitronyl carbon as well as on the free energies of nitrone reactivity with O2(•-) and HO2(•) were computationally rationalized at the PCM/B3LYP/6-31+G**//B3LYP/6-31G* level of theory.Finally, the substituent effect was investigated in cell cultures exposed to hydrogen peroxide and a correlation between the cell viability and the oxidation potential of the nitrones was observed.Through a combination of computational methodologies and experimental methods, new insights into the reactivity of free radicals with nitrone derivatives have been proposed.

View Article: PubMed Central - PubMed

Affiliation: Avignon Université , Equipe Chimie Bioorganique et Systèmes Amphiphiles, 33 rue Louis Pasteur, F-84000 Avignon, France.

ABSTRACT
In this work, a series of α-phenyl-N-tert-butyl nitrones bearing one, two, or three substituents on the tert-butyl group was synthesized. Cyclic voltammetry (CV) was used to investigate their electrochemical properties and showed a more pronounced substituent effect for oxidation than for reduction. Rate constants of superoxide radical (O2(•-)) reactions with nitrones were determined using a UV-vis stopped-flow method, and phenyl radical (Ph(•)) trapping rate constants were measured by EPR spectroscopy. The effect of N-tert-butyl substitution on the charge density and electron density localization of the nitronyl carbon as well as on the free energies of nitrone reactivity with O2(•-) and HO2(•) were computationally rationalized at the PCM/B3LYP/6-31+G**//B3LYP/6-31G* level of theory. Theoretical and experimental data showed that the rates of the reaction correlate with the nitronyl carbon charge density, suggesting a nucleophilic nature of O2(•-) and Ph(•) addition to the nitronyl carbon atom. Finally, the substituent effect was investigated in cell cultures exposed to hydrogen peroxide and a correlation between the cell viability and the oxidation potential of the nitrones was observed. Through a combination of computational methodologies and experimental methods, new insights into the reactivity of free radicals with nitrone derivatives have been proposed.

Show MeSH