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Chemical compounds with antioxidant behavior are recognized as efficient protectors against the harmful effects of reactive oxygen species (ROS) and other chemicals overproduced due to oxidative stress (O.S.). Sesamol has been shown to offer significant benefits in the treatment of many OS-induced diseases. The present work focuses on the free radical scavenging activity of some sesamol derivatives, recently proposed as promising antioxidants. This activity was studied, taking into account three reaction mechanisms: formal hydrogen atom transfer (f-HAT), single electron transfer (SET), and radical adduct formation (RAF). The investigation was based on thermochemistry and kinetics, using solvent models to mimic aqueous and lipid environments. The influence of pH on the investigated activity was also considered. The studied sesamol derivatives were found to be potent peroxyl radical scavengers, which suggests that they have potential use to mitigate O.S. and related diseases. SET and f-HAT were identified as the main reaction mechanisms, while RAF was ruled out as a significant chemical route. It is expected that the results from this work will promote further investigations on the possible health benefits of the newly designed sesamol derivatives studied here.

This article reports a computational kinetic and thermodynamic study of the chemical repair of radical-damaged tryptophan and tyrosine residues by the superoxide radical anion (O2˙−)–hydroperoxyl radical (HO2˙) pair, via single electron transfer (SET) and formal hydrogen transfer (FHAT) mechanisms. It was demonstrated that O2˙− can repair oxidized tyrosyl and tryptophanyl damaged residues, mainly by electron transfer, restoring them to their pristine structure. Acid–base equilibria were considered, and the influence of the pH on the main reaction mechanism was explored. The results presented here are expected to contribute to the better understanding of the complex and dual behaviour of the HO2˙–O2˙− in the context of oxidative stress.

Mechanistic details of hydroxyl radical (•OH) mediated oxidations of 2-aminopurine (2AP) in the aqueous phase have been established in this study via a combination of DFT calculations (at the M05-2X/6-311+G­(d,p) level with SMD solvation) and sonochemical end product analyses by the LC-Q-TOF-MS/MS method. Rate constants and branching ratios for single electron transfer (SET), two H-abstractions (HA), and seven radical adduct formation (RAF) reactions of •OH with 2AP were evaluated using transition state theory (TST). The RAF at the C8-position of 2AP is noted as the dominant process, which constitutes almost 46.1% of overall reaction routes. The SET mechanism accounts for the second major pathway (39.6%) followed by RAF at the C6-position (14.3%). Formations of 14 transformation products (TPs, i.e., the nonradical end products) in the sonochemical reactions of •OH with 2AP have been identified by means of the LC-Q-TOF-MS/MS technique. Among the 14 TPs (designated as TP1 to TP14), the lowest and highest mass to charge ratio (m/z) were respectively observed at 129 and 269 in ESI-MS positive ionization mode. The identities of all TPs have been proposed on the basis of elemental composition of [M + H]+ ions and their respective MS-MS fragmentation pattern. Four TPs (including guanine) are considered as obtained directly from primary transients by radical elimination, radical–radical combination/disproportionation reactions. The remaining 10 TPs are postulated as a result of successive self- and/or cross-reactions of primary transients/four first generation TPs with reagents such as •OH, O2, and solvent H2O molecules.

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 superoxide radical anion can repair oxidative damage. In particular, it was demonstrated that O2˙- can repair oxidized DNA by electron transfer, restoring the original structure of this important molecule. Acid-base equilibria have been considered, and the influence of the pH on the main reaction mechanism has been explored.

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.

In the present work, the antioxidant activity of four ascorbic acid analogs has been studied at the M05-2X/6-31G+(d) computational level using the conventional transition state theory in different solvents, with different polarity and taking into account all possible mechanisms. The obtained results indicate that the antioxidant activity of the ascorbic acid analogs increases with the polarity of the environment. Additionally, their antioxidant activity is higher than ascorbic acid. This result is in line with experimental finding which supports the hypothesis that the analogs that had an endocyclic nitrogen atom instead of a ring oxygen may have a higher antioxidant activity than ascorbic acid. On the other hand, the results also indicate that compound 4 (designed by us) is predicted to be more antioxidant than ascorbic acid and the other analogs 1–3, in both lipid and aqueous solution. Finally, for the first time, pKa values, branching ratios and the rate constants for the reactions of ascorbic acid analogs with methylperoxyl radical CH3OO· are reported.

Anthocyanidins are water-soluble flavonoids that have numerous beneficial effects to human and animal health. At the same time, they present multiple acid–base equilibria that under physiological conditions may lead to a rather wide distribution of species. This particular feature might influence the activity and mechanism of action of anthocyanidins in living systems, depending on the pH of the environment. Therefore, detailed knowledge of the acid–base behavior of these compounds is crucial to fully understand their ways of action. In this work, theoretical calculations within the frame of Density Functional Theory (DFT) were carried out to investigate several aspects or the equilibria for 12 anthocyanidins. Their most likely deprotonation routes were elucidated, and most of their pKa values are reported here for the first time. Their reliability was confirmed by comparison with the available experimental data, which led to a mean unsigned error of 0.31. The obtained pKa values allowed the estimation of the populations of the different species depending on the pH, and particular attention was paid to pH = 7.4. Hopefully, the data provided here may contribute to gain better understanding on the complex processes involving anthocyanidins, under physiological conditions.

The possible antioxidant reaction mechanisms of recently synthesized and tested alkylseleno (telluro) phenols have been explored using density functional theory by considering two solvents physiologically relevant, water and pentylethanoate (PE). In addition, the possible pathway for the antioxidant regeneration with ascorbic acid has been investigated. Results show that selenium and tellurium systems follow different chemical behaviors. In particular, the alkylseleno phenol (ebselenol) antioxidant activity is justified through a sequential proton loss-electron-transfer mechanism in water media, whereas in PE the hydrogen-atom transfer process is favored. In the case of the tellurium derivative, the oxygen-transfer mechanism represents the preferential one. Furthermore, electronic properties have been analyzed to rationalize the different reactivity of the selenium- and tellurium-containing systems. To confirm the results, smaller but similar systems were also investigated. The calculated data support the different mechanism (Se vs. Te) proposals.

Density functional theory calculations, using the SMD continuum model, indicate that hydrogen transfer from totally protonated uric to a tryptophanyl radical in proteins corresponds to a sequential mechanism. Modeling in methyl butanoate indicates that this mechanism is more important in a hydrophobic medium than in water.

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.

Two empirically fitted parameters (m and C 0) for the calculation of pK a values for thiols are provided for the first time, at 74 levels of theory. The coefficients were obtained by least-squares fits of the difference in Gibbs energy between each acid and its conjugated base versus experimental pK a values. The reliability of this fitted parameters approach (FPA) was confirmed using an independent test set of molecules. It was found that deviations from experiments are systematically lower than 0.5 pK a units, in terms of mean unsigned errors. In addition, all the tested levels of theory produced maximum absolute errors lower than 1 pK a unit. The parameters estimated here are expected to facilitate pK a calculations, using electronic structure-based strategies, with uncertainties close to the experimental ones. Albeit the present study deals only with molecules of modest complexity, i.e., the reliability of the FPA for more complex systems remains to be tested, it seems to be a promising approach for obtaining pK a values of thiols in a fast and reliable way.

The results presented in this work demonstrate the high complexity of chemical reactions involving species with multiple acid–base equilibria. For the case study investigated here, it was necessary to consider two radical species for tryptophan (Trp(−H)˙ and Trp˙+) and three fractions for uric acid (H3Ur, H2Ur− and HUr2−) in order to properly reproduce the experimental results. At pH = 7.4, two main reaction mechanisms were identified: proton–electron sequential transfer (PEST) and sequential proton gain-electron transfer (SPGET). Combined, they account for more than 99% of the overall reaction, despite the fact that they involve minor species, i.e., H3Ur and Trp˙+, respectively. The excellent agreement between the calculated overall rate constant and the experimental value seems to support this proposal. In addition, if only the dominant species at pH = 7.4 (H2Ur− and Trp(−H)˙) were considered, there would be a large discrepancy with the experimental value (about 4 orders of magnitude), which also supports the finding that the key species in this case are not the most abundant ones. The influence of the pH on the kinetics of the investigated reaction was explored. It was found that the maximum repairing ability of uric acid does not occur at physiological pH, but at a more acidic pH (pH = 5.0).

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.

The Density Functional Theory was used to investigate oxidative stress related reactions of tryptophan in its free zwitterionic form. It was concluded that free tryptophan cannot be considered as an antioxidant, and that tryptophan residues in proteins are not especially good targets of oxidative stress. Its previously observed antioxidant abilities can then be attributed to tryptophan metabolites.

The accurate prediction of rate constants for chemical reactions in solution, using computational methods, is a challenging task. In this work, a computational protocol designed to be a reliable tool in the study of radical-molecule reactions in solution is presented. It is referred to as quantum mechanics-based test for overall free radical scavenging activity (QM-ORSA) because it is mainly intended to provide a universal and quantitative way of evaluating the free radical scavenging activity of chemical compounds. That is, its primary antioxidant activity. However, it can also be successfully applied to obtain accurate kinetic data for other chemical reactions in solution. The QM-ORSA protocol has been validated by comparison with experimental results, and its uncertainties have been proven to be no larger than those arising from experiments. Further applications of QM-ORSA are expected to contribute increasing the kinetic data for free radical-molecule reactions relevant to oxidative stress, which is currently rather scarce.

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.

DNA nucleobases undergo non-enzymatic glycation to nucleobase adducts which can play important roles in vivo. In this work, we conducted a comprehensive experimental and theoretical kinetic study of the mechanisms of formation of glyoxal-guanine adducts over a wide pH range in order to elucidate the molecular basis for the glycation process. Also, we performed molecular dynamics simulations to investigate how open or cyclic glyoxal-guanine adducts can cause structural changes in an oligonucleotide model. A thermodynamic study of other glycating agents including methylglyoxal, acrolein, crotonaldehyde, 4-hydroxynonenal and 3-deoxyglucosone revealed that, at neutral pH, cyclic adducts were more stable than open adducts; at basic pH, however, the open adducts of 3-deoxyglucosone, methylglyoxal and glyoxal were more stable than their cyclic counterparts. This result can be ascribed to the ability of the adducts to cross-link DNA. The new insights may contribute to improve our understanding of the connection between glycation and DNA cross-linking.

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.

The primary antioxidant activity of coumarin-chalcone hybrids has been investigated using the density functional and the conventional transition state theories. Their peroxyl radical scavenging ability was studied in solvents of different polarity and taking into account different reaction mechanisms. It was found that the activity of the hybrids increases with the polarity of the environment and the number of phenolic sites. In addition, their peroxyl radical scavenging activity is larger than those of the corresponding nonhybrid coumarin and chalcone molecules. This finding is in line with previous experimental evidence. All the investigated molecules were found to react faster than Trolox with (•)OOH, regardless of the polarity of the environment. The role of deprotonation on the overall activity of the studied compounds was assessed. The rate constants and branching ratios for the reactions of all the studied compounds with (•)OOH are reported for the first time.

The peroxyl radical scavenging activity of five guaiacol derivatives (GD) has been studied in nonpolar and aqueous solutions, using the density functional theory. The studied GD are guaiacol, vanillin, vanillic alcohol, vanillic acid, and eugenol. It was found that the environment plays an important role in the peroxyl scavenging activity of these compounds. They were all found to react faster in aqueous solution than in nonpolar media. The order of reactivity in nonpolar environments was found to be vanillic alcoholeugenolguaiacolvanillinvanillic acid, while, in aqueous solution, at physiological pH, it becomes vanillic acidvanillic alcoholguaiacol ≈ eugenolvanillin. It was also found that in aqueous solution as the pH increases so does the reactivity of GD toward peroxyl radicals. The environment also has important effects on the relative importance of the hydrogen transfer (HT) and the sequential proton electron transfer (SPET) mechanisms, which are the ones relevant to the peroxyl radical scavenging activity of GD. The HT from the phenolic OH was identified as the main scavenging process in nonpolar media, and in aqueous solution at pH ≤ 4. On the other hand, SPET is proposed to be the one contributing the most to the overall peroxyl scavenging activity of GD in aqueous solution at pH ≥ 6.

In this work, we have performed a theoretical study on the mechanisms and kinetics of the •OH initiated oxidation of selected ethylene glycol vinyl ethers, using quantum chemistry and computational kinetics methods. We have found that the main reaction path is the •OH-addition to vinyl double bonds, and especially to the vinyl terminal carbon atom. Branching ratios for addition at C1 are larger than 94%. Although divinyl ethers could be expected to react approximately twice as fast as monovinyl ethers, it was found that, in fact, •OH rate constants of monovinyl and divinyl ethers are very similar, in agreement with experimental results. This effect is attributed to the sharing of the oxygen lone pairs effect, when the molecule contains two vinyl groups. Thus, in EGMVE, the vinyl group is more reactive than the one in divinyl ethers. The energy of its highest occupied molecular orbital (HOMO) is closer to that of the OH radical, thus favoring the interaction with the single occupied molecular orbital (SOMO) of the radical. Negative activation enthalpies are obtained for the three molecules studied, implying that the rate constant decreases as temperature increases. This anti-Arrhenius behavior is commonly observed in •OH addition to alkenes. An excellent correlation is observed between experimental and calculated rate constants. © 2012 Wiley Periodicals, Inc.

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.

We study by density functional theory the hydrolysis of a chlorambucil analogue. Three SN(1) and one SN(2) mechanisms have been compared. Results show that the most likely mechanism involves the formation of an aziridinium ion via a first-order reaction subject to an energy barrier of 24.8 kcal/mol. Additionally, a kinetic study, using the thermodynamic formulation of the Transition State Theory, has been carried out. Theoretical results coincide with experimental values obtained under similar conditions of pH, temperature and chloride concentration.

The effect of the inclusion of counterpoise corrections (CP) on the accuracy of interaction energies has been studied for different systems accounting for (1) intermolecular interactions, (2) intramolecular interactions and (3) chemical reactions. To minimize the error associated with the method of choice, the energy calculations were performed using CCSD(T) in all the cases. The values obtained using aug-cc-pVXZ basis sets are compared to CBS-extrapolated values. It has been concluded that at least for the tested systems CP corrections systematically leads to results that differ from the CBS-extrapolated ones to a larger extension than the uncorrected ones. Accordingly, from a practical point of view, we do not recommend the inclusion of such corrections in the calculation of interaction energies, except for CBS extrapolations. The best way of dealing with basis set superposition error (BSSE) is not to use CP corrections, but to make a computational effort for increasing the basis set. This approach does not eliminate BSSE but significantly decreases it, and more importantly it proportionally decreases all the errors arising from the basis set truncation.

An assessment of multireference character in transition states is considered to be an important component in establishing the expected reliability of various electronic structure methods. In the present work, the multireference characters of the transition states and the forming and breaking of bonds for a large set of hydrogen abstraction reactions from phenolic compounds by peroxyl radicals have been analyzed using the T1, M, B1, and GB1 diagnostics. The extent of multireference character depends on the system and on the conditions under which the reaction takes place, and some systematic trends are observed. In particular, the multireference character is found to be reduced by solvation, the size of the phenolic compound, and deprotonation in aqueous solution. However, the deviations of calculated rate constants from experimental ones are not correlated with the extent of multireference character. The performance of single-determinant density functional theory was investigated for the kinetics of these reactions by comparing calculated rate constants to experimental data; the results from these analyses showed that the M05 functional performs well for the task at hand.

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 performance of 18 density functional approximations has been tested for a very challenging task, the calculations of rate constants for radical-molecule reactions in aqueous solution. Despite of the many difficulties involved in such an enterprise, six of them provide high quality results, and are recommended to that purpose. They are LC-ωPBE, M06-2X, BMK, B2PLYP, M05-2X, and MN12SX, in that order. This trend was obtained using experimental data as reference. The other relevant aspects used in this benchmark are: (i) the SMD model for mimicking the solvent; (ii) the conventional transition state, the zero-curvature tunneling correction, and the limit imposed by diffusion for the calculation of the rate constants. Even though changing any of these aspects might alter the trend in performance, at least, when using them, the aforementioned functionals can be successfully used to obtain high quality kinetic data for the kind of reactions investigated in this work.

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.

A theoretical study of the mechanism and kinetics of the OH radical reactions with aliphatic ethers is presented. Several methods were evaluated using the 6-311++G(d,p) basis set, with dimethyl ether as a test molecule. On the basis of the dimethyl ether results, the M05-2X functional was selected for the rest of the calculations. All the possible H abstraction paths have been modeled, and the importance of differentiating among H atoms bonded to the same C atom, according to their orientation with respect to the O atom in the ether, is analyzed. The rate coefficients are calculated using interpolated variational transition-state theory by mapping (IVTST-M), within the IVTST-M-4/4 scheme, in conjunction with small-curvature tunneling (SCT) corrections. The discussion is focused on the 280-400 K temperature range, but additional information is provided for an extended range (280-2000 K). Our analysis suggests a stepwise mechanism involving the formation of H bonded complexes in the entrance and exit channels. The vicinity of the O atom was found to increase the relative site reactivity. In fact, it was found to influence reactivity to a larger extent than the nature of the carbon site (primary, secondary, or tertiary). The overall agreement between the calculated and the available experimental data is very good and supports the reliability of the rate coefficients and the branching ratios proposed here for the first time. It also supports the performance of the M05-2X functional and the IVTST-M-4/4 scheme for kinetic calculations.

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.