Comparative DFT Study of the Spin Trapping of Methyl, Mercapto, Hydroperoxy, Superoxide, and Nitric Oxide Radicals by Various Substituted Cyclic Nitrones

Abstract

The thermodynamics of the spin trapping of various cyclic nitrones with biologically relevant radicals such as methyl, mercapto, hydroperoxy, superoxide anion, and nitric oxide was investigated using computational methods. A density functional theory (DFT) approach was employed in this study at the B3LYP/6-31+G(d,p)//B3LYP/6-31G(d) level. The order of increasing favorability for Delta G(rxn) (kcal/mol) of the radical reaction with various nitrones, in general, follows a trend similar to their respective experimental reduction potentials as well as their experimental second-order rate constants in aqueous solution: NO (14.57) < O2*- (-7.51) < *O2H (-13.92) < *SH (-16.55) < *CH3 (-32.17) < *OH (-43.66). The same qualitative trend is predicted upon considering the effect of solvation using the polarizable continuum model (PCM): i.e., NO (14.12) < O2*- (9.95) < *O2H (-6.95) < *SH (-13.57) < *CH3 (-32.88) < *OH (-38.91). All radical reactions with these nitrones are exoergic, except for NO (and O2*- in the aqueous phase), which is endoergic, and the free energy of activation (Delta G) for the NO additions ranges from 17.7 to 20.3 kcal/mol. This study also predicts the favorable formation of certain adducts that exhibit intramolecular H-bonding interactions, nucleophilic addition, or H-atom transfer reactions. The spin density on the nitronyl N of the superoxide adducts reveals conformational dependences. The failure of nitrones to trap NO at normal conditions was theoretically rationalized due to the endoergic reaction parameters.

Inhibition of ROS-induced apoptosis in endothelial cells by nitrone spin traps via induction of phase II enzymes and suppression of mitochondria-dependent pro-apoptotic signaling

“…For instance, nitrones can exhibit redox properties by virtue of their oxidation state [62], react with a variety of free radicals [63–65], decompose to NO after addition to O 2 •– [40, 41], can form biologically relevant species such as hydroxamic acid, aldehydes, and nitrous acid [62] and more effectively traps O 2 •– at mildly acidic pH than in neutral pH which makes spin trapping relevant in ischemic conditions or cancer cells [66]. Although the mechanism of nitrone-protection is still obscure, earlier studies suggest that the spin trapping properties play an important role in nitrone-mediated cardioprotection [67, 68] but recent experimental evidences pointed out the involvement of other mechanisms of protection other than spin trapping [26].…”

Synthesis, structure, theoretical and experimental in vitro antioxidant/pharmacological properties of α-aryl, N-alkyl nitrones, as potential agents for the treatment of cerebral ischemia

“…In this context, the determination of the reaction free energy in the formation of the adduct-spin gives a good correlation between the values of the potential of ionization and the experimental kinetic constants. 28 Accordingly, this theoretical approach can be useful in order to predict the respective reactivities.…”

Spin Trapping and Cytoprotective Properties of Fluorinated Amphiphilic Carrier Conjugates of Cyclic versus Linear Nitrones

“…However, there are other physical-chemical properties of nitrones that could potentially provide new motivation for their application as therapeutic agent. For example, our previous studies showed that cyclic nitrones react with a variety of free radicals at orders of magnitude faster than O 2 •− (19), the O 2 •− adduct formed decomposes to release NO (20), nitrone reaction with CO 3 •− yields nitrite (21) that can increase NO bioavailability upon reaction with heme iron proteins, and that nitrones are more reactive in acidosis conditions, common in ischemic and tumor cells (22). …”