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Theoretical study on the peroxyl radicals scavenging activity of esculetin and its regeneration in aqueous solution† a Manuel E. Medina,a Annia Galano*b and Juan Rau ´ l Alvarez-Idaboy*

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 Received 12th September 2013, Accepted 22nd October 2013

is proposed that esculetin has moderate peroxyl scavenging activity in lipid media while in aqueous

DOI: 10.1039/c3cp53889c

after scavenging the first radical, was investigated in aqueous solution, at physiological pH. It was found

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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.

solution, at physiological pH, it is excellent for that purpose. In addition, the possible regeneration of ES,

Introduction Reactive oxygen species (ROS) involve a series of oxidants such as hydroxyl radical ( OH) and peroxyl radicals ( OOR). The mitochondrial metabolism and the oxidative phosphorylation cascade have been identified as key factors in the generation of ROS.1 High ROS concentrations are caused by an imbalance between their production and consumption, and is known as oxidative stress (OS). This chemical stress is a health hazard that has been associated with a large number of diseases, including atherosclerosis, Alzheimer’s, Parkinson’s and cancer.2 Therefore, numerous efforts have been devoted to the study of chemical compounds able of ameliorating the deleterious effects of OS. These compounds are frequently referred to as antioxidants, but also as free radical scavengers, since most of the ROS are free radicals. There is a wide variety of molecules that present such a desirable activity. Coumarines constitute a a

´rica, Facultad de Quı´mica, Departamento de Fı´sica y Quı´mica Teo Universidad Nacional Auto´noma de Me´xico, Me´xico D. F. 04510, Me´xico. E-mail: [email protected] b ´sicas e Ingenierı´a, Departamento de Quı´mica, Divisio´n de Ciencias Ba Universidad Auto´noma Metropolitana-Iztapalapa, Av. San Rafael Atlixco No. 186, Col. Vicentina, Me´xico D. F. 09340, Me´xico. E-mail: [email protected] † Electronic supplementary information (ESI) available: Cartesian coordinates, relative energies of main stationary points and imaginary frequencies of transition states for studied reactions. See DOI: 10.1039/c3cp53889c

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family of compounds that stand out for their protective effects against OS. They are naturally occurring phytochemicals, present in numerous plant species, with a wide range of biological activities such as anti-inflammatory,3 anti-tumour,4 hepatoprotective,5 anti-allergic,6 anti-HIV-1,7 antifungal,8 antimicrobial,9 antiasthmatic,10 anti-diabetic,11 antidepressant effects12 and antioxidant.13 Esculetin (ES) (6,7-dihydroxy-coumarin), also known as aesculetin or cichorigenin, is a coumarin derivative found in many plants14,15 such as Artemisia capillaris (Compositae), the leaves of Citrus limonia (Rutaceae), Cortex fraxini16 and Ceratostigma willmottianum, which are commonly used as folk medicine to counteract inflammatory and allergic disorders.17 The antioxidant properties of esculetin have been the focus of several studies. Kim et al.18 found that esculetin efficiently attenuates the OS-induced cell damage via its anti-oxidant properties. As a result, they proposed that esculetin may be useful in the development of functional food and raw materials with medicinal applications. Wang et al.19 investigated the antioxidant properties of esculetin employing various in vitro assays, such as 2,2 0 -diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay and hydroxyl radical scavenging assay; and found that the activity of esculetin is superior to that of the synthetic antioxidant butylated hydroxytoluene. Subramaniam and Ellis20 reported that esculetin protects human hepatoma cells from hydrogen peroxide induced oxidative injury. In addition

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Shaohua and Yubin21 observed that esculetin is remarkably efficient for inhibiting the growth of human gastric carcinoma cells and inducing its apoptosis. It has also been proposed that esculetin may be employed in a novel treatment strategy for oral cancer.22 Esculetin also inhibits growth, and shows antiproliferative action, of human leukemia cells;23,24 and could be useful as an antitumor agent in postmenopausal therapy.25 Esculetin significantly reduced CCl4-induced hepatic apoptosis in rats26 and has been reported to play a chemopreventive role via reducing oxidative stress in living systems.27 Therefore, according to the information gathered so far and mentioned above, there seems to be a general agreement that esculetin is an efficient protector against OS and OS-related diseases. However, to our best knowledge there is no information available on the mechanism or mechanisms involved in such action. There are no reports either on the kinetic data associated to esculetin free radical scavenging activity. Therefore it is the main goal of the present work to provide detailed and quantitative information on the mechanism and kinetics of esculetin reactions with peroxyl radicals. To that purpose the esculetin reactions with  OOH,  OOCH3 and  OOCHCH2 radicals, have been modelled in aqueous solution, at physiological pH, and in non-polar environments to mimic lipid solution. The  OOR radicals have been chosen because they are among the free radicals of biological relevance that can be effectively scavenged to retard OS.28,29 This is because they have not too short half-lives, which is required for efficient interception by chemical scavengers.30 ROO are formed within living organisms, where they are involved in DNA cleavage and protein backbone modification.31 They are also involved in the oxidation of lipoproteins and biological membranes and have been held responsible for microvascular damage.32 In addition, radicals of intermediate to low reactivity have been recommended for studying the relative scavenging activity of different compounds.33,34 This is because when reacting with highly reactive radicals, such as  OH, there is a large variety of compounds that would react at similar rates (close to the diffusion-limit). Thus comparisons based on such reactions might lead to mis-conclusion that all analyzed compounds are equally efficient as antioxidants even when that might not be the case for a wider variety of free radicals. Moreover, it has been proposed that such highly reactive radicals cannot be intercepted in biological systems with reasonable efficiency.35 Four different mechanisms of reactions have been considered in this work: single electron transfer (SET), hydrogen transfer (HT), radical adduct formation (RAF), and sequential proton electron transfer (SPET). In addition, the SET mechanism has been investigated for a larger set of free radicals in aqueous media. Thermodynamic and kinetic data are provided, as well as the contributions of different mechanisms to the overall peroxyl radicals scavenging activity of esculetin. The possible regeneration of esculetin, after scavenging the first free radical, has also been investigated in aqueous solution, at physiological pH.

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Computational details All electronic calculations were performed with the Gaussian 09 package of programs.36 Geometry optimizations and frequency calculations were carried out using the M05-2X37 and 6311+G(d,p) basis set, in conjunction with the SMD continuum model38 using pentyl ethanoate and water as solvents to mimic lipid and aqueous environments, respectively i.e. geometry optimizations and thermodynamic corrections include continuum solvation as proposed by the SMD developers for cases where solvent could significantly influence the geometries. The M05-2X functional has been recommended for kinetic calculations by its developers,37 and has been successfully used by independent authors for that purpose.39–41 It is also among the best performing functionals for calculating reaction energies involving free radicals.42 SMD is considered a universal solvation model, due to its applicability to any charged or uncharged solute in any solvent or liquid medium for which few key descriptors are known.38 Unrestricted calculations were used for open shell systems. Local minima and transition states were identified by the number of imaginary frequencies: local minima have only real frequencies, while transition states are identified by the presence of a single imaginary frequency that corresponds to the expected motion along the reaction coordinate. When necessary, IRC calculations were performed to confirm that the transition states properly connect with the intended reactants and products. Relative energies are calculated with respect to the sum of isolated reactants. Thermodynamic corrections at 298.15 K were included in the calculation of relative energies, which correspond to 1 M standard state. In addition, the solvent cage effects have been included according to the corrections proposed by Okuno,43 taking into account the free volume theory.44 The rate constants (k) were calculated using the conventional transition state theory (TST):45–47 kB T DGa =RT e k ¼ sk h where kB and h are the Boltzmann and Planck constants; DGa is the Gibbs free energy of activation; s represents the reaction path degeneracy, accounting for the number of equivalent reaction paths; and k accounts for tunnelling corrections. The latter are defined as the Boltzmann average of the ratio of the quantum and classical probabilities, and were calculated using the zero curvature tunnelling corrections (ZCT).48 For the electron transfer reactions the barriers were estimated using the Marcus theory.49,50 It relies on the transition state formalism, defining the SET activation barrier (DGa SET) in terms of two thermodynamic parameters, the free energy of reaction (DG0SET) and the nuclear reorganization energy (l)  2 DG0SET l DGa ¼ 1 þ SET l 4 The reorganization energy (l) has been calculated as: l = DESET  DG0SET

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where DESET is the non-adiabatic energy difference between reactants and vertical products. This approach is similar to the one previously used by Nelsen and co-workers51 for a large set of self-exchange reactions. Some of the calculated rate constant (k) values are close to, or within, the diffusion-limit regime. Accordingly, the apparent rate constant (kapp) cannot be directly obtained from TST calculations. In the present work the Collins–Kimball theory52 is used to that purpose: kapp ¼

kD k kD þ k

where k is the thermal rate constant, obtained from TST calculations, and kD is the steady-state Smoluchowski53 rate constant for an irreversible bimolecular diffusion-controlled reaction: kD = 4pRDABNA where R denotes the reaction distance, NA is the Avogadro number, and DAB is the mutual diffusion coefficient of the reactants A (free radical) and B (esculetin). DAB has been calculated from DA and DB according to ref. 54 and DA and DB have been estimated from the Stokes–Einstein approach:55 D¼

kB T 6pZa

where kB is the Boltzmann constant, T is the temperature, Z denotes the viscosity of the solvent, in our case water (Z = 8.91  104 Pa s) and pentylethanoate (Z = 8.62  104 Pa s); and a is the radius of the solute. For the kinetic study we have not included the reaction paths found as endergonic because, even if they take place at significant rates, they would be reversible and, therefore, the formed products will not be observed. However, it should be noted that they might still represent significant channels if their products rapidly react further. This would be particularly important if these further stages are sufficiently exergonic to provide a driving force, and if their barriers of reactions are low. This could be the case for the SET reactions in aqueous solution since they yield reactive species, and take place at relative large reaction distances. In addition, slightly endergonic processes can be important when there are no exergonic competing paths, but such a case was not found in the present study. The used methodology in referred to as QM-ORSA, and is described in more details elsewhere.56

more recent publication by the same group,59 it was found that the transition state of the H abstraction, by  OOH, from the hydroxyl group in methanol, also presents a significant multireference character, according to the T1 diagnostic. This suggests that multireference issues may also affect saturated systems. Moreover, it has been proposed that density functionals with a high fraction of Hartree–Fock (HF) exchange are often inaccurate for systems with a significant multireference character.60 Thus such systems would not be properly described using the M05-2X functional, which is based on a single-determinant reference state and has 56% HF exchange. Therefore, to validate the study of the system of interest with this functional, it is important to assess whether such formalism is suitable. Accordingly, the reliability of M05-2X has been tested for systems studied in the present work. We have performed the T1 diagnostic at CCSD(T)/6-311+G(d,p)//M05-2X/6-311+G(d,p) level of theory for the transition states corresponding to the H abstractions of the main channels of reactions, which involve the OH moieties. In addition, the T1 diagnostic has also been applied to the H abstraction from the hydroxyl group in other compounds for comparison purposes. The values obtained from the T1 diagnostics are presented in Table 1. The value for the methanol +  OOH system was taken from ref. 59, and was obtained at CCSD(T)/aug-cc-pVDZ//M06-2X/MG3S level of theory. The value for the canolol +  OOH system was taken from ref. 61 and was obtained at CCSD(T)/6-311+G(d)//M05-2X/ 6-311+G(d,p) level of theory. It has been established that T1 Z 0.02 indicates a significant multireference character for closed-shell systems, while for open shell systems the currently accepted value is considerably larger and equal to 0.045.62 The T1 values obtained for the ethanol +  OH and phenol +  OOCH3 systems are close to, but slightly lower than, this limit. For the phenol +  OH system the T1 value is lower than the limit (0.041) but much higher than that obtained for the canolol +  OOH system and also than those obtained for neutral and anionic esculetin, which are the species of interest in the present work. The largest T1 value is the one reported for methanol +  OOH, which exceeds the 0.045 limit by 0.003. However, Alecu and Truhlar59 reported that in this particular case ‘‘The fact that M05 and M06 are outperformed by their 2X counterparts, which contain twice the percentages of Hartree–Fock exchange further indicates that the reactions studied here are not

Results and discussion

Table 1 T1 diagnostic for transition states involved H abstractions, by oxygenated radicals, form the OH moiety in different systems

T1 diagnostics for multireference character

System

In recent publications Tishchenko et al.57,58 proposed that the transition states corresponding to the H abstraction from the hydroxyl group in phenol by  OOCH3,57 and from the hydroxyl group in vinyl alcohol by  OH,58 are affected by multireference effects. These findings may lead to the conclusion that H transfers from OH groups, linked to p electron systems, to oxygenated radicals; present a multireference character. In a

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T1 diag. 

Ethanol + OH Phenol +  OOCH3 Phenol +  OH Methanol +  OOH Canolol +  OOH H2ES +  OOH (TS6a) HES +  OOH (TS6a) a

From ref. 59.

b

0.044 0.044 0.041 0.048a 0.023b 0.030c 0.028c

From ref. 61. c This work, main HT reaction channels.

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significantly affected by multireference effects, because in the cases characterized by a significant multireference character, one would expect increasing the fraction of HF exchange to diminish the quality of results’’ (quotation from ref. 59). The T1 values for the TS of the reactions of H2ES and HES are lower than the threshold value for open shell systems (0.015 and 0.017, respectively). Consequently it can be safely stated that they do not present significant multireference character, and therefore that the results presented in this work, from M05-2X calculations, are reliable. It should be note, however, that it is not possible to predict a priori if such effects would be present based only on the kind of reaction that takes place, and that probably the best way to be sure if a singledeterminantal method can provide reliable data on HT reactions from OH moieties is to verify the possible multireference character of the involved species using some adequate diagnostic. Acid–base equilibrium The pKa value of ES, determined by capillary zone electrophoresis, is 5.62; and it has been proposed to correspond to deprotonation from site 7.63,64 According to this pKa value, the predominant form of ES, at physiological pH (7.4), is the monoanion (HES). To identify which phenolic OH is involved in the first deprotonation, both processes were investigated. It was confirmed that the Gibbs free energy of the deprotonation from site 7 is 3.95 kcal mol1 lower than that of the deprotonation from site 6 (Scheme 1). Therefore this is the deprotonated form used in this work, for the reactions in aqueous solution, albeit the neutral form is also considered. The molar fractions used in this manuscript are calculated from the experimental pKa at pH = 7.4. The calculated pKa was found to be 4.73, using the isodesmic method and catechol as reference. For more details on this methodology please see ref. 65 On the other hand, in non-polar (lipid) media only the neutral form is used, since such media do not promote the necessary solvation to stabilize the ionic species. Reaction mechanisms As is the case for many other compounds,66–70 the free radical scavenging activity of H2ES and HES can take place through different mechanisms. Those considered in this work are the following: Single electron transfer (SET): H2ES +  OOR - H2ES + + OOR Sequential proton electron transfer (SPET): H2ES - HES + H+; HES +  OOR - HES + OOR

Scheme 1 Neutral (H2ES) and deprotonated (HES) forms of esculetin, and reaction sites.

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Hydrogen transfer (HT), from sites 6a, 7a in H2ES: H2ES +  OOR - HES + HOOR Hydrogen transfer (HT), from site 6a, in HES: HES +  OOR - ES  + HOOR Radical adduct formation (RAF), from sites 2–10, in H2ES: H2ES +  OOR - [H2ES–OOR] Radical adduct formation (RAF), from sites 2–10, HES: HES +  OOR - [HES–OOR] Peroxyl radical scavenging activity of esculetin in lipid environment In non-polar environments the SET mechanism is not expected to contribute to the overall reactivity of H2ES towards free radicals since, as mentioned before, such environments do not promote the necessary solvation of the intermediate ionic species yielded by this mechanism. However, just to prove this point, the Gibbs energies of reaction (DG) for the SET processes were calculated. It was found to be higher than 67 kcal mol1 for all the studied peroxyl radicals (Table 2). Therefore, the viability of this mechanism in lipid media has been definitively ruled out. All RAF reaction paths were also found to be endergonic, with DG values ranging from B12 to B30 kcal mol1, thus the RAF mechanism has also been ruled out as viable for the peroxyl radical scavenging activity of esculetin in non-polar (lipid) media. On the other hand the HT reaction paths were both found to be exergonic, with HT from site 6 being the most thermochemically favored. Therefore, it seems that the peroxyl radical scavenging activity of H2ES, in non polar environments, takes place exclusively through the HT mechanism. The fully optimized geometries of the HT transition states (TS), corresponding to the peroxyl radicals with H2ES, are shown in Fig. 1. The TSs involved in the  OOH reactions were found to be systematically earlier than those corresponding to  OOCH3 and  OOCHCH2 reactions. According to the Hammond postulate, this suggests that the reactivity of  OOH towards esculetin is higher than those of the other two peroxyl radicals. The kinetic data are reported in Table 3. The lowest barrier was found to systematically be corresponding to HT from site 6, regardless of the particular peroxyl radical that esculetin is reacting with. This is also the reaction path with the largest rate Table 2 Gibbs free energy of reaction (DG, kcal mol1) for the SET, HT and RAF mechanisms in pentyl ethanoate solution, at 298.15 K

Path SET HT 6a 7a RAF 2 3 4 5 6 7 8 9 10



OOH



OOCH3



OOCHCH2

77.60

79.13

67.49

4.37 3.86

2.48 1.98

3.20 2.69

19.66 12.55 16.37 16.75 17.28 15.45 20.64 17.28 28.08

18.91 15.13 18.86 18.42 19.92 18.23 24.60 19.39 30.66

15.58 14.09 17.80 17.64 19.11 17.19 23.17 17.82 29.32

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Fig. 1 Optimized geometries of the HT transition states for the reaction between H2ES and peroxyl radicals, in lipid (water) media, distances are in Å. Imaginary frequencies are provided as ESI.†

Table 3 Gibbs free energy of activation (DGa, kcal mol1), apparent rate constants and total rate coefficients (M1 s1); and branching ratios (G) of the different channels of reaction, in pentyl ethanoate solution, at 298.15 K

Path

DGa

k

G

13.12 14.91

4.34  104 5.93  103 4.93  104

88.0 12.0



OOH 6a 7a Total

OOCHCH2 radicals, respectively. Taking into account that the rate constants corresponding to the  OOH damage to unsaturated fatty acids are in the range 1.18–3.05  103 M1 s1,35 it can be stated that esculetin can efficiently act as peroxyl radical scavenger in lipid media, albeit it is only moderately good for that purpose under such conditions. Since identifying the relative activity of antioxidants under different conditions is important to facilitate further designs of efficient strategies for fighting oxidative stress; we have compared esculetin with other compounds. To that purpose, we have chosen the reaction with  OOH since it has been used and recommended to that purpose,33,34 and there are data available for its reactions with a wide variety of radical scavengers. It was found that, in lipid media, the  OOH scavenging activity of esculetin is lower than those of carotenes (B105–106 M1 s1),71 dopamine (8.2  105 M1 s1),72 canolol (6.8  105 M1 s1),61 and hydroxytyrosol (6.4  105 M1 s1);73 similar to those of sesamol (3.3  104 M1 s1),74 and sinapinic acid (1.7  104 M1 s1);75 slightly higher than those of protocatechuic acid (5.1  103),76 capsaicin (6.5  103 M1 s1),77 and a-mangostin (7.8  103 M1 s1);78 and significantly higher than those of tyrosol (7.1  102 M1 s1),73 melatonin (3.1  102 M1 s1)79 and caffeine (3.2  10 M1 s1).70 In addition, esculetin was found to react with  OOH 14.5 times faster than Trolox. Peroxyl radical scavenging activity of esculetin in water



OOCH3 6a 7a Total

12.88 14.79

1.06  105 1.18  104 1.18  105

90.0 10.0

10.85 12.64

6.34  105 1.95  105 8.29  105

76.5 23.5



OOCHCH2 6a 7a Total

constant, since the tunneling effects are similar for both paths. Accordingly, the radical formed by HT from site 6 was identified as the main product of the reaction. The branching ratios of the different reaction channels, which represent the percent of their contribution to the total reaction, have been calculated as: Gi ¼

ki ktotal

 100

where i represents each particular channel. The contribution of path 6 to the overall reactivity of esculetin towards the peroxyl radical was found to be larger than 75% in all the studied cases. However the contributions of path 7, while minor, cannot be neglected and increases with the reactivity of the radical. The total rate coefficients were calculated as the sum of the rate constants for the different viable reaction paths: 2 ES 2 ES;HTð6aÞ 2 ES;HTð7aÞ kH ¼ kH þ kH tot app app

They were found to be 4.39  104, 1.18  105 and 8.29  10 M1 s1, for the reactions of H2ES with  OOH,  OOCH3 and 5

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Similar to what was found in lipid media, all RAF reaction paths are significantly endergonic in aqueous solution for all the studied peroxyl radicals (Table 4), regardless of the reacting species (H2ES or HES). This means that independent of the environment’s polarity the RAF mechanism is not expected to contribute to the peroxyl radical scavenging activity of esculetin. Regarding the HT mechanism all the reaction paths were found to be exergonic. The DG values of the HT reaction paths involving H2ES are slightly less negative in aqueous solution than in lipid environment. On the other hand, the HT from the non-deprotonated site in HES (6a) is more exergonic than the corresponding channel in H2ES by about 5 kcal mol1. Table 4 Gibbs free energy of reaction (DG, kcal mol1), at 298.15 K, in aqueous solution 



OOH



OOCH3

OOCHCH2

Path

DGH2ES

DGHES

DGH2ES

DGHES

DGH2ES

DGHES

SET HT 6a 7a RAF 2 3 4 5 6 7 8 9 10

32.66

10.00

34.49

11.83

27.89

5.23

3.60 3.53

9.10 —

1.94 1.87

7.45 —

3.14 3.07

8.65 —

25.18 12.90 15.62 16.09 17.89 14.14 20.33 15.75 28.07

11.23 13.00 14.48 14.79 11.31 18.97 16.31 14.32 24.23

27.79 14.51 17.01 17.94 19.73 15.91 22.45 17.28 29.43

14.80 14.86 16.82 17.29 14.42 21.41 20.16 15.99 26.25

25.61 13.88 15.33 16.63 18.24 15.28 21.38 15.60 27.12

12.75 12.92 13.91 15.46 11.20 17.91 17.67 14.05 Unstable

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This indicates that the thermochemical viability of the HT mechanism increases at pHs where the anionic form of esculetin prevails. For the SET reactions with the studied peroxyl radicals, the DG values remain positive in aqueous solution. Logically the values corresponding to SET from H2ES are lower than those in pentyl ethanoate solution, due to the increased polarity of the environment. In addition, albeit SET processes from HES to the studied peroxyl radicals were also found to be endergonic, their DG values are significantly lower than those of the corresponding SET from H2ES (DG o 12 kcal mol1). Therefore we have included the SET reactions from HES in the kinetic study. This is because, as mentioned in the Computational details section, SET takes place at relatively large reaction distances, and yields reactive species that may react further, at high rates, through exergonic enough reactions to provide a driving force. Therefore such kind of reactions may be important in biological systems. Moreover, the finding that SET from esculetin to the studied peroxyl radicals, in aqueous solution, is to some extent endergonic does not mean that the SET mechanism is not important for other free radicals. In fact the viability of such processes would be strongly influenced by the electro-accepting nature of the reacting free radical. Therefore we will address this point in more detail later. The fully optimized geometries of the HT transition states for the reactions of HES are shown in Fig. 2. In this case the behavior is different from that previously discussed for the neutral species. The earliest transition state is that involved in the reaction with  OOCHCH2, and the latest one corresponds to the  OOCH3 reaction. This suggests that the reactivity of the studied radicals towards the anionic form of esculetin should present the following trend:  OOCH3 o  OOH o  OOCHCH2. The Gibbs free energies of activation (DGa) for the HT and SET reactions of both, H2ES and HES, are reported in Table 5. For the reaction of the neutral form of esculetin the lowest

Fig. 2 Optimized geometries of the HAT transition states in the reaction between HES and peroxyl radicals, at the 6 positions, in water media, distances are in angstroms. Imaginary frequencies are provided as ESI.†

Table 5 Gibbs free energy of activation (DGa, kcal mol1), at 298.15 K, in aqueous solution 



OOH DGHES



OOCH3

OOCHCH2

Path

DGH2ES

DGH2ES

DGHES

DGH2ES

DGHES

SET HT 6a 7a

26.68

7.60

39.01

12.05

29.42

7.07

14.23 15.99

11.88 —

13.92 16.13

11.87 —

11.67 12.96

8.88 —

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DGa systematically corresponds to the HT mechanism, in particular to reaction path 6a, while the highest DGa is that of the SET process. Moreover, the DGa for the SET reaction is more than 10 kcal mol1 higher than those of the HT reaction paths. Thus, it can be anticipated that SET would be of minor importance for the peroxyl scavenging activity of H2ES, in aqueous solution. On the other hand, SET becomes the process with the lowest DGa, for the anionic form of esculetin when reacting with  OOH and  OOCHCH2. In the first case the difference is rather larger (about 4 kcal mol1) than in the second case (about 2 kcal mol1). On the contrary, for the reaction of HES with  OOCH3, HT has the lowest barrier. However, compared with SET it is only slightly lower (about 0.2 kcal mol1). Therefore for the reactions of HES it can be anticipated that the relative importance of SET and HT would be determined by the reacting free radical. The trends on the DGa values are directly reflected in the rate coefficients (k, Table 6). According to the calculated k values, the SET processes from H2ES to the studied peroxyl radicals are very small, while they become significant or even major for the SET reactions involving HES. The total values reported in Table 6 correspond to the sum of the different reaction paths for each species: 2 ES 2 ES;SET 2 ES;HTð6aÞ 2 ES;HTð7aÞ kH ¼ kH þ kH þ kH tot app app app



HES kHES ¼ kapp tot



;SET

HES þ kapp



;HTð6aÞ

The reported overall k values correspond to the rate constant that would be observed at physiological pH, i.e. taking into account the molar fractions ( p) of H2ES and HES at pH = 7.4: 

H2 ES H2 ES kpH¼7:4 ktot þ pHES kHES tot overall ¼ p



In all cases it was found that the anion (HES) is the species contributing the most to the overall reactivity of esculetin towards the studied peroxyl radicals. Therefore the phenoxide anion seems to be the key species in the peroxyl radical scavenging activity of esculetin. The reactions with  OOH and  OOCHCH2 were found to be rather fast, with overall rate constants in the order of 107 M1 s1. The slowest process is that corresponding to the esculetin reaction with  OOCH3. This trend is in line with the relative reactivity of the studied radicals. To put these values in perspective, we have compared the  OOH scavenging activity of esculetin in aqueous solution, at physiological pH, with those of other antioxidants. Under such conditions, based on kinetic considerations, the protective effects of esculetin against oxidative stress is predicted to be much higher than that of melatonin (2.0  10 M1 s1),79 caffeine (3.3  101 M1 s1),70 allicin (7.4  103 M1 s1)80 and thioacrolein (2.9  104 M1 s1);80 similar to that of canolol (2.50  106 M1 s1)61 a-mangostin (1.4  106 M1 s1)78 and dopamine (2.2  105 M1 s1);72 and lower than that of protocatechuic acid (1.3  107 M1 s1),76 2-propenesulfenic acid (2.6  107 M1 s1),80 glutathione (2.7  107 M1 s1),81 and sesamol (2.4  108 M1 s1).74 In addition it was found that

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Paper Apparent rate constants and total rate coefficients (k, M1 s1), in aqueous solution, at 298.15 K

Table 6

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SET HT 6a 7a Total Overalla a



OOH



OOCH3

OOCHCH2

kH2ES

kHES

kH2ES

kHES

kH2ES

kHES

1.73  107

1.67  107

1.59  1016

9.10  103

1.68  109

4.07  107

4.89  105 — 1.72  107

6.21 5.61 6.78 9.92

9.98  105 — 1.01  106

2.97 1.30 4.27 6.65

3.77 1.12 4.89 1.69

   

104 104 104 107

   

104 103 104 105

   

105 105 105 107

2.69  107 — 6.76  107

Considering the molar fractions of H2ES and HES, at physiological pH.

esculetin reacts about 188 times faster than Trolox. Based on these results it can be stated that esculetin is an efficient peroxyl radical scavenger in aqueous solution, at physiological pH, and this is considering only its efficiency for scavenging the first radical. However it seems to be possible that esculetin scavenges more than that. This point will be addressed in the next section. Regarding the relative importance of the different mechanism and sites of the reaction, it was found that for H2ES HT is the only important mechanism (Table 7). In addition, the contributions of HT paths 6a and 7a were found to be influenced by the reacting radical, despite the fact that for all the studied peroxy radicals path 6a was found to have the largest contributions to the overall peroxyl scavenging activity of H2ES. When reacting with radical  OOCH3, more than 90% of the formed products are expected to be those yielded by path 6a. For the reactions of H2ES with the other two, more reactive, peroxyl radicals, the branching ratio corresponding to path 6a is reduced to 70 and 77% for  OOCHCH2 and  OOH, respectively. The nature of the reacting free radical was also found to be important for the reactions of HES. In this case its influence is even larger. For the HES +  OOH reaction the main reaction mechanism is SET, contributing about 97% to the overall reactivity. For the reaction between HES and  OOCHCH2, SET remains the main reaction mechanism, but its contribution to the overall reactivity of HES is significantly lower (B60%). On the contrary, for the HES +  OOCH3 reaction, HT becomes the main reaction mechanism by far (B99%). Therefore the electrophilic character of the radical involved in the reaction seems to be the key factor ruling the rate of the SET reaction. According to these results, it seems worthwhile to investigate this mechanism in more details. To that purpose the set of reacting radicals has been extended (Table 8). As the values in this table show esculetin is an excellent free radical scavenger

Table 7 Branching ratios (G) of the different channels of the reaction, in aqueous solution, at 298.15 K 



OOH

Path

DGH2ES

DGHES

DGH2ES

SET HT 6a 7a

B0.0

97.16

B0.0

77.10 22.90

2.84 —



OOCH3

91.71 8.29

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DGHES 0.90 99.10 —

OOCHCH2

via SET. Its rate constants were found to be in the order of 107–109 M1 s1 with a large variety of free radicals, which indicates that this compound is a versatile scavenger. The only exceptions are  OCHCH2 (koverall = 4.51  105 M1 s1) and  OOCH3 (koverall = 8.95  103 M1 s1). Regeneration and multi-scavenging activity It has been previously proposed that in aqueous solution, at physiological pH, after the first peroxyl radical is scavenged by a compound with the catechol moiety, and in the presence of a good electron-donor species, such as the superoxide radical anion, the latter is consumed the catechol group is regenerated. This means that, under such conditions, chemical compounds presenting this structural characteristics have the ability of scavenging several radical equivalents, two per cycle.76 Since esculetin presents a catechol group, such possibility has also been explored in this work. For that purpose we have considered the same peroxyl radicals, ROO , used for the first part of the investigation (HOO , CH3OO , and CH2CHOO ). Taken into account that at physiological pH the dominant form of esculetin is HES, and it is also the most active species, it has been used for the investigation of the catechol regeneration. The investigated reaction routes are shown in Scheme 2. The first step corresponds to the SET reaction from HES to ROO which yields the radical species HESr1. The deprotonation of the later produces the radical-anion ESr2, which was found to be an exergonic process, with DG = 1.86 kcal mol1 at pH under standard conditions. However, this reaction actually corresponds to an acid–base equilibrium: HESr1 # ESr2 + H+ Therefore it is affected by the pH of environment, and when it takes place under physiological conditions, i.e. with the pH buffered to a value of 7.4, a conditional equilibrium constant (K 0 ) can be defined,82 according to: 0

K0 ¼

eDG =RT 0 ¼ eDG =RT 10pH

DGH2ES

DGHES

B0.0

60.21

Hence, the conditional Gibbs energy of reaction at each particular buffered pH would be:

39.79 —

DG 0 = DG0  2.303RT (pH)

69.56 30.44

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Table 8 Reorganization term (l), Gibbs free energy of activation (DGa, kcal mol1), apparent rate constant (kapp, M1 s1) for H2ES and HES; and overall rate coefficient (koverall, M1 s1) at physiological pH for SET reactions with different free radicals, in aqueous solution

HES

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H2ES Radical

l

DGa

kapp

DPPH NO2 N3  SO4   OH  OCH3  OCH2Cl  OCHCl2  OCCl3  OCHCH2  OOH  OOCH3  OOCH2Cl  OOCHCl2  OOCCl3  OOCHCH2

21.26 30.72 4.65 18.95 12.91 18.49 24.26 25.99 23.53 10.19 23.31 16.97 17.63 18.35 18.19 17.53

26.99 14.55 15.93 0.31 4.32 15.39 3.89 0.08 0.26 44.43 26.68 39.01 28.12 17.65 12.62 29.42

1.02 1.33 1.30 7.53 2.77 3.24 4.06 7.45 7.64 1.69 1.73 1.59 1.53 7.15 3.47 1.68

               

107 102 10 109 109 10 109 109 109 1020 107 1016 108 101 103 109

l

DGa

kapp

19.83 29.30 3.22 17.53 11.49 17.07 22.84 24.56 22.11 8.77 21.89 15.55 16.21 16.92 16.77 16.11

7.15 2.83 3.67 5.28 1.82 1.37 0.24 4.58 9.56 9.73 7.60 12.05 6.45 2.09 0.58 7.07

3.54 6.75 4.81 7.58 7.88 7.68 7.55 2.00 6.12 4.58 1.67 9.10 1.15 7.18 7.44 4.07

pH = 7.4 koverall                

107 109 109 108 109 109 109 109 105 105 107 103 108 109 109 107

3.48 6.64 4.73 8.69 7.80 7.55 7.49 2.09 1.25 4.51 1.64 8.95 1.13 7.06 7.32 4.00

               

107 109 109 108 109 109 109 109 108 105 107 103 108 109 109 107

ES2 + H+ = HES The standard Gibbs energy corresponding to the forward reaction is 22.31 kcal mol1, while the conditional value (at pH = 7.4) is DG 0 = 12.21 kcal mol1, and can be calculated as: DG 0 = DG0 + 2.303RT (pH) Regarding the competition between the esculetin regeneration and the quinone formation, it was found that the former has a higher rate constant in most of the cases (Table 9). The exceptions correspond to the most reactive radicals (the same above mentioned). However, even in those cases the reaction with O2  (regeneration), is expected to be the major one

Table 9 Gibbs free energy of activation (DGa, kcal mol1), the diffusion controlled rate constant (kD, M1 s1) and the apparent reaction rate constant (kapp, M1 s1) in the SET reactions involved in the antioxidant regeneration, in aqueous media at physiological pH Scheme 2 Mechanisms for the peroxyl scavenging activity of esculetin in aqueous solution at physiological pH.

ESr2 + O2

The deprotonation of HESr1, at pH = 7.4, is exergonic to a larger extent than under standard conditions (pH = 0) with DG 0 = 11.96 kcal mol1. This process takes place without barrier and is only controlled by the [H+] of the surrounding. ESr2 can also be formed through HT from HES to a free radical. For those studied in this work, the corresponding rate constants are those reported in Table 6. ESr2 can react with the anion superoxide, via SET from the latter, producing the dianion ES2 and O2, with a rate constant equal to 7.81  109 M1 s1 (Table 6). Thus it is within the diffusion-limited regime. The formed dianion is involved in an acid–base equilibrium, yielding HES, i.e. regenerating the anionic form of esculetin:

1204 | Phys. Chem. Chem. Phys., 2014, 16, 1197--1207

l

Radical O2

- ES

2

DGa

kapp

2

+O 18.64

2.54

ESr2 +  OOR - Q + OOR DPPH 20.75 NO2 30.22 N3  4.14  SO4 18.45  OH 12.40  OCH3 17.99  OCH2Cl 23.76  OCHCl2 25.48  OCCl3 23.02  OCHCH2 9.68  OOH 22.80  OOCH3 16.47  OOCH2Cl 17.13  OOCHCl2 17.84  OOCCl3 17.69  OOCHCH2 17.03

6.02 2.32 4.20 5.81 2.27 0.93 0.39 5.04 10.12 7.47 6.49 10.20 5.26 1.53 0.32 5.80

7.15  109 2.32 7.33 3.11 3.30 7.70 7.78 7.58 1.07 2.35 2.08 1.07 2.09 7.76 7.38 7.47 3.32

               

108 109 109 108 109 109 109 109 105 107 108 105 108 109 109 108

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In addition, the possible regeneration of esculeting, 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.

Acknowledgements ´n General de Co ´mputo y We gratefully acknowledge the Direccio ´n y Comunicacio ´n (DGTIC) at de Tecnologı´as de Informacio ´noma de Me ´xico, and the LaboraUniversidad Nacional Auto ´n y Co ´mputo Paralelo at Universidad torio de Visualizacio ´noma Metropolitana-Iztapalapa. This work was partially Auto supported by a grant from the DGAPA UNAM (PAPIITIN209812), and projects SEP-CONACyT 167430 and 167491. M.E.M. thanks CONACyT for Postdoctoral fellowship. Fig. 3 Reaction profiles of catechol regeneration (black line) and quinone formation (grey line), at pH = 7.4 (physiological pH); for reactions involving (A) CH3OO , (B) CH2CHOO , and (C) HOO .

because the concentration of O2  is probably higher than those of other radicals under physiological conditions. For the radicals studied in this work, the reaction profiles of both competing processes are shown in Fig. 3. As this figure shows, the minimum energy path corresponding to regeneration is lower than that of the quinone formation. Moreover the quinone formation was found to be endergonic for the three peroxyl radicals, at physiological pH. This supports the preponderance of the regeneration route over that yielding the quinone.

Conclusions A theoretical study of the peroxyl radical scavenging capacity of esculetin in aqueous solution, at physiological pH, and in lipid media was performed. Three reaction mechanisms were considered: single electron transfer (SET), hydrogen transfer (HT) and radical adduct formation (RAF). It was found that in lipid media the main mechanism of the 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, while for the anion the relative importance of the different mechanisms changes with the reacting radical. In lipid media esculetin can efficiently act as peroxyl radical scavenger, albeit it is only moderately good for that purpose under such conditions. On the other hand, esculetin is an efficient peroxyl radical scavenger in aqueous solution, at physiological pH. Under such conditions it is also a versatile scavenger able of deactivating a wide variety of free radicals.

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Phys. Chem. Chem. Phys., 2014, 16, 1197--1207 | 1207

Theoretical study on the peroxyl radicals scavenging activity of esculetin and its regeneration in aqueous solution.

The study of the ˙OOH, ˙OOCH3 and ˙OOCHCH2 radicals scavenging processes by esculetin (ES) was carried out in aqueous and lipid media, using the densi...
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