Co-reporter:Romina Castañeda-Arriaga and Annia Galano
Chemical Research in Toxicology June 19, 2017 Volume 30(Issue 6) pp:1286-1286
Publication Date(Web):May 5, 2017
DOI:10.1021/acs.chemrestox.7b00024
Several chemical routes related to the toxicity of paracetamol (APAP, also known as acetaminophen), its analogue N-acetyl-m-aminophenol (AMAP), and their deacetylated derivatives, were investigated using the density functional theory. It was found that AMAP is more resilient to chemical oxidation than APAP. The chemical degradation of AMAP into radical intermediates is predicted to be significant only when it is induced by strong oxidants. This might explain the apparent contradictions among experimental evidence regarding AMAP toxicity. All of the investigated species are incapable of oxidizing DNA, but they can damage lipids by H atom transfer (HAT) from the bis-allylic site, with the phenoxyl radical of AMAP being the most threatening to the lipids’ chemical integrity. Regarding protein damage, Cys residues were identified as the most likely targets. The damage in this case may involve two different routes: (i) HAT from the thiol site by phenoxyl radicals and (ii) protein arylation by the quinone imine (QI) derivatives. Both are not only thermochemically viable, but also are very fast reactions. According to the mechanism identified here as the most likely one for protein arylation, a rather large concentration of QI would be necessary for this damage to be significant. This might explain why APAP is nontoxic in therapeutic doses, while overdoses can result in hepatic toxicity. In addition, the QI derived from both APAP and AMAP were found to be capable of inflicting this kind of damage. In addition, it is proposed that they might increase •OH production via the Fenton reaction, which would contribute to their toxicity.
Co-reporter:Manuel Alejandro Hernández-Olivares, Agustin Ibarra-Escutia, Gabriela Mendoza-Sarmiento, Alberto Rojas-Hernández, Annia Galano
Computational and Theoretical Chemistry 2017 Volume 1115(Volume 1115) pp:
Publication Date(Web):1 September 2017
DOI:10.1016/j.comptc.2017.06.023
•19 polyprotic compounds with potential pharmacological properties are investigated.•Their deprotonation routes are proposed for the first time.•They present high conformational and acid-base complexity.•Intramolecular H bonding interactions influence conformations and site acidity.•Combined (LUMO+1) + LUMO analyses are proposed for predicting site acidity.Elucidating the most likely deprotonation routes for polyprotic molecules is crucial in order to know the structures of the species prevailing under specific pH conditions. This is particularly important for molecules with potential applications as medical drugs, since different acid-base species, with the same deprotonation degree, may not interact in the same way with biological targets. The 19 polyprotic molecules investigated here are particularly challenging because they present phenolic and tertiary amino groups, which have similar ease of deprotonation, and also a high conformational complexity. Deprotonation energies in aqueous solution were estimated using the Density Functional Theory, and used as a quantitative criterion to identify the most likely deprotonation routes for the target molecules, which are proposed here for the first time. In addition, the LUMO and LUMO+1 distributions were also analyzed, and used as a qualitative criterion to support the proposed deprotonation routes. It is suggested that using both molecular orbitals combined for systems with small (LUMO+1) - LUMO energy gaps may provide a more useful picture in this context.Download high-res image (196KB)Download full-size image
Co-reporter:Gloria Mazzone, Annia Galano, Juan R. Alvarez-Idaboy, and Nino Russo
Journal of Chemical Information and Modeling 2016 Volume 56(Issue 4) pp:662-670
Publication Date(Web):March 21, 2016
DOI:10.1021/acs.jcim.6b00006
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.
Co-reporter:Annia Galano
RSC Advances 2016 vol. 6(Issue 27) pp:22951-22963
Publication Date(Web):22 Feb 2016
DOI:10.1039/C6RA00549G
A set of 19 melatonin analogues, intended to be better antioxidants than the parent molecule, have been computationally designed. Eight of them were planned to have good primary antioxidant capacity (AOC), i.e., being good free radical scavengers. Seven of them were designed for their secondary AOC, being able to inhibit ˙OH production by acting as metal ion chelators. Based on their predicted behavior for the intended functions, four multifunctional melatonin analogues were proposed. They were found to be among the best peroxyl radical scavengers identified so far, in aqueous solution, at physiological pH. They were also found to be capable of turning off Cu(II) reduction by O2˙− and Asc−, thus fully inhibiting the associated ˙OH production. Two of them, namely the IIcD and IbG analogues, were identified as the ones with the best multifunctional AOC. They both fulfill the Lipinski's and Ghose's rules for orally active drugs. However, IIcD has been chosen as the best prospect for possible application based on potential toxicity and synthetic accessibility estimations. Hopefully, these results might provide motivation for further investigations on the subject, and the synthesis of this compound, so its potential role as protector against oxidative stress – and the associated health issues – could be experimentally confirmed or refuted.
Co-reporter:Misaela Francisco-Marquez, Mario Aguilar-Fernández, Annia Galano
Computational and Theoretical Chemistry 2016 Volume 1077() pp:18-24
Publication Date(Web):1 February 2016
DOI:10.1016/j.comptc.2015.09.025
•Anthranilic acid is an excellent secondary antioxidant, through metal chelation.•It is efficient for sequestering Cu(II) ions from not too strong reductants.•It is able of fully preventing oxidation by Cu(II)–ascorbate mixtures as oxidant.•It is efficient for deactivating OH immediately after formation by Fenton-like reactions.•It is proposed as a proper OH-inactivating ligand.The protection exerted by anthranilic acid against oxidative stress was investigated using the Density Functional Theory. It was found to be a rather poor primary antioxidant, not efficient as a peroxyl radical scavenger, albeit it may be able of scavenging other, more reactive, free radicals. On the contrary, it was found to be an excellent secondary antioxidant, through metal chelation. Anthranilic acid is proposed to be a proper OH-inactivating ligand, with ways of action that depend on the strength of the reductant. It is able of chelating Cu(II) ions and fully prevent them from reduction by not too strong reductants such as the ascorbate ion. Accordingly, it is predicted to behave as an efficient antioxidant for in vitro experiments using Cu(II)–ascorbate mixtures as oxidant. On the other hand, anthranilic acid is able of downgrading the production of OH in biological systems, where stronger reductants such as the superoxide radical anion are present, but only partially. However, under such conditions it would be efficient for deactivating this radical as it is formed through Fenton-like reactions. Accordingly, anthranilic would be an efficient protector against the OH associated oxidative stress through its secondary antioxidant activity.
Co-reporter:Annia Galano, Nino Russo
Computational and Theoretical Chemistry 2016 Volume 1077() pp:1
Publication Date(Web):1 February 2016
DOI:10.1016/j.comptc.2015.11.005
•There is compelling evidence indicating that oxidative stress (OS) is an important health risk.•For a complete picture of the OS chemistry the joint efforts of numerous scientist is needed.•Quantum mechanics based studies can provide valuable information regarding OS.Graphical abstract
Co-reporter:Yenny Villuendas-Rey, Juan Raul Alvarez-Idaboy, and Annia Galano
Journal of Chemical Information and Modeling 2015 Volume 55(Issue 12) pp:2552-2561
Publication Date(Web):December 1, 2015
DOI:10.1021/acs.jcim.5b00513
The protection exerted by 3,5-dihydroxy-4-methoxybenzyl alcohol (DHMBA), a phenolic compound recently isolated from the Pacific oyster, against oxidative stress (OS) is investigated using the density functional theory. Our results indicate that DHMBA is an outstanding peroxyl radical scavenger, being about 15 times and 4 orders of magnitude better than Trolox for that purpose in lipid and aqueous media, respectively. It was also found to react faster with HOO• than other known antioxidants such as resveratrol and ascorbic acid. DHMBA is also predicted to be able to sequester Cu(II) ions, consequently inhibiting the OS induced by Cu(II)–ascorbate mixtures and downgrading the •OH production via the Haber-Weiss reaction. However, it is proposed that DHMBA is more efficient as a primary antioxidant (free radical scavenger), than as a secondary antioxidant (metal ion chelator). In addition, it was found that DHMBA can be efficiently regenerated in aqueous solution, at physiological pH. Such regeneration is expected to contribute to increase the antioxidant protection exerted by DHMBA. These results suggest that probably synthetic routes for this compound should be pursued, because albeit its abundance in nature is rather low, its antioxidant activity is exceptional.
Co-reporter:Manuel E. Medina;Ángel Trigos
Journal of Physical Organic Chemistry 2015 Volume 28( Issue 7) pp:504-508
Publication Date(Web):
DOI:10.1002/poc.3449
Abstract
The density functional and the transition state theories were used to estimate detailed thermochemical and kinetic data for the oxidative damage to cholesterol induced by peroxyl radicals (ROO•) in lipid media. Two mechanisms of reactions were considered, the hydrogen transfer and the radical adduct formation, and it was found that hydrogen transfer is the only important route in this case, particularly at allylic sites. 7α products are predicted to represent more than 90% of the total initial damage, albeit 7β products are expected to be found in small but not negligible proportion. The chlorination degree was found to play an important role in the extent of the oxidative damage to cholesterol inflicted by the ROO• family. The estimated rate constants are 2.74 × 105, 1.32 × 105, 3.09 × 102, 6.07 × 101, and 8.75 × 10−1 M−1 s−1 for the reactions with •OOCHCl2, •OOCCl3, •OOCH2Cl, •OOH, and •OOCH3, respectively. These values indicate that only chlorinated peroxyl radicals represent a significant hazard to the chemical integrity of cholesterol. Copyright © 2015 John Wiley & Sons, Ltd.
Co-reporter:Ruslán Álvarez-Diduk and Annia Galano
The Journal of Physical Chemistry B 2015 Volume 119(Issue 8) pp:3479-3491
Publication Date(Web):February 3, 2015
DOI:10.1021/acs.jpcb.5b00052
Density functional theory was used to investigate the potential role of neurotransmitters adrenaline and noradrenaline regarding oxidative stress. It is predicted that they can be efficient as free radical scavengers both in lipid and aqueous media, with the main reaction mechanism being the hydrogen transfer and the sequential proton loss electron transfer, respectively. Despite the polarity of the environment, adrenaline and noradrenaline react with •OOH faster than Trolox, which suggests that they are better peroxyl radical scavengers than the reference compound. Both catecholamines are also proposed to be capable of efficiently inhibiting the oxidative stress induced by copper(II)–ascorbate mixtures, and the •OH production via Haber–Weiss reaction, albeit the effects on the later are only partial. They exert such beneficial effects by sequestering Cu(II) ions. In summary, these catecholamines can be capable of reducing oxidative stress, by scavenging free radicals and by sequestering metal ions. However, at the same time they might lose their functions in the process due to the associated structural modifications. Consequently, adrenaline and noradrenaline can be considered as both protectors and molecular targets of oxidative stress. Fortunately, under the proper conditions, both catecholamines can be regenerated to their original form so their functions are restored.
Co-reporter:Ruslán Álvarez-Diduk, Annia Galano, Dun Xian Tan, and Russel J. Reiter
The Journal of Physical Chemistry B 2015 Volume 119(Issue 27) pp:8535-8543
Publication Date(Web):June 16, 2015
DOI:10.1021/acs.jpcb.5b04920
The protection exerted by N-acetylserotonin (NAS) and 6-hydroxymelatonin (6OHM) against oxidative stress was investigated using the density functional theory. It was found that these compounds are better peroxyl radical scavengers than melatonin itself, Trolox, caffeine, or genistein both in lipid and aqueous solutions. The related kinetic data is provided for the first time. The solvent polarity influences not only the absolute reactivity of NAS and 6OHM toward peroxyl radicals, but also their relative scavenging activity. In addition, they both fully inhibit the oxidative effects of copper-ascorbate mixtures, and •OH production via the Haber–Weiss reaction, albeit the effects on the later are only partial. On the basis of comparisons with other melatonin-related compounds, it is proposed that the role of NAS and 6OHM on the overall protection exerted by melatonin against oxidative stress is mainly related to their free radical scavenging activities. Moreover, they increase such protection. The role of the phenol moiety on such activity is demonstrated.
Co-reporter:Manuel E. Medina, Annia Galano and Juan Raúl Alvarez-Idaboy
Physical Chemistry Chemical Physics 2014 vol. 16(Issue 3) pp:1197-1207
Publication Date(Web):25 Oct 2013
DOI:10.1039/C3CP53889C
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.
Co-reporter:Annia Galano, Misaela Francisco Marquez, and Adriana Pérez-González
Chemical Research in Toxicology 2014 Volume 27(Issue 5) pp:904
Publication Date(Web):April 3, 2014
DOI:10.1021/tx500065y
Several aspects related to the antioxidant activity of ellagic acid were investigated using the density functional theory. It was found that this compound is unusually versatile for protecting against the toxic effects caused by oxidative stress. Ellagic acid, in aqueous solution at physiological pH, is able of deactivating a wide variety of free radicals, which is a desirable capability since in biological systems, these species are diverse. Under such conditions, the ellagic acid anion is proposed as the key species for its protective effects. It is predicted to be efficiently and continuously regenerated after scavenging two free radicals per cycle. This is an advantageous and unusual behavior that contributes to increase its antioxidant activity at low concentrations. In addition, the ellagic acid metabolites are also capable of efficiently scavenging a wide variety of free radicals. Accordingly, it is proposed that the ellagic acid efficiency for that purpose is not reduced after being metabolized. On the contrary, it provides continuous protection against oxidative stress through a free radical scavenging cascade. This is an uncommon and beneficial behavior, which makes ellagic acid particularly valuable to that purpose. After deprotonation, ellagic acid is also capable of chelating copper, in a concentration dependent way, decreasing the free radical production. In summary, ellagic acid is proposed to be an efficient multiple-function protector against oxidative stress.
Co-reporter:Annia Galano, Dun Xian Tan and Russel J. Reiter
RSC Advances 2014 vol. 4(Issue 10) pp:5220-5227
Publication Date(Web):12 Dec 2013
DOI:10.1039/C3RA44604B
The reactions of cyclic 3-hydroxymelatonin (3-OHM) with hydroxyl (˙OH) and hydroperoxyl (˙OOH) radicals were studied using Density Functional Theory. Two environments, mimicking lipid and aqueous solutions, have been modelled. Three mechanisms of reaction were considered: radical adduct formation (RAF), hydrogen transfer (HT), and single electron transfer (SET). Their relative importance for the free radical scavenging activity of 3-OHM was assessed. It was found that 3-OHM reacts with ˙OH at diffusion-limited rates, regardless of the polarity of the environment, which supports its excellent ˙OH radical scavenging activity. The overall reactivity of 3-OHM towards this radical was found to be similar, but slightly higher than those of melatonin and two other metabolites (N1-acetyl-5-methoxykynuramine, AMK; and N1-acetyl-N2-formyl-5-methoxykynuramine, AFMK). For the reaction with ˙OOH, 3-OHM was found to react several orders of magnitude faster, in aqueous solution, than melatonin, AMK and AFMK. Furthermore, under these conditions 3-OHM was found to react with ˙OOH about 98.4 times faster than Trolox. This seems to be a very important finding since it has been proposed that melatonin, AMK and AFMK are rather ineffective as peroxyl radical scavengers, while 3-OHM is predicted to be very efficient. Therefore, it is proposed that the protective effects of melatonin against peroxyl radicals become important after being metabolized into 3-OHM. Accordingly, the results presented in this work not only support the continuous protection against oxidative stress exerted by melatonin, through its free radical scavenging cascade, but also the important role of 3-OHM on the peroxyl radical scavenging activity of melatonin.
Co-reporter:Adriana Pérez-González, Annia Galano and Juan Raúl Alvarez-Idaboy
New Journal of Chemistry 2014 vol. 38(Issue 6) pp:2639-2652
Publication Date(Web):18 Mar 2014
DOI:10.1039/C4NJ00071D
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.
Co-reporter:Marta E. Alberto, Nino Russo, Andre Grand and Annia Galano
Physical Chemistry Chemical Physics 2013 vol. 15(Issue 13) pp:4642-4650
Publication Date(Web):31 Jan 2013
DOI:10.1039/C3CP43319F
The free radical scavenging activity of Trolox was studied for aqueous and lipid environments using the Density Functional Theory. Several reaction mechanisms and free radicals of different chemical nature have been included in this study, as well as the influence of the pH. Trolox was found to be a powerful ˙OH and alkoxy scavenger, regardless of the conditions under which the reaction takes place. It was also found to be very efficient as a peroxy radical scavenger in aqueous solution, while its protective effects against this particular kind of free radicals are significantly reduced in lipid solution. Four reaction mechanisms were found to significantly contribute to the ˙OH scavenging activity of Trolox in aqueous solution: hydrogen transfer (HT), radical adduct formation (RAF), single electron transfer (SET), and sequential proton loss electron transfer (SPLET), while in lipid media two of them are relevant: HT and RAF. The ˙OCH3, ˙OOH, and ˙OOCHCH2 scavenging processes are predicted to take place almost exclusively by HT from the phenolic OH group in lipid media, and in aqueous solution at pH < 11, while at higher pH values the SPLET mechanism is proposed as the main one. This is also the case for other non-halogenated alkyl or alkenyl peroxy (and alkoxy) radicals. The agreement with the available experimental data supports the reliability of the presented calculations.
Co-reporter:Adriana Pérez-González
Journal of Physical Organic Chemistry 2013 Volume 26( Issue 3) pp:261-268
Publication Date(Web):
DOI:10.1002/poc.3082
The free radical scavenging activity of two Edaravone (EDA) derivatives (C1 and D1) has been studied in aqueous and lipid solutions using the Density Functional Theory. Different mechanisms of reaction have been considered, as well as the acid/base equilibrium in aqueous solution. The studied compounds were found to be rather poor •OOH scavengers in non-polar environments, but better than the parent molecule, EDA, which suggests that the peroxyl scavenging activity of this kind of compounds in lipid media could be increased via structural modifications. In aqueous solution, at physiological pH, D1 is predicted to be a better peroxyl scavenger than C1, and slightly better than its parent molecule, EDA. Their excellent activity, under such conditions, is attributed to the electron transfer from their anionic forms. D1 was found to be among the best peroxyl scavengers known so far, with a rate constant for its reaction with •OOH near the diffusion limit regime (2.3 × 108 M−1s−1). Copyright © 2013 John Wiley & Sons, Ltd.
Co-reporter:Elizabeth Hernandez-Marin, Annia Galano, and Ana Martínez
The Journal of Physical Chemistry B 2013 Volume 117(Issue 15) pp:4050-4061
Publication Date(Web):April 5, 2013
DOI:10.1021/jp401647n
We present a density functional theory (DFT) and time-dependent density functional theory (TD-DFT) study on the stability, antioxidant properties with respect to the single electron transfer mechanism, and electronic absorption spectra of some isomers (9-cis, 13-cis, and 15-cis) of carotenoids such as astaxanthin, lycopene, and those present in virgin olive oil (lutein, β-carotene, neoxanthin, antheraxanthin, violaxanthin, neochrome, luteoxanthin, mutatoxanthin, and violaxanthin). In general, the calculated relative stability of the cis isomers appears to be in line with experimental observations. It is predicted that the above-mentioned carotenoids (cis and trans isomers) will transfer one electron to the •OH radical. However, this transference is not plausible with radicals such as •OOH, •OC2H5, •OOC2H5, •NO2, and •OOCH2CH═CH2. On the other hand, some carotenoids (β-carotene, lycopene, lutein, astaxanthin, violaxanthin, and antheraxanthin) will likely accept, in a medium of low polarity, one electron from the radical •O2–. However, neoxanthin, auroxanthin, mutatoxanthin, luteoxanthin, and neochrome would not participate in such an electronic transfer mechanism. The TD-DFT studies show that neutral species of the cis and trans isomers maintain the same color. On the contrary, the ionic species undergo a “bleaching” process where the absorption wavelengths shift to longer values (>700 nm). Additionally, the formation of a complex between astaxanthin and Cu2+ is explored as well as the effect that the metal atom will have in the UV–vis spectrum.
Co-reporter:Jorge Rafael León-Carmona, Juan Raúl Alvarez-Idaboy and Annia Galano
Physical Chemistry Chemical Physics 2012 vol. 14(Issue 36) pp:12534-12543
Publication Date(Web):26 Mar 2012
DOI:10.1039/C2CP40651A
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.
Co-reporter:Annia Galano and Juan Raúl Alvarez-Idaboy
Physical Chemistry Chemical Physics 2012 vol. 14(Issue 36) pp:12476-12484
Publication Date(Web):30 Apr 2012
DOI:10.1039/C2CP40799J
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.
Co-reporter:Annia Galano and Ana Martínez
The Journal of Physical Chemistry B 2012 Volume 116(Issue 3) pp:1200-1208
Publication Date(Web):December 22, 2011
DOI:10.1021/jp211172f
The free radical scavenging activity of capsaicin (CAP), which is the pungent component of hot chili peppers, has been studied in aqueous and lipid solutions, using the density functional theory. Different mechanisms of reaction have been considered: single electron transfer (SET), hydrogen transfer (HT), and radical adduct formation (RAF). Rate constants and branching ratios of the different channels of reaction are provided, as well as an interpretation of the UV–vis spectra. CAP is predicted to react faster in aqueous solution than in nonpolar media with oxygenated free radicals, and it was found to be a more efficient scavenger than melatonin and caffeine. It was also found that while SET does not contribute to the overall reactivity of CAP toward •OOH, •OOCH3, and •OCH3 radicals, it might be important for the reactions with more electrophilic radicals such as •OH, •OCCl3, and •OOCCl3. The main process, responsible for the peroxyl scavenging activity of CAP, was found to be the HT from the OH phenolic group. For the reaction with •OCH3, on the other hand, the HT from allylic sites are predicted to be the main channels of reaction. In this particular case a wider product distribution is predicted. This supports the role of the reacting free radical on the preponderant mechanism of action of free radical scavengers.
Co-reporter:Juan Raúl Alvarez-Idaboy and Annia Galano
The Journal of Physical Chemistry B 2012 Volume 116(Issue 31) pp:9316-9325
Publication Date(Web):July 17, 2012
DOI:10.1021/jp303116n
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.
Co-reporter:Annia Galano, Martín Gómez, Felipe J. González, and Ignacio González
The Journal of Physical Chemistry A 2012 Volume 116(Issue 43) pp:10638-10645
Publication Date(Web):October 15, 2012
DOI:10.1021/jp309085g
The functional M05-2X together with the SMD solvent model have been used to calculate hydrogen bonding association constants in dimethylsulfoxide (DMSO) solution. Data of equilibrium constants in DMSO for the case of electrochemically generated dianions interacting with methanol have been considered to test the reliability of the chemistry theoretical approach. From this approach, it was found that the successive association constants involved in the formation of the complexes depend on a linear combination of three quantum chemistry indexes which are the ionization energy, the electron affinity, and the charge on the oxygen atom receiving the methanol molecule. Under this perspective, the stoichiometry of all the dianion–methanol complexes was explained on the basis of the relative strength of the hydrogen bonding interaction compared to that of the methanol–DMSO and methanol dimer complexes. This linear combination seems to be valid regardless of the nature of the dianion structure and the number of methanol molecules in the complex, which is a relevant finding to generalize the applicability of both the functional M05-2X and the SMD solvent model, to calculate association constants for any other neutral or anionic molecules interacting by hydrogen bonding with proton donors.
Co-reporter:Annia Galano, Jorge Rafael León-Carmona, and Juan Raúl Alvarez-Idaboy
The Journal of Physical Chemistry B 2012 Volume 116(Issue 24) pp:7129-7137
Publication Date(Web):May 30, 2012
DOI:10.1021/jp302810w
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 alcohol > eugenol > guaiacol > vanillin > vanillic acid, while, in aqueous solution, at physiological pH, it becomes vanillic acid > vanillic alcohol > guaiacol ≈ eugenol > vanillin. 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.
Co-reporter:Annia Galano, Misaela Francisco-Márquez and J. Raúl Alvarez-Idaboy
Physical Chemistry Chemical Physics 2011 vol. 13(Issue 23) pp:11199-11205
Publication Date(Web):13 May 2011
DOI:10.1039/C1CP20722A
The OOH radical scavenging activity of sinapinic acid (HSA) has been studied in aqueous and lipid solutions, using the Density Functional Theory. HSA is predicted to react about 32.6 times faster in aqueous solution than in lipid media. The overall rate coefficients are predicted to be 5.39 × 105 and 1.66 × 104 M−1 s−1, respectively. Branching ratios for the different channels of reaction are also reported for the first time, as well as the UV-Vis spectra of the main products of reaction. It was found that the reactivity of sinapinic acid towards OOH radicals takes place almost exclusively by H atom transfer from its phenolic moiety. However it was found to react via SET, at diffusion-limit controlled rate constants, with ˙OH, ˙OCCl3 and ˙OOCCl3 radicals. It was found that the polarity of the environment and the deprotonation of HSA in aqueous solution, both increase the reactivity of this compound towards peroxyl radicals.
Co-reporter:Annia Galano and J. Raúl Alvarez-Idaboy
RSC Advances 2011 vol. 1(Issue 9) pp:1763-1771
Publication Date(Web):25 Oct 2011
DOI:10.1039/C1RA00474C
Glutathione, which is the most abundant cytosolic thiol, plays important roles in the non-enzymatic antioxidant defence system. Its free radical scavenging activity towards radicals of different nature (·OH, ·OOH, ·OCH3, ·OOCH3, ·OOCHCH2 and ·OOCCl3) have been studied in aqueous solution, using the Density Functional Theory. It was found that the rate constants range from 2.02 × 104 M−1s−1 to diffusion limit (7.68 × 109 M−1s−1). Therefore it can be stated that glutathione is an excellent free radical scavenger, able of efficiently scavenging a wide variety of free radicals. It reacts exclusively by H transfer, and with the exception of its reaction with ·OH there is only one important channel of reaction, yielding to the S-centered radical. For the reaction with ·OH, on the other hand, a wide product distribution is expected, which explains the formation of C-centered radicals experimentally observed. Glutathione was found to be exceptionally good as a OOH radical scavenger, comparable to 2-propenesulfenic acid. This has been explained based on the strong H bonding interactions found in the transition states, which involves the carboxylate moiety. Therefore this might have implications for other biological systems where this group is present.
Co-reporter:Jorge Rafael León-Carmona and Annia Galano
The Journal of Physical Chemistry B 2011 Volume 115(Issue 51) pp:15430-15438
Publication Date(Web):November 18, 2011
DOI:10.1021/jp209776x
The reactions of uric and 1-methyluric acids in nonpolar environments, as well as those of the corresponding urate anions in aqueous solution, with •OH, •OCH3, •OOH, and •OOCH3 have been studied using the density functional theory. Different mechanisms of reactions have been taken into account, and their relative importance on the antiradical activity of these compounds is analyzed. Both uric and methyluric acids are better scavengers in aqueous solution than in nonpolar media, which indicates that the urate anions are the most active species. The free radical scavenging activity of the studied compounds was found to be excellent for •OH, and very good for •OCH3. In addition, 1-methyluric acid is predicted to moderately protect against peroxyl oxidation, while the protective effects of uric acid against these particular species are not expected to be significant. In addition, 1-methyluric acid was found to be a better radical scavenger than its precursor, caffeine, suggesting that the antiradical activity of the latter might be explained by the action of its metabolites, rather than by its direct activity.
Co-reporter:Perla D. Maldonado, J. Raúl Alvarez-Idaboy, Adriana Aguilar-González, Alfonso Lira-Rocha, Helgi Jung-Cook, Omar Noel Medina-Campos, José Pedraza-Chaverrí, and Annia Galano
The Journal of Physical Chemistry B 2011 Volume 115(Issue 45) pp:13408-13417
Publication Date(Web):October 13, 2011
DOI:10.1021/jp208233f
S-Allylcysteine (SAC) is the most abundant compound in aged garlic extracts, and its antioxidant properties have been demonstrated. It is known that SAC is able to scavenge different reactive species including hydroxyl radical (•OH), although its potential ability to scavenge peroxyl radical (ROO•) has not been explored. In this work the ability of SAC to scavenge ROO• was evaluated, as well as the role of the allyl group (—S—CH2—CH═CH2) in its free radical scavenging activity. Two derived compounds of SAC were prepared: S-benzylcysteine (SBC) and S-propylcysteine (SPC). Their abilities to scavenge •OH and ROO• were measured. A computational analysis was performed to elucidate the mechanism by which these compounds scavenge •OH and ROO•. SAC was able to scavenge •OH and ROO•, in a concentration-dependent way. Such activity was significantly ameliorated when the allyl group was replaced by benzyl or propyl groups. It was shown for the first time that SAC is able to scavenge ROO•.
Co-reporter:Jorge Rafael León-Carmona and Annia Galano
The Journal of Physical Chemistry B 2011 Volume 115(Issue 15) pp:4538-4546
Publication Date(Web):March 25, 2011
DOI:10.1021/jp201383y
The reactions of caffeine (CAF) with different reactive oxygen species (ROS) have been studied using density functional theory. Five mechanisms of reaction have been considered, namely, radical adduct formation (RAF), hydrogen atom transfer (HAT), single electron transfer (SET), sequential electron proton transfer (SEPT), and proton coupled electron transfer (PCET). The SET, SEPT, and PCET mechanisms have been ruled out for the reactions of CAF with •OH, O2•−, ROO•, and RO• radicals. It was found that caffeine is inefficient for directly scavenging O2•− and •OOCH3 radicals and most likely other alkyl peroxyl radicals. The overall reactivity of CAF toward •OH was found to be diffusion-controlled, regardless of the polarity of the environment, supporting the excellent •OH scavenging activity of CAF. On the other hand, it is predicted to be a modest scavenger of •OCH3, and probably of other alkoxyl radicals, and a poor scavenger of HOO•. RAF has been identified as the main mechanism involved in the direct ROS scavenging activity of CAF. The excellent agreement with the available experimental data supports the reliability of the present calculations.
Co-reporter:Annia Galano, Misaela Francisco-Márquez, and Juan R. Alvarez-Idaboy
The Journal of Physical Chemistry B 2011 Volume 115(Issue 26) pp:8590-8596
Publication Date(Web):May 30, 2011
DOI:10.1021/jp2022105
The OOH radical scavenging activity of canolol (CNL) has been studied in aqueous and lipid solutions, using the density functional theory. CNL is predicted to react about 3.6 times faster in aqueous solution than in lipid media. The overall rate coefficients are predicted to be 2.5 × 106 and 6.8 × 105 M–1 s–1, respectively. The OOH radical scavenger activity of canolol is predicted to be similar to that of carotenes, higher than that of allicin, and much higher than that of melatonin. Branching ratios for the different channels of reaction are reported for the first time. It was found that the reactivity of canolol toward OOH radicals takes place almost exclusively by H atom transfer from the phenolic moiety in canolol, regardless of the polarity of the environment. Taking into account that the reactivity of peroxyl radicals is significantly lower than that of other reactive oxygen species, canolol is proposed to be a very good antioxidant.
Co-reporter:Annia Galano, Juan Raúl Alvarez-Idaboy, and Misaela Francisco-Márquez
The Journal of Physical Chemistry B 2011 Volume 115(Issue 44) pp:13101-13109
Publication Date(Web):October 3, 2011
DOI:10.1021/jp208315k
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.
Co-reporter:Annia Galano
Theoretical Chemistry Accounts 2011 Volume 130( Issue 1) pp:51-60
Publication Date(Web):2011 September
DOI:10.1007/s00214-011-0958-0
The ·OH and ·OOH radical scavenging activity of N-acetylcysteine amide (NACA) has been studied using density functional theory, specifically the M05-2X functional. All possible reaction sites have been considered, and the branching ratios have been estimated. The efficiency of different mechanisms of reaction has been evaluated, and it has been concluded that NACA reacts exclusively by hydrogen atom transfer (HAT). The overall reactivity of NACA toward OH radicals is proposed to be diffusion-controlled in both non-polar and polar media. The values of the overall rate coefficients are 3.80 × 109 and 1.36 × 109 L mol−1 s−1 for benzene and aqueous solutions, respectively. The reactivity of NACA toward ·OOH, on the other hand, is much lower but still higher than those of melatonin and caffeine. HAT from the –SH site is proposed to be the channel accounting for most of the radical scavenging activity of NACA in aqueous solution. In non-polar environments, two channels of reaction were found to similarly contribute to the overall reactivity of NACA toward OH radicals. They are those corresponding to hydrogen atom transfer from –CH2 and –SH sites.
Co-reporter:Marta E. Alberto, Nino Russo, Andre Grand and Annia Galano
Physical Chemistry Chemical Physics 2013 - vol. 15(Issue 13) pp:NaN4650-4650
Publication Date(Web):2013/01/31
DOI:10.1039/C3CP43319F
The free radical scavenging activity of Trolox was studied for aqueous and lipid environments using the Density Functional Theory. Several reaction mechanisms and free radicals of different chemical nature have been included in this study, as well as the influence of the pH. Trolox was found to be a powerful ˙OH and alkoxy scavenger, regardless of the conditions under which the reaction takes place. It was also found to be very efficient as a peroxy radical scavenger in aqueous solution, while its protective effects against this particular kind of free radicals are significantly reduced in lipid solution. Four reaction mechanisms were found to significantly contribute to the ˙OH scavenging activity of Trolox in aqueous solution: hydrogen transfer (HT), radical adduct formation (RAF), single electron transfer (SET), and sequential proton loss electron transfer (SPLET), while in lipid media two of them are relevant: HT and RAF. The ˙OCH3, ˙OOH, and ˙OOCHCH2 scavenging processes are predicted to take place almost exclusively by HT from the phenolic OH group in lipid media, and in aqueous solution at pH < 11, while at higher pH values the SPLET mechanism is proposed as the main one. This is also the case for other non-halogenated alkyl or alkenyl peroxy (and alkoxy) radicals. The agreement with the available experimental data supports the reliability of the presented calculations.
Co-reporter:Manuel E. Medina, Annia Galano and Juan Raúl Alvarez-Idaboy
Physical Chemistry Chemical Physics 2014 - vol. 16(Issue 3) pp:NaN1207-1207
Publication Date(Web):2013/10/25
DOI:10.1039/C3CP53889C
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.
Co-reporter:Annia Galano, Misaela Francisco-Márquez and J. Raúl Alvarez-Idaboy
Physical Chemistry Chemical Physics 2011 - vol. 13(Issue 23) pp:NaN11205-11205
Publication Date(Web):2011/05/13
DOI:10.1039/C1CP20722A
The OOH radical scavenging activity of sinapinic acid (HSA) has been studied in aqueous and lipid solutions, using the Density Functional Theory. HSA is predicted to react about 32.6 times faster in aqueous solution than in lipid media. The overall rate coefficients are predicted to be 5.39 × 105 and 1.66 × 104 M−1 s−1, respectively. Branching ratios for the different channels of reaction are also reported for the first time, as well as the UV-Vis spectra of the main products of reaction. It was found that the reactivity of sinapinic acid towards OOH radicals takes place almost exclusively by H atom transfer from its phenolic moiety. However it was found to react via SET, at diffusion-limit controlled rate constants, with ˙OH, ˙OCCl3 and ˙OOCCl3 radicals. It was found that the polarity of the environment and the deprotonation of HSA in aqueous solution, both increase the reactivity of this compound towards peroxyl radicals.
Co-reporter:Jorge Rafael León-Carmona, Juan Raúl Alvarez-Idaboy and Annia Galano
Physical Chemistry Chemical Physics 2012 - vol. 14(Issue 36) pp:NaN12543-12543
Publication Date(Web):2012/03/26
DOI:10.1039/C2CP40651A
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.
Co-reporter:Annia Galano and Juan Raúl Alvarez-Idaboy
Physical Chemistry Chemical Physics 2012 - vol. 14(Issue 36) pp:NaN12484-12484
Publication Date(Web):2012/04/30
DOI:10.1039/C2CP40799J
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.
