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The activity of 12 thiophenols as primary antioxidants in aqueous solution has been studied using density functional theory. Twelve different substituted thiophenols were tested as peroxyl radicals scavengers. Single electron transfer (SET) and formal hydrogen transfer (FHT) were investigated. The SET mechanism was found to be the main mechanism, with rate constants that are close to the diffusion limit, which means that these thiophenolic compounds have the capacity to scavenge peroxyl radicals before they can damage biomolecules. All 12 thiophenolic compounds react faster with methylperoxyl than with hydroperoxyl radicals. In addition, it was found that pH plays an important role in the reactivity of these compounds. © 2019 Wiley Periodicals, Inc.

Repair is a procedure widely used in nature to heal a variety of biomolecules that have been damaged by oxidative stress. It is an important field of research with many unanswered questions. This article reports a computational kinetic and thermodynamic study of the chemical repair of radical-damaged leucine residues by the antioxidants glutathione (GSH) and Trolox via hydrogen-atom transfer under physiological conditions. The single-electron transfer mechanism is also considered for both antioxidants. Calculations are performed at the M06-2X-SMD/6-31++G(d,p) level of theory using the SMD solvation model to simulate polar and nonpolar environments. Calculated rate constants in water and pentyl ethanoate are reported. Our results show that GSH can repair carbon-centred protein radicals with rate constants in the diffusion limit, but Trolox repairs of this kind of radical are much slower and not likely to be physiologically relevant. Intrinsic barrier calculations confirm that the different reactivities of GSH and Trolox arise from the different strengths of their S–H and O–H bonds; antioxidants with thiol groups repair damaged proteins via hydrogen atom transfer reactions much faster than those with hydroxyl groups.

The antioxidant and pro-oxidant behavior of 3-hydroxyanthranilic acid was investigated using density functional theory. In the absence of metal ions 3-hydroxyanthranilic acid acts as an excellent antioxidant by scavenging free radicals. It was found to be an excellent peroxyl radical scavenger in both lipid and aqueous solution, reacting with ˙OOH faster than Trolox. Moreover, the gathered kinetic data support the idea that 3-hydroxyanthranilic acid significantly contributes to the antioxidant activity usually attributed to tryptophan. In contrast, in the presence of metal ions (at physiological pH) it exhibits pro-oxidant behavior. This behavior arises from the Cu(II) reducing ability of the anionic fractions of this compound, which would contribute to producing Cu(I) and consequently promote ˙OH production via the Fenton reaction. Accordingly, the environmental factor identified to be crucial for ruling the dual behavior of 3-hydroxyanthranilic acid is the presence of metal ions. In addition, the pH is also predicted to influence the pro-oxidant effects of this compound.

Several recent computational studies have tried to explain the observed selectivity in radical damage to proteins. In this work we use Density Functional Theory and Transition State Theory including tunnelling corrections, reaction path degeneracy, the effect of diffusion, and the role of free radicals to get further insights into this important topic. The reaction between a leucine derivative and free radicals of biological significance, in aqueous and lipid media, has been investigated. Both thermochemical and kinetic analyses, in both hydrophilic and hydrophobic environments, have been carried out. DPPH, ˙OOH, ˙OOCH3, ˙OOCH2Cl, ˙OOCHCl2 and ˙OOCHCH2 radicals do not react with the target molecule. The reactions are proposed to be kinetically controlled. The leucine gamma site was the most reactive for the reactions with ˙N3, ˙OOCCl3, ˙OCH3, ˙OCH2Cl, and ˙OCHCl2 radicals, with rate constants equal to 1.97 × 10(5), 3.24 × 10(4), 6.68 × 10(5), 5.98 × 10(6) and 8.87 × 10(8) M(-1) s(-1), respectively, in aqueous solution. The ˙Cl, ˙OH and ˙OCCl3 radicals react with leucine at the beta, gamma, and delta positions at rates close to the diffusion limit with the alpha position which is the slowest path and the most thermodynamically favored. The presented results confirm that the Bell-Evans-Polanyi principle does not apply for the reactions between amino acid residues and free radicals. Regarding the influence of the environment on the reactivity of the studied series of free radicals towards leucine residues, it is concluded that hydrophilic media slightly lower the reactivity of the studied radicals, compared to hydrophobic ones, albeit the trends in reactivity are very similar.

In this work, we have carried out a quantum chemistry and computational kinetics study on the reactivity of fraxetin towards two peroxyl free radicals (˙OOH and ˙OOCH3), in aqueous and lipid simulated biological environments. We have considered three reaction mechanisms: hydrogen transfer (HT), radical adduct formation (RAF), and single electron transfer (SET). Rate constants and relative branching ratios for the different paths contributing to the overall reaction, at 298.15 K, are reported. In aqueous media, fraxetin exists in two forms, depending on pH. Neutral fraxetin reacts mainly through the HT mechanism, while the deprotonated fraxetin reacts mainly through the SET mechanism. The overall reaction rate constants are 3.99 × 108 and 2.76 × 109 M−1 s−1 for reaction with ˙OOH and ˙OOCH3 peroxyl radicals, respectively. In addition, we have shown that fraxetin is a versatile antioxidant in aqueous media, since it has a great scavenger activity towards other free radicals, under the same conditions. Furthermore, the possible regeneration of fraxetin after scavenging a first radical was investigated in aqueous solution at physiological pH. It was found that regeneration is very likely to occur, which suggests that this compound has the ability to scavenge several radical equivalents (two per cycle), under such conditions. In lipid media, fraxetin reacts with the peroxyl radicals only through the HT mechanism, and the calculated reaction rate constants are 2.43 × 104 and 2.81 × 103 M−1 s−1 for ˙OOH and ˙OOCH3 radicals, respectively.

2-Thiocytosine (TC) and 2-thiouracil (TU) were subjected to hydrated electron (eaq−), formate radical (CO2˙−) and 2-hydroxypropan-2-yl radical ((CH3)2˙COH) reactions in aqueous medium. Transients were characterized by absorption spectroscopy and the experimental findings were rationalized by DFT calculations at LC-ωPBE and M06-2X levels using a 6-311+G(d,p) basis set and SMD solvation. In eaq− reactions, a ring N-atom protonated radical of TC and an exocyclic O-atom protonated radical of TU were observed via addition of eaq− and subsequent protonation by solvent molecules. However, two competing but simultaneous mechanisms are operative in CO2˙− reactions with TC and TU. The first one corresponds to formations of N(O)-atom protonated radicals (similar to eaq− reactions); the second mechanism led to 2 center–3 electron, sulfur–sulfur bonded neutral dimer radicals, TCdim˙ and TUdim˙. DFT calculations demonstrated that H-abstraction by CO2˙− from TC(TU) results in S-centered radical which upon combination with TC(TU) provide the dimer radical. In some cases, DFT energy profiles were further validated by CBS-QB3//M06-2X calculations. This is the first time report for a contradictory behavior in the mechanisms of eaq− and CO2˙− reactions with any pyrimidines or their thio analogues.

The reactions of carbonate (CO 3 ·− ), nitric oxide (NO·) and nitrogen dioxide (NO 2 · ) radicals with free zwitterionic tryptophan and N-formyl-tryptophanamide (a model for tryptophan as a protein residue) have been studied using density functional theory and transition state theory. All possible reactions mechanisms have been analyzed. They are single electron transfer (SET), radical adduct formation and formal hydrogen transfer. The aqueous solution has been mimicked at physiological pH. Thermochemical and kinetic data are reported for both tryptophan models. We find that the reaction rate constants for CO 3 ·− with both tryptophan models are limited by diffusion, while for reaction with NO 2 · they are approximately 3.00 × 106 M−1 s−1, and NO· does not react at all. The overall rate constants of free zwitterionic tryptophan with NO 2 · and CO 3 ·− are 1.11 and 1.29 times larger than those of the N-formyl-tryptophanamide model, respectively. Therefore, it seems that the free amino acid and the residue in the protein have similar reactivities. While CO 3 ·− reacts via all three studied mechanisms at similar rates, NO 2 · reacts exclusively via SET. Our work suggests that free tryptophan has some scavenging activity and protective effect, but that bonded tryptophan could be a target for oxidative stress.

In this work, we have performed quantum chemistry and computational kinetics calculations to study the OH radical initiated oxidation of four saturated esters: methyl formate, ethyl formate, ethyl acetate, and n-propyl acetate. All possible mechanisms have been considered, and rate constants have been calculated using Conventional Transition State Theory. Systematic branching ratios for the different paths contributing to the overall reaction, at 298 K, are reported. In all cases, the calculated overall rate coefficients are in excellent agreement with reported experimental data, thus supporting the proposed mechanisms. The different site reactivity is rationalized in terms of the activation by different groups present in each molecule. The order of site reactivities for H abstraction was found to be OCH2 > CCH2 > HC(O)O > OCH3 > CH3C(O)O. This order explains the observed rate constants in the studied esters and can be extrapolated to similar compounds. The role of hydrogen bond-like interactions in the transition states and their influence on the observed site reactivities is discussed. © 2012 Wiley Periodicals, Inc.

Free-radical scavenging by tryptophan and eight of its metabolites through electron transfer was investigated in aqueous solution at physiological pH, using density functional theory and the Marcus theory. A test set of 30 free radicals was employed. Thermochemical and kinetic data on the corresponding reactions are provided here for the first time. Two different pathways were found to be the most important: sequential proton loss electron transfer (SPLET) and sequential double proton loss electron transfer (SdPLET). Based on kinetic analyses, it is predicted that the tryptophan metabolites kynurenic acid and xanthurenic acid are the best free-radical scavengers among the tested compounds; they were estimated to be at least 24 and 12 times more efficient than Trolox for scavenging (•)OOH. These findings are in line with previous reports suggesting that the antioxidant activity that has been attributed to tryptophan is actually due to its metabolites, and they demonstrate the particular importance of phenolic metabolites to such activity. Graphical Abstract Kynurenic acid (KNA) and xanthurenic acid (XNA) are the major contributors to the free-radical scavenging activity of tryptophan.

Oxidative damage to biomolecules is a serious health-threatening issue, which leads to the development of several diseases. Oxidative conditions are frequently catalyzed by metal ions. In this study, the role of purines in the copper-catalyzed oxidative stress was investigated using the density functional theory. The obtained results indicate that purines can have a dual behavior, acting as both protectors and promoters of oxidative stress. Their protection role arises from their known radical scavenging activity, as well as their ability to chelate Cu(II) leading to complexes that are—to some extent—harder to reduce than free Cu(II). Conversely, their pro-oxidant role is a consequence of their reductant behavior, when deprotonated. Thus, the purines’ anions can reduce Cu(II) to Cu(I), making the latter available to be involved in Fenton-like reactions. Consequently, mixtures of purines and Cu(II), at pHs where the fraction of deprotonated purines is rather significant, would yield •OH radicals. In turn, these very reactive radicals would damage biological targets such as lipids, proteins, and DNA.

The study of the ˙OOH, ˙OOCH3 and ˙OOCHCH2 radicals scavenging processes by esculetin (ES) was carried out in aqueous and lipid media, using the density functional theory. Three reaction mechanisms were considered: single electron transfer (SET), hydrogen transfer (HT) and radical adduct formation (RAF). Rate constants and branching ratios for the different paths are reported. It was found that in lipid media the main mechanism of reaction is HT, while in aqueous solution it depends on the predominant acid-base form of esculetin. HT was found to be the main mechanism involved in the free radical scavenging activity of neutral esculetin (H2ES), while for anionic esculetin (HES(-)) the relative importance of the different mechanisms changes with the reacting radical. Based on the calculated rate constants, it is proposed that esculetin has moderate peroxyl scavenging activity in lipid media while in aqueous solution, at physiological pH, it is excellent for that purpose. In addition, the possible regeneration of ES, after scavenging the first radical, was investigated in aqueous solution, at physiological pH. It was found that regeneration is very likely to occur, which suggests that this compound has the ability to scavenge several radical equivalents (two per cycle), under such conditions.

In this work, we have carried out a quantum chemistry and computational kinetics study on the reactivity of propyl gallate towards ˙OOH, ˙OOCH3 and ˙OOCHCH2 radicals, in aqueous and lipid media. We have considered three reaction mechanisms: hydrogen transfer (HT), radical adduct formation (RAF) and single electron transfer (SET). Rate constants and relative branching ratios for the different paths contributing to the overall reaction, at 298.15 K, are reported. Our results show that propyl gallate reacts mainly through the HT mechanism, independently of the solvent or the peroxyl radical, contrary to other phenols such as catechols and guayacols previously studied, which react mainly via the SET mechanism. In aqueous media at physiological pH, the calculated rate constants towards the ˙OOH, ˙OOCH3 and ˙OOCHCH2 radicals are 4.56 × 10(8), 1.59 × 10(6) and 4.05 × 10(8) M(-1) s(-1), while in lipid media the rate constants are 2.94 × 10(4), 7.73 × 10(3) and 9.94 × 10(5) M(-1) s(-1). Thus, a propyl gallate molecule acts as a very efficient peroxyl radical scavenger, both in aqueous and lipid media. Since the gallate moiety is a part of other naturally occurring polyphenols such as aflavine gallates and epigallocatechin gallates, the results of this study could be extrapolated to these compounds. Even if these compounds have other antioxidant structures or enhancers, the activity of the gallate moiety could be considered as a lower limit to their antioxidant activity.

The chemical repair of radical-damaged DNA by glutathione in aqueous solution has been studied using density functional theory. Two main mechanisms were investigated: the single electron transfer (SET) and the hydrogen transfer (HT). Glutathione was found to repair radical damaged DNA by HT from the thiol group with rate constants that are close to the diffusion-limited regime, which means that the process is fast enough for repairing the damage before replication and therefore for preventing permanent DNA damage. The SET mechanism was found to be of minor importance for the activity of glutathione. In addition while SET can be essential for other compounds when repairing radical cation species, repairing the C'-centered guanosyl radicals via SET is not a viable mechanism, due to the very low electron affinity of these species. The importance of considering pH-related physiological conditions and using complex enough models, including the ribose moiety and the H bonding between base pairs, to study this kind of systems is discussed.

Different deprotonation paths of the radical cation formed by one-electron oxidation of 2'-deoxyguanosine (2dG) sites in DNA have been studied using Density Functional Theory (M05-2X/6-31+G(d,p)) and ONIOM methodology (M05-2X/6-31+G(d,p):PM6) in conjunction with the SMD model to include the solvent effects. Models of increased complexity have been used ranging from the isolated nucleoside to a three unit double-stranded oligomer including the sugar units, the base pairing with cytidine, and the phosphate linkage. The reported results correspond to aqueous solution, at room temperature, and pH = 7.4. Under such conditions it was found that the proton transfer (PT) within the base pair is a minor path compared to the PT between the base pair and the surrounding water. It was also found that the deprotonation of ground-state 2dG˙(+) sites mainly yields C centered radicals in the sugar unit, with the largest populations corresponding to C4'˙ and C5'˙, followed by C3'˙. The different aspects of the presented theoretical study have been validated with experimental results.

The free radical scavenging activity of hydroxytyrosol (HTyr) and tyrosol (Tyr) has been studied in aqueous and lipid solutions, using the density functional theory. Four mechanisms of reaction have been considered: single electron transfer (SET), sequential electron proton transfer (SEPT), hydrogen transfer (HT), and radical adduct formation. It was found that while SET and SEPT do not contribute to the overall reactivity of HTyr and Tyr toward ·OOH and ·OCH3 radicals, they can be important for their reactions with ·OH, ·OCCl3, and ·OOCCl3. The ·OOH-scavenging activity of HTyr and Tyr was found to take place exclusively by HT, and it is also predicted to be the main mechanism for their reactions with ·OCH3. HT is proposed as the main mechanism for the scavenging activity of HTyr and Tyr when reacting with other ·OR and ·OOR radicals, provided that R is an alkyl or an alkenyl group. The major products of reaction are predicted to be the phenoxyl radicals. In addition, Tyr was found to be less efficient than HTyr as free radical scavenger. Moreover, while HTyr is predicted to be a good peroxyl scavenger, Tyr is predicted to be only moderately for that purpose.

Reactions of sesamol with different free radicals, in lipid and aqueous media, have been studied at the M05-2X/6-311+G(d,p) level of theory in conjunction with the SMD continuum model. Different mechanisms of reaction have been considered as well as polar and nonpolar environments. According to the overall rate coefficients, sesamol is predicted to react significantly faster in aqueous solution than in nonpolar media. The polarity of the environment also changes the relative importance of the reaction mechanisms. The anionic form of sesamol was found to be particularly reactive toward peroxyl radicals by transferring one electron. This mechanism was found responsible for the exceptional peroxyl radical scavenging activity of sesamol in aqueous solution, which was found to be even better than carotenoids, 2-propenesulfenic acid, and glutathione under physiological conditions. The agreement between experimental and calculated data supports the presented results as well as the methodology used in this work.

The free radical scavenging activity of dihydroxybenzoic acids (DHBA) has been studied in non-polar and aqueous solutions, using the Density Functional Theory. It was found that the environment plays an important role in the free radical scavenging activity of DHBA. The hydrogen transfer (HT) from the phenolic OH was identified as the main mechanism of reaction in non-polar media, while the single electron transfer (SET) from the di-anions is proposed as the mechanism contributing the most to the peroxyl scavenging activity of DHBA in aqueous solution, at physiological pH. Two key structural features are associated with the reactivity of DHBA towards peroxyl radicals, via HT. The OH from which the H is transferred should be: (i) in the meta position with respect to the carboxyl group; and (ii) in the para or ortho position with respect to the other hydroxyl group. Regarding SET, the key factors are the formation of the di-anion, and its molar fraction at the anticipated pH. DHBA are predicted to be versatile scavengers in aqueous solution, capable of efficiently scavenging a wide variety of free radicals via SET. In addition, 25-DHBA, 34-DHBA and 23-DHBA were found to be among the best peroxyl radical scavengers identified so far, in aqueous solution, at physiological pH.

Oxidation of 2-aminopyrimidine (2Apy) by hydroxyl radicals (˙OH) in aqueous medium has been studied using pulse radiolysis coupled to optical absorption and M05-2X/6-311++G(d,p) level DFT calculations aimed at elucidation of the reaction mechanism. The rate constant (k) 2.76 ± 0.06 × 109 M−1 s−1 determined by the pulse radiolysis method for the title reaction at neutral pH reflects a diffusion-controlled process. The maximum absorption wavelength (λmax 330 and 550 nm) of transient(s) remains intact in the pH range 10.5–7. Radical adduct formation (RAF) reactions with N1 (N3 is an identical site), C2, C4 (C6 is an identical site) and C5 as the target atoms, hydrogen transfer (HT) reaction with amino group and single electron transfer (SET) of 2Apy with ˙OH were modelled theoretically. Lowest Gibbs free energy of activation (ΔG≠) in solution, 1.72 kcal mol−1, was calculated for RAF at C5; the computed k value for this process is 2.0 × 109 M−1 s−1 using the transition state theory (TST). The relative yield (87%) of this major product predicted from the computed k value shows excellent agreement with the results of the pulse radiolysis redox titrations. Subsequently, the possibilities for other RAF reactions, HT and SET were ruled out. As an extension to the above work, we have carried out a theoretical survey of the reactivity of ˙OH with 4-aminopyrimidine (4Apy); wherein the RAF at C5 is proposed as the most probable mechanism with a ΔG≠ of 2.15 kcal mol−1.

The peroxyl radical scavenging activity of four hydroxycinnamic acid derivatives (HCAD) has been studied in non-polar and aqueous solutions, using the density functional theory. The studied HCAD are: ferulic acid (4-hydroxy-3-methoxycinnamic acid), p-coumaric acid (trans-4-hydroxycinnamic acid), caffeic acid (3,4-dihydroxycinnamic acid), and dihydrocaffeic acid (3-(3,4-dihydroxyphenyl)-2-propionic acid). It was found that the polarity of the environment plays an important role in the relative efficiency of these compounds as peroxyl scavengers. It was also found that in aqueous solution the pH is a key factor for the overall reactivity of HCAD towards peroxyl radicals, for their relative antioxidant capacity, and for the relative importance of the different mechanisms of reaction. The H transfer from the phenolic OH has been identified as the main mechanism of reaction in non-polar media and in aqueous solution at acid pHs. On the other hand, the single electron transfer mechanism from the phenoxide anion is proposed to be the one contributing the most to the overall peroxyl scavenging activity of HCAD in aqueous solution at physiological pH (7.4). This process is also predicted to be a key factor in the reactivity of these compounds towards a large variety of free radicals.