Para-Substituted α-Phenyl-N-tert-butyl Nitrones: Spin-Trapping, Redox and Neuroprotective Properties

Abstract

In this work, a series of para-substituted α-phenyl-N-tert-butyl nitrones (PBN) were studied. Their radical-trapping properties were evaluated by electron paramagnetic resonance, with 4-CF 3 -PBN being the fastest derivative to trap the hydroxymethyl radical ( • CH 2 OH). The redox properties of the nitrones were further investigated by cyclic voltammetry, and 4-CF 3 -PBN was the easiest to reduce and the hardest to oxidize. This is due to the presence of the electron-withdrawing CF 3 group. Very good correlations between the Hammett constants (σ p ) of the substituents and both spin-trapping rates and redox potentials were observed. These correlations were further supported by computationally determined ionization potentials and atom charge densities. Finally, the neuroprotective effect of these derivatives was studied using two different in vitro models of cell death on primary cortical neurons injured by glutamate exposure or on glial cells exposed to t BuOOH. Trends between the protection afforded by the nitrones and their lipophilicity were observed. 4-CF 3 -PBN was the most potent agent against t BuOOH-induced oxidative stress on glial cells, while 4-Me 2 N-PBN showed potency in both models.

Therapeutic Potential of Small Molecules Targeting Oxidative Stress in the Treatment of Chronic Obstructive Pulmonary Disease (COPD): A Comprehensive Review

“…Spin trapping agents have been extensively investigated in vitro. Their therapeutic potential has also been investigated in in vivo animal models of lung inflammation by utilizing α-phenyl-N-tert-butyl nitrone [ 260 , 261 , 262 ]. Spin trapping agents that were created earlier had very short half-lives and produced toxic hydroxyl radicals on decay.…”

Antioxidant for Neurological Diseases and Neurotrauma and Bioengineering Approaches

“…The weak radical trapping activity, low BBB penetration and inadequate trial design were cited to be the reasons behind the failure of NXY-059 in phase III clinical trials. Recently, there has been a renewed interest in developing PBN analogs as radical scavengers in neuroprotective applications (including neurodegenerative diseases) [ 44 , 129 , 130 , 131 ]. However, despite some promising results in in vitro and in vivo rodent models, considerable research is needed to establish their effectiveness for clinical translation, in particular, their bioavailability in the brain.…”

Insights into the Antioxidant Mechanism of Newly Synthesized Benzoxazinic Nitrones: In Vitro and In Silico Studies with DPPH Model Radical

“…Among all nitrone families, two classes have been mainly researched, the cyclic ones derived from the 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) [ 13 , 14 , 15 , 16 , 17 ], and the linear ones derived from the α-phenyl-N-tert-butyl nitrone (PBN) [ 18 , 19 , 20 ]. Several derivatives of PBN, and to a lesser extent those of DMPO, have been recently synthesized with appropriate chemical modifications that have significantly improved the reactivity of the nitronyl group and the stability of the nitroxide spin-adduct [ 21 , 22 , 23 , 24 ]. Although it would be reasonable to attribute their biological action to their spin trapping activity, a clear picture of the actual mechanism of action of nitrones has not yet been reported.…”

“…Over the past years, several para -substituted nitrones [ 22 , 24 , 34 ], bearing electron-withdrawing groups have shown improved radical detection and antioxidant properties. The improved reactivity has been ascribed to the electronic nature of the substituent that appears to affect the rate of radical trapping on the nitronyl function by increasing the reactivity toward radical addition reactions [ 23 , 34 , 35 ]. Therefore, in this study we synthesized two constitutional isomers of benzoxazinic nitrones bearing a methoxycarbonyl group on the benzo moiety (in para - and meta -position) with the aim to enhance the reactivity of the already studied unsubstituted parent compound.…”