Comparison of Vitamin C and Its Derivative Antioxidant Activity: Evaluated by Using Density Functional Theory
- Yuyang LiuYuyang LiuDepartment of Orthopedics, Shengjing Hospital of China Medical University, Shenyang 110004, ChinaMore by Yuyang Liu
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- Chuanqun LiuChuanqun LiuSchool of Energy and Power Engineering, Northeast Electric Power University, Jilin 132000, ChinaMore by Chuanqun Liu
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- Jianjun Li*Jianjun Li*Email: [email protected]. Phone: +86-18940259895.Department of Orthopedics, Shengjing Hospital of China Medical University, Shenyang 110004, ChinaMore by Jianjun Li
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Abstract
Vitamin C (VC) is an essential antioxidant, but its application is limited because of its unstable chemical properties. Hence, a variety of VC derivatives have emerged in practical antioxidant applications. To explore the relationship between the antioxidant properties and the chemical structures of vitamin C and its derivatives, density functional theory (DFT) was used in this work to calculate the reaction enthalpies of the mechanisms related to radical scavenging activity. The structures were optimized at the B3LYP-D3(BJ)/6-31G* level of theory. Single point calculations (SPE) were performed at the PWPB95-D3 (BJ)/def2-QZVPP level. To estimate the solvent effect on antioxidant properties, the SMD (solvation model based on density) method was used. The results showed that in the process of optimizing the chemical structure of vitamin C, the antioxidant capacity of its derivatives decreased slightly in aqueous solvents. In the calculation process, it is also found that in the choice of antioxidant mechanism, these compounds are more inclined to the hydrogen atom transfer (HAT) mechanism, and from the chemical structure point of view, the double bond of the lactone ring is essential for its free radical scavenging activity. In general, it is necessary to continue to optimize the structure of VC to obtain derivatives with better oxidation resistance and more practical value.
Introduction
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Oxidative stress is one of the reasons for promoting the aging of the body and many diseases, and its mechanism is mostly related to the generation of reactive oxygen species (ROS). (1−5) The generation of ROS is due to the double radical nature of molecular oxygen, which makes it easy to accept electrons, thereby generating free radicals, such as hydroxyl radicals HO•, superoxide radical anions (O2•–), peroxyl radicals (ROO•), hydrogen peroxide (H2O2), and alkoxyl radicals (RO•), etc. (6) Substances that eliminate free radicals, also known as the antioxidant capacity of antioxidants, can slow the process of human aging and many diseases to a certain extent. (7) Therefore, exploring the antioxidant capacity of substances has been a hot topic. Vitamin C (VC), also known as ascorbic acid (AA), is one of the essential trace elements in the human body and considered to be the most effective water-soluble antioxidant. (8,9) It cannot be synthesized by the body and needs to be supplemented through diet or medicine. Due to their antioxidant capacity, VC and its derivatives have excellent performance in chemical and medical applications. They not only are active ingredients of whitening products but also show therapeutic effects in the treatment of many diseases, including cancer. (10−19)
There are many ways to compare the antioxidant capacity of antioxidants, but no matter what kind of method is used, the quenching of free radicals is a step that cannot be ignored. AA and its derivatives can certainly quench the free radicals produced by oxidative stress, (20,21) and the quenching process is mainly explained by the following three antioxidant mechanisms: (5,22−24) the hydrogen atom transfer (HAT) mechanism, the single electron transfer proton transfer (SET-PT) mechanism, and the sequential proton loss electron transfer (SPLET) mechanism. The antioxidant efficiency of these mechanisms can be represented by thermochemical parameters, including bond dissociation enthalpy (BDE), adiabatic ionization potential (IP), proton dissociation enthalpy (PDE), proton affinity (PA), and electron transfer enthalpy (ETE).
BDE is an important parameter for estimating antioxidant activity in the HAT mechanism. (5,25−27) IP and PDE represent the two-step process of the SET-PT mechanism. PA and ETE are used to study the SPLET mechanism, as shown in Scheme 1.
Scheme 1
Scheme 1. Antioxidant Reaction Mechanism and Corresponding Enthalpy Symbols of VC and Its Derivatives
Density functional theory (DFT) calculations are often used to analyze the chemical properties of biomolecules (including antioxidant capacity, intermolecular force, and enzyme catalytic ability). Based on the development of DFT computational chemistry in recent years, the current theoretical research results are often used to predict the oxidation resistance of substances, and the calculations related to the oxidation resistance of VC have also gradually deepened. (28−31) In practical applications, VC and its derivatives still have a variety of factual problems. (32−34) For example, the efficient dosage of VC in cancer treatment is very controversial, and related research shows that a low concentration of VC has a certain degree of pro-oxidation, while a high concentration will inhibit the free radical chain reaction. Therefore, a more in-depth exploration of VC and the improvement of its chemical structure to obtain more active and stable derivatives is also an increasingly important direction of study. Compared with its derivatives, such as ascorbyl 2-glucoside (AA2G), 3-o-ethyl-l-ascorbic acid (AAE), and ascorbyl 6-palmitate (AA6P), AA has poor molecular stability, (35−37) and their oxidation strength has not been compared by DFT calculations. Therefore, in this work, DFT calculations were used to evaluate the antioxidant capacity of vitamin C and its derivatives (Figure 1), and the theoretical comparison of antioxidant capacity was carried out to explore the change in the antioxidant capacity of vitamin C in the process of chemical structure optimization and the most probable antioxidant mechanism of these compounds.
Figure 1
Figure 1. Schematic structures of VC and its derivatives.
Results and Discussion
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To further understand the antioxidant properties of VC and its derivatives, we studied the mechanism of antioxidant activity based on thermodynamic parameters. The reactants and products of the three mechanisms of HAT, SET-PT, and SPLET are the same (Scheme 1), so they should have the same thermodynamic balance. The competition of the above mechanisms depends on the energy required for each of the key steps. Here, density functional theory is used at the B3LYP/6-31G* level (38) in combination with Grimme’s DFT-D3, (39) and the Becke–Johnson damping function (40) is used for dispersion correction. The ORCA program (41) used to optimize the conformation of vitamin C and its derivatives, and the accurate single-point energy calculation of the water and gas phases is done at the theoretical level of PWPB95-D3(BJ) (42)/def2-QZVPP. The most stable structures of VC and its three derivatives in the air (gas phase) and water (aqueous phase) (Figure 2) are used for the further calculation of thermodynamic parameters (BDE, IP, PDE, AP, and ETE).
Figure 2
Figure 2. Optimized structure of VC (a), AA2G (b), AAE (c), and AA6P (d) in the gas phase.
HAT Mechanism
The principal factor in the ability of antioxidants to scavenge free radicals is their chemical structure. VC and its derivatives (AA2G, AAE, and AA6P) have multiple hydroxyl groups, which is very important for their antioxidant properties. As is known to all, BDE is an important parameter related to the HAT mechanism. (26) The lower the BDE value, the lower the stability of the corresponding O–H bond, which indicates that the O–H bond is more accessible to break, that is, the smaller the BDE of the bond, the stronger the oxidation resistance of the substance.
As shown in Figure 3, in the gas phase, the BDE values of various substances are in the order AA6P < AA < AAE < AA2G, and in the aqueous phase, the order is AA < AAE < AA2G < AA6P. The comparison of BDE values between AA and AA6P is consistent with the experimental results of Amorati et al. (43) Therefore, in terms of the HAT mechanism in the gas or liquid phase, AA2G is relatively underprivileged in oxidation resistance, while AA has the highest oxidation resistance in the aqueous phase, and AA6P has the highest antioxidant potential in the gas phase. As shown in Table S1, the bond dissociation energy of the O–H bond of each substance under the gas phase condition is lower than the corresponding BDE in the liquid phase condition, apart from O7–H bond in the AA molecule, which in the water phase(308.9 kJ/mol) is lower than its BDE value in the gas phase (323.2 kJ/mol). That is to say, the water solvent can prevent VC and its derivatives from quenching free radicals through the HAT mechanism.
Figure 3
Figure 3. Comparison of bond dissociation enthalpies (BDEs) of VC and its derivatives.
A phenomenon is detected from the calculation results: the hydroxyl groups with the lowest BDE values of VC and its derivatives are all on the lactone ring, and the C atoms connected to these hydroxyl groups have a double bond structure. When the hydroxyl group on the lactone ring loses H atoms to form free radicals, the conjugated double bond provides a resonance environment for unpaired single electrons. Single electrons are delocalized on the lactone ring, enabling the stable structures of free radicals. (44) As shown in Figure 4, the spin population distribution of the free radicals formed by the cleavage of O8–H and O7–H bonds in AA molecules, unpaired single electrons, is mainly distributed on the lactone ring, especially on the hydroxyl group, the C atom that is bonded to the hydroxyl group, and the carbonyl group. The use of unrestricted open shells in the calculation will cause the α and β spin orbits to mismatch. The shapes of the two sets of orbits slightly deviate, and two spin states will appear even when the spin multiplicity is 2. As shown in Figure 4, the spin direction represented by blue is relatively weak, so it can be ignored. The singly occupied molecular orbital (SOMO) orbit contributes to all the spin populations.
Figure 4
Figure 4. Spin population distribution in the radical species of AA. (a, b) Spin population distribution of the radicals formed by the cleavage of O7–H bond in the gas phase and the water phase, respectively. (c, d) Spin population distribution of the radicals formed by the cleavage of O8–H bond in the gas phase and the water phase, respectively. Red and blue indicate two spins in different directions.
It is worth noting that AA and AA6P both have two hydroxyl groups on the lactone ring. The BDE value of AA6P’s O6–H bond is lower than that of O7–H, regardless of the water phase or gas phase conditions. The BDE values under gas and liquid phase conditions differed by 10.019 and 1.258 kJ/mol, respectively. The BDE value of O8–H in the AA molecule is also lower than that of O7–H in different phases. The difference is 7.11 kJ/mol in the water phase and 26.052 kJ/mol in the gas phase. It shows that under the liquid phase conditions, due to the polarization of water, it will reduce the difference between the BDE values of the two hydroxyl groups on the AA and AA6P lactone rings. The spin population (Figure 4) of AA–O7–H free radicals breaking in water is wider with better delocalization of single electrons; the spin population distribution on O7, O8, and C4 decreases, and the spin layout on O1, C2, C3, and O6 increases, inducing a lower BDE value of O7–H in aqueous simulated media. For the O8–H radical, the spin population does not show a large decrease in the value, but an increase in the small value, and the value becomes smaller for O6 and O8, resulting in a slight increase in BDE in water.
SET-PT Mechanism
IP and PDE values are the enthalpies of the reaction related to the SET-PT mechanism. In the mechanism of SET-PT, antioxidant transfer electrons form free radical cations, which subsequently cause their protonation or deprotonation. IP is the energy of cationic radicals minus the energy of neutral molecules, which can reflect the overall electron-donating ability of molecules. Its influencing factors mainly depend on the degree of conjugation of the system and the electronic effect of the substituent. The lower the IP value, the easier the electron transfer reaction proceeds, and the stronger the antioxidant activity of the substance. Therefore, IP can well represent the antioxidant activity of the substance in the mechanism of SET-PT.
As shown in Figure 5, the sequence of the IP values of various substances in the gas phase is AAE < AA6P < AA < AA2G, and in the water phase, it is AA < AAE < AA2G < AA6P. As far as the SET-PT mechanism is concerned, AA is more accessible to give electrons in polar solvents and has the strongest resistance to oxidation. Compared with gas, the IP value of VC and its derivatives in water is lowered by about 173–222 kJ/mol (Table S2). It shows that VC and its derivatives are more likely to lose electrons in the water phase.
Figure 5
Figure 5. Comparison of the adiabatic ionization potentials (IPs) of VC and its derivatives.
The calculated PDE values in polar solvents (water phase) (Table S3) are lower than the corresponding IP values (Table S2). Because the energy required for the deprotonation of radical cations (ROH•+) in polar solvents is greater than the energy required for the first step of SET-PT, the IP and PDE values of VC and its derivatives can be mutually verified. As shown in Figure 6, the sequence of the calculated PDE values in the gas phase is AAE < AA6P < AA < AA2G, and in the water phase, it is AA < AAE < AA2G < AA6P.
Figure 6
Figure 6. Comparison of the proton dissociation enthalpies (PDEs) of VC and its derivatives.
The antioxidation result of the SET-PT mechanism is obtained by the energy of two steps, that is, the result of the calculation by IP + PDE (shown in Figure 7). As shown in the above calculation results, irrespective of water or gas, the calculated IP value of each substance (575.0–826.7 kJ/mol) is higher than the corresponding BDE value (301.8–409.3 kJ/mol). Therefore, it is speculated thermodynamically that the SET-PT mechanism is less likely to occur than the HAT mechanism. Moreover, related research shows that the radical cation of VC is kinetically unstable, (29) which is relatively unfavorable for the mechanism of SET-PT. Of course, from theoretical calculations, the antioxidant capacity of VC derivatives is worse than that of VC in the SET-PT mechanism because the sum of the IP and PDE values of VC is the smallest (Figure 8).
Figure 7
Figure 7. Comparison of the sum of IP and PDE values for VC and its derivatives.
Figure 8
Figure 8. Comparison of the proton affinities (PAs) of VC and its derivatives.
SPLET Mechanism
The first step of the SPLET mechanism is the process of antioxidant deprotonation (generation of A–O−), which is often represented by the value of proton affinity (Table S4). The order of the PA values of VC and its derivatives (shown in Figure 8) is AA2G < AA < AA6P < AAE, which is the result in both the water phase and the gas phase.
It is worth noting that the proton affinity of the hydroxyl group (AA–O7–H and AA–O8–H) on the lactone ring of VC is higher than that of AA–O12–H and AA–O10–H, which is very different from the three derivatives of AA (AAE, AA2G, and AA6P). By comparing the initial structure of AA–O12–H and AA–O10–H proton loss and the final optimized structure (as shown in Figure 8), it was detected that when the proton transfer of O10–H and O12–H occurs, the conformation of AA changes greatly. When O10–H loses a proton, the proton on O12 is subsequently transferred to O10, and the proton on O8 is transferred to O12. The final stable conformation is actually that O8 loses a proton, and in this conformation, O10–H···O12 and O12–H···O8 form intramolecular hydrogen bonds, resulting in the fact that the conformation formed after the deprotonation of O10–H is more stable than that formed after the direct deprotonation of O8–H. Therefore, the Gibbs free energy of O10–H deprotonation is lower than that of O8–H deprotonation. Similarly, when O12–H loses a proton, it is also found that during the optimization process, the H on O8 is transferred to O12 and O12–H···O8 forms intramolecular hydrogen bonds. Here, by comparing the initial conformation, it can be found that O12–H and O10–H have the lowest energy to overcome the proton loss of O8, which means that the O atom of the double bond on the lactone ring is more chemically reactive. This result is similar to that of the HAT mechanism, suggesting that the double bond of lactone is very important for the antioxidant capacity of VC and its derivatives. Some experimental results also suggest that the antioxidant activity of AA2G comes from the lactone ring of VC rather than from glucose, which is consistent with the above results. (45)
A–O– is generated in the first step of SPLET, and the second step exhibits electron transfer. Electron transfer enthalpy is adopted to study the antioxidant efficiency of this step. The ETE values (shown in Table S5) of VC and its derivatives in the water phase are in the order (Figure 9) AA < AAE < AA6P < AA2G. Relatively speaking, the sequence in the gas phase is AAE < AA2G < AA < AA6P.
Figure 9
Figure 9. Comparison of the electron transfer enthalpies (ETEs) of VC and its derivatives.
Among these substances, AAE has a higher PA, but a relatively lower ETE. Therefore, from a thermodynamic point of view, the deprotonated form of AAE should be the best electron donor. The SPLET mechanism is the sum of the effects of PA and ETE, and owing to the SPLET process affected by environmental acidity and electron-withdrawing groups, the result of the comparison of the oxidation resistance of various substances in this aqueous phase is that VC has the best oxidation resistance. AAE is followed by AA6P, while AA2G is less resistant to oxidation.
As shown in Table S5, the ETE of each substance increases in the gas phase compared to the water solvent, indicating that the energy requirement for anion radicalization in the solvent increases. In addition to the O12 of VC, the consideration is because its position is far away from the lactone ring, and its PA value is much larger than the other spots of VC, but the total PA + ETE quantity (Figure 10) is relatively small, so in general, the solvent will make anionic radicals the demand for chemical energy has increased. Irrespective of gas or water, the ETE value of the reaction of each substance is less than the corresponding IP value, indicating that the ability of neutral molecules to extract electrons is less than that of anions.
Figure 10
Figure 10. Comparison of the sum of PA and ETE for VC and its derivatives.
From Table S6, it is observed that the total energy requirements of VC and its derivatives related to the HAT mechanism (BDE) are much lower than that of the SPLET mechanism (PA + ETE). Therefore, from the thermodynamic point of view, the antioxidant mechanism of VC and its derivatives is more inclined to hydrogen atom transfer.
Potential Energy Surfaces
To study the antioxidant effect of VC and its derivatives on HO• radical, we used the Fukui (46) function to predict the reaction site. As shown in Figure 11, the C═C double bond on the lactone ring and the O functional group on the hydroxyl group are the free radical attack sites. From the above calculation and comparison, it is speculated that the most likely antioxidant mechanism of VC and its derivatives is the HAT mechanism (because the BDE value is relatively small), and the sites that are more likely to react with free radicals are AA-O8, AA2G-O1, AAE-O5, and AA6P-O6, which are the hydroxyl groups with the lowest BDE values of VC and its derivatives. Therefore, to better explore the antioxidant capacity of these substances, we continue to calculate the reaction of these hydroxyl groups with HO• free radicals in aqueous simulated media.
Figure 11
Figure 11. Surface plot of the Fukui function of f0(r) of VC (a), AA2G (b), AAE (c), and AA6P (d).
The potential energy surface (PES) of the reaction of the above substances with the HO• group in water is displayed in Figure 12. It shows that VC is most likely to react with HO• groups (−109.237 kJ/mol) to form free radical adducts, indicating that VC has the advantage of free radical scavenging compared to its derivatives. However, from the calculation results of the transition state (TS), VC and its derivatives can easily eliminate the HO• group by the reaction because the energy of this process is not high (33.844–52.979 kJ/mol). AA needs to overcome the highest energy barrier of 162.216 kJ/mol to form H2O, so the process is kinetically unfavorable. But this barrier is calculated at room temperature and the body temperature is about 37 °C, which may help overcome it.
Figure 12
Figure 12. Potential energy surfaces (PES) of the reaction between VC and its derivatives with the HO• group in water.
Calculation Details
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Low-lying isomers are randomly generated using the Molclus program. (47) This program is designed to search for clusters and molecular conformations. Batch optimization was carried out under the GFN2-xTB of the xtb program package (48) combined with the implicit water model. Thus, hundreds of isomers are obtained for each molecule. Multiple most stable conformations are obtained, and then ORCA is used in B3LYP-D3(BJ)/6-31G* to reoptimize important conformations, followed by vibration analysis in the gas phase to verify whether it is a local minimum. The transition state (TS) has only one virtual frequency, and the transition state connecting reactants and products is determined by the intrinsic reaction coordinate (IRC). To obtain more reliable thermal correction of the Gibbs free energy, PWPB95-D3 (BJ)/def2-QZVPP was combined with the SMD model to perform the high-precision single-point energy (SPE) calculation for the most stable isomer obtained from each molecule optimization.
The calculation of the following reaction formula is carried out under the condition of T = 298.15 K using uncalibrated zero-point energy (ZPE) as the condition.
The HAT process is
BDE calculation method is
SET-PT is a two-step reaction, electron transfer followed by protonation of free radical cations, that is
The IP and PDE values represent the above two-step process and are evaluated by the following equations
Similar to SET-PT, the SPLET mechanism is also a two-step process. On the contrary, the SPLET mechanism first converts VC and its derivatives into anions and then transfers electrons to free radicals in the second step
PA and ETE here represent the energy information calculation method of two steps as follows
The enthalpies of H(H+) and H(e–) in the calculation process were 6.197 and 3.145 kJ/mol, respectively. (49) In the above equations, R•, A–OH, A–O•, A–OH•+, and A–O– represent free radicals; VC and its derivatives; and VC and its derivatives in the free radical form, cationic form, and anionic form, respectively.
(1)
(2)
(3)
(4)
(5)
(6)
(7)
(8)
(9)
(10)
Conclusions
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This theoretical calculation study shows that the oxidation resistance of the derivatives of VC (AA2G, AAE, and AA6P) decreases with the increase of molecular structure stability. By comparing BDE, IP, PDE, PA, and ETE, our results show that no matter what the mechanism (HAT, SET-PT, and SPLET) compares in the aqueous phase, VC has the highest antioxidant performance. The calculated results in the air environment deviate from this, suggesting that the solvent effect influences the antioxidant capacity of VC and its derivatives. We plan to continue to explore the effects of other solvents on the ability of VC and its derivatives to quench free radicals. The HAT mechanism seems to be the most likely mechanism of VC in its free radical scavenging effect. Compared with BDE values, the IP values in the SET-PT mechanism and the PA values in the SPLET mechanism are relatively higher, so it is speculated that the HAT mechanism described by the BDE value is more suitable than the SET-PT and SPLET mechanisms. The results also show that, in the process of quenching radicals, the most likely reaction sites of VC and its derivatives are on the double bond of lactone ring, whether by hydrogen atom transfer, electron transfer, or proton transfer.
Derivatives produced in the process of optimizing the chemical structure of vitamin C are more stable and soluble. This study implies that there is a partial loss of antioxidant properties of VC derivatives during this process. Therefore, it is particularly important to continue to optimize its chemical structure. In this paper, the calculation and comparison of antioxidant properties of VC and its derivatives wish to provide a new direction for the optimization of the chemical structure of simple vitamins such as VC.
Supporting Information
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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.0c04318.
Values of thermodynamic parameters related to the antioxidant mechanism of VC and its derivatives calculated in the water and gas phases at the B3LYP/6-31G* level; and optimized geometries of TS in the reaction between VC and its derivatives with OH• (PDF)
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Author Information
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- Yuyang Liu - Department of Orthopedics, Shengjing Hospital of China Medical University, Shenyang 110004, China;
http://orcid.org/0000-0003-3973-0177
Acknowledgments
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The authors are grateful for financial support from the National Natural Science Foundation of China (81972829), Shengjing Hospital of China Medical University, and Northeast Electric Power University.
References
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- 4Liguori, I.; Russo, G.; Curcio, F.; Bulli, G.; Aran, L.; Della-Morte, D.; Gargiulo, G.; Testa, G.; Cacciatore, F.; Bonaduce, D. Oxidative stress, aging, and diseases. Clin. Interventions Aging 2018, 13, 757, DOI: 10.2147/CIA.S158513[Crossref], [PubMed], [CAS], Google Scholar4https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtlCmtrrL&md5=d41718641bd2744185e1eeccd4758ccdOxidative stress, aging, and diseasesLiguori, Ilaria; Russo, Gennaro; Curcio, Francesco; Bulli, Giulia; Aran, Luisa; Della-Morte, David; Gargiulo, Gaetano; Testa, Gianluca; Cacciatore, Francesco; Bonaduce, Domenico; Abete, PasqualeClinical Interventions in Aging (2018), 13 (), 757-772CODEN: CIALBC; ISSN:1178-1998. (Dove Medical Press Ltd.)Reactive oxygen and nitrogen species (RONS) are produced by several endogenous and exogenous processes, and their neg. effects are neutralized by antioxidant defenses. Oxidative stress occurs from the imbalance between RONS prodn. and these antioxidant defenses. Aging is a process characterized by the progressive loss of tissue and organ function. The oxidative stress theory of aging is based on the hypothesis that age-assocd. functional losses are due to the accumulation of RONS-induced damages. At the same time, oxidative stress is involved in several age-related conditions (ie, cardiovascular diseases [CVDs], chronic obstructive pulmonary disease, chronic kidney disease, neurodegenerative diseases, and cancer), including sarcopenia and frailty. Different types of oxidative stress biomarkers have been identified and may provide important information about the efficacy of the treatment, guiding the selection of the most effective drugs/dose regimens for patients and, if particularly relevant from a pathophysiol. point of view, acting on a specific therapeutic target. Given the important role of oxidative stress in the pathogenesis of many clin. conditions and aging, antioxidant therapy could pos. affect the natural history of several diseases, but further investigation is needed to evaluate the real efficacy of these therapeutic interventions. The purpose of this paper is to provide a review of literature on this complex topic of ever increasing interest.
- 5Esfandi, R.; Walters, M. E.; Tsopmo, A. Antioxidant properties and potential mechanisms of hydrolyzed proteins and peptides from cereals. Heliyon 2019, 5, e01538 DOI: 10.1016/j.heliyon.2019.e01538
- 6Brand, M. D. The sites and topology of mitochondrial superoxide production. Exp. Gerontol. 2010, 45, 466– 472, DOI: 10.1016/j.exger.2010.01.003[Crossref], [PubMed], [CAS], Google Scholar6https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXmslGjt70%253D&md5=bdf5ea100a6ccb83d791d0f8b36ffa3aThe sites and topology of mitochondrial superoxide productionBrand, Martin D.Experimental Gerontology (2010), 45 (7-8), 466-472CODEN: EXGEAB; ISSN:0531-5565. (Elsevier)A review. Mitochondrial superoxide prodn. is an important source of reactive oxygen species in cells, and may cause or contribute to ageing and the diseases of ageing. Seven major sites of superoxide prodn. in mammalian mitochondria are known and widely accepted. In descending order of max. capacity they are the ubiquinone-binding sites in complex I (site IQ) and complex III (site IIIQo), glycerol 3-phosphate dehydrogenase, the flavin in complex I (site IF), the electron transferring flavoprotein:Q oxidoreductase (ETFQOR) of fatty acid beta-oxidn., and pyruvate and 2-oxoglutarate dehydrogenases. None of these sites is fully characterized and for some we only have sketchy information. The topol. of the sites is important because it dets. whether or not a site will produce superoxide in the mitochondrial matrix and be able to damage mitochondrial DNA. All sites produce superoxide in the matrix; site IIIQo and glycerol 3-phosphate dehydrogenase also produce superoxide to the intermembrane space. The relative contribution of each site to mitochondrial reactive oxygen species generation in the absence of electron transport inhibitors is unknown in isolated mitochondria, in cells or in vivo, and may vary considerably with species, tissue, substrate, energy demand and oxygen tension.
- 7Pan, Y.; Lin, Z. Anti-aging Effect of Ganoderma (Lingzhi) with Health and Fitness; Springer, 2019; Vol. 1182, pp 299– 309.
- 8Frei, B.; England, L.; Ames, B. N. Ascorbate is an outstanding antioxidant in human blood plasma. Proc. Natl. Acad. Sci. U.S.A. 1989, 86, 6377– 6381, DOI: 10.1073/pnas.86.16.6377[Crossref], [PubMed], [CAS], Google Scholar8https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL1MXltlWrsb4%253D&md5=9fc1ad7b2617d2673dae4cb9e9fb75baAscorbate is an outstanding antioxidant in human blood plasmaFrei, Balz; England, Laura; Ames, Bruce N.Proceedings of the National Academy of Sciences of the United States of America (1989), 86 (16), 6377-81CODEN: PNASA6; ISSN:0027-8424.The temporal order of antioxidant consumption in human blood plasma exposed to a const. flux of aq. peroxyl radicals is ascorbate = protein thiols > bilirubin > urate > α-tocopherol, and detectable lipid peroxidn. starts only after ascorbate has been consumed completely. Ascorbate completely protected plasma lipids against detectable peroxidative damage induced by aq. peroxyl radicals and ascorbate was the only plasma antioxidant that can do so. Plasma devoid of ascorbate, but no other endogenous antioxidant, was extremely vulnerable to oxidant stress and susceptible to peroxidative damage to lipids. The plasma protein's thiols, although they became oxidized immediately upon exposure to aq. peroxyl radicals, were inefficient radical scavengers and appeared to be consumed mainly by autoxidn. Ascorbate in the most effective aq.-phase antioxidant in human blood plasma and, in humans, ascorbate is a physiol. antioxidant of major importance for protection against diseases and degenerative processes caused by oxidant stress.
- 9Chen, Q.; Espey, M. G.; Sun, A. Y.; Lee, J.-H.; Krishna, M. C.; Shacter, E.; Choyke, P. L.; Pooput, C.; Kirk, K. L.; Buettner, G. R. Ascorbate in pharmacologic concentrations selectively generates ascorbate radical and hydrogen peroxide in extracellular fluid in vivo. Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 8749– 8754, DOI: 10.1073/pnas.0702854104[Crossref], [PubMed], [CAS], Google Scholar9https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXmt1aktbo%253D&md5=07ab8305b9c3e577515ede9cbb1f5d6fAscorbate in pharmacologic concentrations selectively generates ascorbate radical and hydrogen peroxide in extracellular fluid in vivoChen, Qi; Espey, Michael Graham; Sun, Andrew Y.; Lee, Je-Hyuk; Krishna, Murali C.; Shacter, Emily; Choyke, Peter L.; Pooput, Chaya; Kirk, Kenneth L.; Buettner, Garry R.; Levine, MarkProceedings of the National Academy of Sciences of the United States of America (2007), 104 (21), 8749-8754CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Ascorbate (ascorbic acid, vitamin C), in pharmacol. concns. easily achieved in humans by i.v. administration, selectively kills some cancer cells but not normal cells. We proposed that pharmacol. ascorbate is a prodrug for preferential steady-state formation of ascorbate radical (Asc•-) and H2O2 in the extracellular space compared with blood. Here we test this hypothesis in vivo. Rats were administered parenteral (i.v. or i.p.) or oral ascorbate in typical human pharmacol. doses (≈0.25-0.5 mg per g of body wt.). After i.v. injection, ascorbate baseline concns. of 50-100 μM in blood and extracellular fluid increased to peaks of >8 mM. After i.p. injection, peaks approached 3 mM in both fluids. By gavage, the same doses produced ascorbate concns. of <150 μM in both fluids. In blood, Asc•- concns. measured by EPR were undetectable with oral administration and always <50 nM with parenteral administration, even when corresponding ascorbate concns. were >8 mM. After parenteral dosing, Asc•- concns. in extracellular fluid were 4- to 12-fold higher than those in blood, were as high as 250 nM, and were a function of ascorbate concns. By using the synthesized probe peroxyxanthone, H2O2 in extracellular fluid was detected only after parenteral administration of ascorbate and when Asc•- concns. in extracellular fluid exceeded 100 nM. The data show that pharmacol. ascorbate is a prodrug for preferential steady-state formation of Asc•- and H2O2 in the extracellular space but not blood. These data provide a foundation for pursuing pharmacol. ascorbate as a prooxidant therapeutic agent in cancer and infections.
- 10Elmore, A. R. Final report of the safety assessment of L-Ascorbic Acid, Calcium Ascorbate, Magnesium Ascorbate, Magnesium Ascorbyl Phosphate, Sodium Ascorbate, and Sodium Ascorbyl Phosphate as used in cosmetics. Int. J. Toxicol. 2005, 24, 51– 111, DOI: 10.1080/10915810590953851[Crossref], [PubMed], [CAS], Google Scholar10https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2Mrit1Gjsw%253D%253D&md5=64c3eb96fd44600d0075ea8350fb0d4eFinal report of the safety assessment of L-Ascorbic Acid, Calcium Ascorbate, Magnesium Ascorbate, Magnesium Ascorbyl Phosphate, Sodium Ascorbate, and Sodium Ascorbyl Phosphate as used in cosmeticsElmore Amy RInternational journal of toxicology (2005), 24 Suppl 2 (), 51-111 ISSN:1091-5818.L-Ascorbic Acid, Calcium Ascorbate, Magnesium Ascorbate, Magnesium Ascorbyl Phosphate, Sodium Ascorbate, and Sodium Ascorbyl Phosphate function in cosmetic formulations primarily as antioxidants. Ascorbic Acid is commonly called Vitamin C. Ascorbic Acid is used as an antioxidant and pH adjuster in a large variety of cosmetic formulations, over 3/4 of which were hair dyes and colors at concentrations between 0.3% and 0.6%. For other uses, the reported concentrations were either very low (<0.01%) or in the 5% to 10% range. Calcium Ascorbate and Magnesium Ascorbate are described as antioxidants and skin conditioning agents--miscellaneous for use in cosmetics, but are not currently used. Sodium Ascorbyl Phosphate functions as an antioxidant in cosmetic products and is used at concentrations ranging from 0.01% to 3%. Magnesium Ascorbyl Phosphate functions as an antioxidant in cosmetics and was reported being used at concentrations from 0.001% to 3%. Sodium Ascorbate also functions as an antioxidant in cosmetics at concentrations from 0.0003% to 0.3%. Related ingredients (Ascorbyl Palmitate, Ascorbyl Dipalmitate, Ascorbyl Stearate, Erythorbic Acid, and Sodium Erythorbate) have been previously reviewed by the Cosmetic Ingredient Review (CIR) Expert Panel and found "to be safe for use as cosmetic ingredients in the present practices of good use." Ascorbic Acid is a generally recognized as safe (GRAS) substance for use as a chemical preservative in foods and as a nutrient and/or dietary supplement. Calcium Ascorbate and Sodium Ascorbate are listed as GRAS substances for use as chemical preservatives. L-Ascorbic Acid is readily and reversibly oxidized to L-dehydroascorbic acid and both forms exist in equilibrium in the body. Permeation rates of Ascorbic Acid through whole and stripped mouse skin were 3.43 +/- 0.74 microg/cm(2)/h and 33.2 +/- 5.2 microg/cm(2)/h. Acute oral and parenteral studies in mice, rats, rabbits, guinea pigs, dogs, and cats demonstrated little toxicity. Ascorbic Acid and Sodium Ascorbate acted as a nitrosation inhibitor in several food and cosmetic product studies. No compound-related clinical signs or gross or microscopic pathological effects were observed in either mice, rats, or guinea pigs in short-term studies. Male guinea pigs fed a control basal diet and given up to 250 mg Ascorbic Acid orally for 20 weeks had similar hemoglobin, blood glucose, serum iron, liver iron, and liver glycogen levels compared to control values. Male and female F344/N rats and B6C3F(1) mice were fed diets containing up to 100,000 ppm Ascorbic Acid for 13 weeks with little toxicity. Chronic Ascorbic Acid feeding studies showed toxic effects at dosages above 25 mg/kg body weight (bw) in rats and guinea pigs. Groups of male and female rats given daily doses up to 2000 mg/kg bw Ascorbic Acid for 2 years had no macro- or microscopically detectable toxic lesions. Mice given Ascorbic Acid subcutaneous and intravenous daily doses (500 to 1000 mg/kg bw) for 7 days had no changes in appetite, weight gain, and general behavior; and histological examination of various organs showed no changes. Ascorbic Acid was a photoprotectant when applied to mice and pig skin before exposure to ultraviolet (UV) radiation. The inhibition of UV-induced suppression of contact hypersensitivity was also noted. Magnesium Ascorbyl Phosphate administration immediately after exposure in hairless mice significantly delayed skin tumor formation and hyperplasia induced by chronic exposure to UV radiation. Pregnant mice and rats were given daily oral doses of Ascorbic Acid up to 1000 mg/kg bw with no indications of adult-toxic, teratogenic, or fetotoxic effects. Ascorbic Acid and Sodium Ascorbate were not genotoxic in several bacterial and mammalian test systems, consistent with the antioxidant properties of these chemicals. In the presence of certain enzyme systems or metal ions, evidence of genotoxicity was seen. The National Toxicology Program (NTP) conducted a 2-year oral carcinogenesis bioassay of Ascorbic Acid (25,000 and 50,000 ppm) in F344/N rats and B6C3F(1) mice. Ascorbic Acid was not carcinogenic in either sex of both rats and mice. Inhibition of carcinogenesis and tumor growth related to Ascorbic Acid's antioxidant properties has been reported. Sodium Ascorbate has been shown to promote the development of urinary carcinomas in two-stage carcinogenesis studies. Dermal application of Ascorbic Acid to patients with radiation dermatitis and burn victims had no adverse effects. Ascorbic Acid was a photoprotectant in clinical human UV studies at doses well above the minimal erythema dose (MED). An opaque cream containing 5% Ascorbic Acid did not induce dermal sensitization in 103 human subjects. A product containing 10% Ascorbic Acid was nonirritant in a 4-day minicumulative patch assay on human skin and a facial treatment containing 10% Ascorbic Acid was not a contact sensitizer in a maximization assay on 26 humans. Because of the structural and functional similarities of these ingredients, the Panel believes that the data on one ingredient can be extrapolated to all of them. The Expert Panel attributed the finding that Ascorbic Acid was genotoxic in these few assay systems due to the presence of other chemicals, e.g., metals, or certain enzyme systems, which effectively convert Ascorbic Acid's antioxidant action to that of a pro-oxidant. When Ascorbic Acid acts as an antioxidant, the Panel concluded that Ascorbic Acid is not genotoxic. Supporting this view were the carcinogenicity studies conducted by the NTP, which demonstrated no evidence of carcinogenicity. Ascorbic Acid was found to effectively inhibit nitrosamine yield in several test systems. The Panel did review studies in which Sodium Ascorbate acted as a tumor promoter in animals. These results were considered to be related to the concentration of sodium ions and the pH of urine in the test animals. Similar effects were seen with sodium bicarbonate. Because of the concern that certain metal ions may combine with these ingredients to produce pro-oxidant activity, the Panel cautioned formulators to be certain that these ingredients are acting as antioxidants in cosmetic formulations. The Panel believed that the clinical experience in which Ascorbic Acid was used on damaged skin with no adverse effects and the repeat-insult patch test (RIPT) using 5% Ascorbic Acid with negative results supports the finding that this group of ingredients does not present a risk of skin sensitization. These data coupled with an absence of reports in the clinical literature of Ascorbic Acid sensitization strongly support the safety of these ingredients.
- 11Mohamed, R.; Tarannum, S.; Yariswamy, M.; Vivek, H. K.; Siddesha, J. M.; Angaswamy, N.; Vishwanath, B. S. Ascorbic acid 6-palmitate: a potent inhibitor of human and soybean lipoxygenase-dependent lipid peroxidation. J. Pharm. Pharmacol. 2014, 66, 769– 778, DOI: 10.1111/jphp.12200[Crossref], [PubMed], [CAS], Google Scholar11https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXns1Sru7k%253D&md5=c9c3f943899899ce9e8096f0aa511e49Ascorbic acid 6-palmitate: a potent inhibitor of human and soybean lipoxygenase-dependent lipid peroxidationMohamed, Riyaz; Tarannum, Shaista; Yariswamy, Manjunath; Vivek, Hamse K.; Siddesha, Jalahalli M.; Angaswamy, Nataraju; Vishwanath, Bannikuppe S.Journal of Pharmacy and Pharmacology (2014), 66 (6), 769-778CODEN: JPPMAB; ISSN:0022-3573. (John Wiley & Sons Ltd.)Lipoxygenases (LOX) are the key enzymes involved in the biosynthesis of leukotrienes and reactive oxygen species, which are implicated in pathophysiol. of inflammatory disorders. This study was conducted to evaluate the inhibitory effect of water-sol. antioxidant ascorbic acid and its lipophilic deriv., ascorbic acid 6-palmitate (Vcpal) on polymorphonuclear lymphocyte 5-LOX and soybean 15-LOX (sLOX) in vitro. LOX activity was detd. by measuring the end products, 5-hydroperoxy eicosatetraenoic acid (5-HETE) and lipid hydroperoxides, by spectrophotometric and high performance liq. chromatog. methods. The substrate-dependent enzyme kinetics and docking studies were carried out to understand the nature of inhibition. Vcpal potently inhibited 5-LOX when compared with its inhibitory effect on sLOX (IC50; 2.5 and 10.3 μm resp.). Further, Vcpal inhibited 5-LOX more strongly than the known synthetic drugs: phenidone and nordihydroguaiaretic acid. Enzyme kinetic studies demonstrated Vcpal as a non-competitive reversible inhibitor of 5-LOX. In-silico mol. docking revealed high MolDock and Rerank score for Vcpal than ascorbic acid, complementing in-vitro results. Both in-vitro and docking studies demonstrated Vcpal but not ascorbic acid as a non-competitive inhibitor of 5-LOX- and sLOX-induced lipid peroxidn., suggesting a key role for lipophilic nature in bringing about inhibition.
- 12Amirlak, B.; Mahedia, M.; Shah, N. A clinical evaluation of efficacy and safety of hyaluronan sponge with vitamin C versus placebo for scar reduction. Plast. Reconstr. Surg. Glob. Open 2016, 4 (7), e792 DOI: 10.1097/GOX.0000000000000734
- 13Hill, A.; Wendt, S.; Benstoem, C.; Neubauer, C.; Meybohm, P.; Langlois, P.; Adhikari, N. K.; Heyland, D. K.; Stoppe, C. Vitamin C to improve organ dysfunction in cardiac surgery patientsreview and pragmatic approach. Nutrients 2018, 10, 974, DOI: 10.3390/nu10080974[Crossref], [CAS], Google Scholar13https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXisFKmt7vN&md5=1c7175759721cbf7271c6f65eb58c91eVitamin C to improve organ dysfunction in cardiac surgery patients-review and pragmatic approachHill, Aileen; Wendt, Sebastian; Benstoem, Carina; Neubauer, Christina; Meybohm, Patrick; Langlois, Pascal; Adhikari, Neill K. J.; Heyl, Daren K.; Stoppe, ChristianNutrients (2018), 10 (8), 974/1-974/29CODEN: NUTRHU; ISSN:2072-6643. (MDPI AG)A review. The pleiotropic biochem. and antioxidant functions of vitamin C have sparked recent interest in its application in intensive care. Vitamin C protects important organ systems (cardiovascular, neurol. and renal systems) during inflammation and oxidative stress. It also influences coagulation and inflammation; its application might prevent organ damage. The current evidence of vitamin C's effect on pathophysiol. reactions during various acute stress events (such as sepsis, shock, trauma, burn and ischemia-reperfusion injury) questions whether the application of vitamin Cmight be esp. beneficial for cardiac surgery patientswho are routinely exposed to ischemia/reperfusion and subsequent inflammation, systematically affecting different organ systems. This review covers current knowledge about the role of vitamin C in cardiac surgery patients with focus on its influence on organ dysfunctions. The relationships between vitamin C and clin. health outcomes are reviewed with special emphasis on its application in cardiac surgery. Addnl., this review pragmatically discusses evidence on the administration of vitamin C in every day clin. practice, tackling the issues of safety,monitoring, dosage, and appropriate application strategy.
- 14Nauman, G.; Gray, J. C.; Parkinson, R.; Levine, M.; Paller, C. J. Systematic review of intravenous ascorbate in cancer clinical trials. Antioxidants 2018, 7, 89, DOI: 10.3390/antiox7070089[Crossref], [CAS], Google Scholar14https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhvFGhtLzI&md5=a30c975f696436d1b75751b23c314178Systematic review of intravenous ascorbate in cancer clinical trialsNauman, Gina; Gray, Javaughn Corey; Parkinson, Rose; Levine, Mark; Paller, Channing J.Antioxidants (2018), 7 (7), 89/1-89/22CODEN: ANTIGE; ISSN:2076-3921. (MDPI AG)A review. Background: Ascorbate (vitamin C) has been evaluated as a potential treatment for cancer as an independent agent and in combination with std. chemotherapies. This review assesses the evidence for safety and clin. effectiveness of i.v. (IV) ascorbate in treating various types of cancer. Methods: Single arm and randomized Phase I/II trials were included in this review. The PubMed, MEDLINE, and Cochrane databases were searched. Results were screened by three of the authors (GN, RP, and CJP) to det. if they met inclusion criteria, and then summarized using a narrative approach. Results: A total of 23 trials involving 385 patients met the inclusion criteria. Only one trial, in ovarian cancer, randomized patients to receive vitamin C or std. of care (chemotherapy). That trial reported an 8.75 mo increase in progression-free survival (PFS) and an improved trend in overall survival (OS) in the vitamin C treated arm. Conclusion: Overall, vitamin C has been shown to be safe in nearly all patient populations, alone and in combination with chemotherapies. The promising results support the need for randomized placebo-controlled trials such as the ongoing placebo-controlled trials of vitamin C and chemotherapy in prostate cancer.
- 15Taira, N.; Katsuyama, Y.; Yoshioka, M.; Muraoka, O.; Morikawa, T. Structural requirements of alkylglyceryl-L-ascorbic acid derivatives for melanogenesis inhibitory activity. Int. J. Mol. Sci. 2018, 19, 1144, DOI: 10.3390/ijms19041144[Crossref], [CAS], Google Scholar15https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXisVOqurfK&md5=de1be49d36505658c02db86c8031d534Structural requirements of alkylglyceryl-L-ascorbic acid derivatives for melanogenesis inhibitory activityTaira, Norihisa; Katsuyama, Yushi; Yoshioka, Masato; Muraoka, Osamu; Morikawa, ToshioInternational Journal of Molecular Sciences (2018), 19 (4), 1144/1-1144/22CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)L-Ascorbic acid has multifunctional benefits on skin aesthetics, including inhibition of melanin prodn., and is widely used in cosmetics. It, however, has low stability and poor skin penetration. We hypothesize that alkylglyceryl-L-ascorbic acid derivs., highly stable vitamin C-alkylglycerol conjugates, would have similar anti-melanogenic activity with better stability and penetration. We test 28 alkylglyceryl-L-ascorbic acid derivs. (1-28) on theophylline-stimulated B16 melanoma 4A5 cells to det. if they inhibit melanogenesis and establish any structure-function relationships. Although not the most potent inhibitors, 3-O-(2,3-dihydroxypropyl)-2-O-hexyl-L-ascorbic acid (6, IC50 = 81.4μM) and 2-O-(2,3-dihydroxypropyl)-3-O-hexyl-L-ascorbic acid (20, IC50 = 117μM) are deemed the best candidate derivs. based on their inhibitory activities and low toxicities. These derivs. are also found to be more stable than L-ascorbic acid and to have favorable characteristics for skin penetration. The following structural requirements for inhibitory activity of alkylglyceryl-L-ascorbic acid derivs. are also detd.: (i) alkylation of glyceryl-L-ascorbic acid is essential for inhibitory activity; (ii) the 3-O-alkyl-derivs. (2-14) exhibit stronger inhibitory activity than the corresponding 2-O-alkyl-derivs. (16-28); and (iii) derivs. with longer alkyl chains have stronger inhibitory activities. Mechanistically, our studies suggest that L-ascorbic acid derivs. exert their effects by suppressing the mRNA expression of tyrosinase and tyrosine-related protein-1.
- 16Isola, G.; Polizzi, A.; Muraglie, S.; Leonardi, R.; Lo Giudice, A. Assessment of vitamin C and antioxidant profiles in saliva and serum in patients with periodontitis and ischemic heart disease. Nutrients 2019, 11, 2956, DOI: 10.3390/nu11122956
- 17Meščić Macan, A.; Gazivoda Kraljević, T.; Raić-Malić, S. Therapeutic perspective of vitamin C and its derivatives. Antioxidants 2019, 8, 247, DOI: 10.3390/antiox8080247
- 18Miao, F.; Su, M.-Y.; Jiang, S.; Luo, L.-F.; Shi, Y.; Lei, T.-C. Intramelanocytic acidification plays a role in the antimelanogenic and antioxidative properties of vitamin C and its derivatives. Oxid. Med. Cell. Longevity 2019, 2019, 1– 14, DOI: 10.1155/2019/2084805
- 19Maekawa, T.; Uchida, T.; Nakata-Horiuchi, Y.; Kobayashi, H.; Kawauchi, S.; Kinoshita, M.; Saitoh, D.; Sato, S. Oral ascorbic acid 2-glucoside prevents coordination disorder induced via laser-induced shock waves in rat brain. PLoS One 2020, 15, e0230774 DOI: 10.1371/journal.pone.0230774[Crossref], [PubMed], [CAS], Google Scholar19https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXnvVGnsrw%253D&md5=a3a5ce53948182c6281724d42049d059Oral ascorbic acid 2-glucoside prevents coordination disorder induced via laser-induced shock waves in rat brainMaekawa, Takaaki; Uchida, Takahiro; Nakata-Horiuchi, Yuka; Kobayashi, Hiroaki; Kawauchi, Satoko; Kinoshita, Manabu; Saitoh, Daizoh; Sato, ShunichiPLoS One (2020), 15 (4), e0230774CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)Oxidative stress is considered to be involved in the pathogenesis of primary blast-related traumatic brain injury (bTBI). We evaluated the effects of ascorbic acid 2-glucoside (AA2G), a well-known antioxidant, to control oxidative stress in rat brain exposed to laser-induced shock waves (LISWs). The design consisted of a controlled animal study using male 10-wk-old Sprague-Dawley rats. The study was conducted at the University research lab. Low-impulse (54 Pa•s) LISWs were transcranially applied to rat brain. Rats were randomized to control group (anesthesia and head shaving, n = 10), LISW group (anesthesia, head shaving and LISW application, n = 10) or LISW + post AA2G group (AA2G administration after LISW application, n = 10) in the first study. In another study, rats were randomized to control group (n = 10), LISW group (n = 10) or LISW + pre and post AA2G group (AA2G administration before and after LISW application, n = 10). The measured outcomes were as follows: (i) motor function assessed by accelerating rotarod test; (ii) levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG), an oxidative stress marker; (iii) ascorbic acid in each group of rats. Ascorbic acid levels were significantly decreased and 8-OHdG levels were significantly increased in the cerebellum of the LISW group. Motor coordination disorder was also obsd. in the group. Prophylactic AA2G administration significantly increased the ascorbic acid levels, reduced oxidative stress and mitigated the motor dysfunction. In contrast, the effects of therapeutic AA2G administration alone were limited. The results suggest that the prophylactic administration of ascorbic acid can reduce shock wave-related oxidative stress and prevented motor dysfunction in rats.
- 20Gašperlin, M.; Gosenca, M. Main approaches for delivering antioxidant vitamins through the skin to prevent skin ageing. Expert Opin. Drug Delivery 2011, 8, 905– 919, DOI: 10.1517/17425247.2011.581657[Crossref], [PubMed], [CAS], Google Scholar20https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3MngvVWjsw%253D%253D&md5=c9bb3ac0d877a86dae48f79a120f8d54Main approaches for delivering antioxidant vitamins through the skin to prevent skin ageingGasperlin Mirjana; Gosenca MirjamExpert opinion on drug delivery (2011), 8 (7), 905-19 ISSN:.INTRODUCTION: One of the major contributions to skin photoageing and diseases is oxidative stress, caused by UV radiation inducing reactive oxygen and nitrogen species. Successful prophylaxis and therapy would necessitate control of the oxidant/antioxidant balance at the affected site, which can be achieved through the external supply of endogenous antioxidants. AREAS COVERED: This review discusses possible strategies for dermal delivery of the antioxidant vitamins E and C, as oral supplementation has proved insufficient. These antioxidants have low skin bioavailability, owing to their poor solubility, inefficient skin permeability, or instability during storage. These drawbacks can be overcome by various approaches, such as chemical modification of the vitamins and the use of new colloidal drug delivery systems. New knowledge is included about the importance of: enhancing the endogenous skin antioxidant defense through external supply; the balance between various skin antioxidants; factors that can improve the skin bioavailability of antioxidants; and new delivery systems, such as microemulsions, used to deliver vitamins C and E into the skin simultaneously. EXPERT OPINION: A promising strategy for enhancing skin protection from oxidative stress is to support the endogenous antioxidant system, with antioxidants containing products that are normally present in the skin.
- 21Yim, S.; Lee, J.; Jo, H.; Scholten, J.; Willingham, R.; Nicoll, J.; Baswan, S. M. Chrysanthemum morifolium extract and Ascorbic Acid-2-Glucoside (AA2G) blend inhibits UVA-induced delayed cyclobutane pyrimidine dimer (CPD) production in melanocytes. Clin., Cosmet. Invest. Dermatol. 2019, 12, 823, DOI: 10.2147/CCID.S223802[Crossref], [PubMed], [CAS], Google Scholar21https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXns1Gitbk%253D&md5=a41c0709afdd3619c5cb7de1af997a97Chrysanthemum Morifolium extract and Ascorbic Acid-2-Glucoside (AA2G) blend inhibits UVA-induced delayed cyclobutane pyrimidine dimer (CPD) Production In MelanocytesYim, Sunghan; Lee, Jeesun; Jo, Hae; Scholten, Jeff; Willingham, Ryan; Nicoll, Jim; Baswan, Sudhir M.Clinical, Cosmetic and Investigational Dermatology (2019), 12 (), 823-832CODEN: CCIDCL; ISSN:1178-7015. (Dove Medical Press Ltd.)Background: Solar UV radiation (UV) induces DNA damages in skin via direct absorption of UVB or indirectly by photosensitization mediated through UVA. Recent findings have revealed that UVA induces cyclobutane pyrimidine dimer (CPD) generation via chemiexcitation in melanocytes hours after the exposure. This UVA-induced delayed CPD (dark CPD) constitutes the majority of CPD in melanocytes. These findings indicate that sun light can damage the skin hours after the exposure, suggesting the need for skin care products post sun exposure. The main objective of this study was to investigate whether a blend of Chrysanthemum Morifolium flower ext. (Chrys) and vitamin C deriv., Ascorbic Acid-2-Glucoside (AA2G), can provide protective effects against reactive oxygen species, melanin formation and UVA-induced dark CPD. Methods: Intracellular ROS levels were measured in epidermal keratinocytes using DHR123 dye. Melanogenesis inhibition efficacy was detd. using B16 cells. As for the dark CPD measurement, Melan-a cells were treated with or without actives for 6 days, then irradiated with UVA at various doses. Cells were exposed with anti-CPD mAb followed by secondary Ab. CPD levels were detd. by measuring fluorescent intensity using a high content imaging anal. Results: Chrys, AA2G and their blend at various concns. demonstrated ROS scavenging activity. Though Chrys alone did not show significant melanogenesis inhibition in B16 assay, the blend of Chrys with AA2G demonstrated additive effects in comparison with AA2G alone. The blend of AA2G and Chrys at various concns. exhibited enhanced efficacy for inhibiting dark CPD compared to AA2G alone. Conclusion: The results from this study indicate that the use of natural antioxidant, Chrys in combination with AA2G, provides protection against UVA-induced delayed CPD formation by enhancing ROS scavenging activity and melanogenesis inhibition. These findings could potentially be applied for formulating post-sun exposure skin care products, possibly extending to evening-after care products.
- 22Pandithavidana, D. R.; Jayawardana, S. B. Comparative Study of Antioxidant Potential of Selected Dietary Vitamins; Computational Insights. Molecules 2019, 24, 1646, DOI: 10.3390/molecules24091646[Crossref], [CAS], Google Scholar22https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtF2jtLnI&md5=e6f1b3bf185104529e1bed5c3543fcd0Comparative study of antioxidant potential of selected dietary vitamins; computational insightsPandithavidana, Dinesh R.; Jayawardana, Samith B.Molecules (2019), 24 (9), 1646CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)D. functional theory (DFT) was used to explore the antioxidant properties of some naturally occurring dietary vitamins, and the reaction enthalpies related to various mechanisms of primary antioxidant action, i.e., hydrogen atom transfer, single electron transfer-proton transfer, and sequential proton loss-electron transfer were discussed in detail. B3LYP, M05-2X, and M06-2X functionals were utilized in this work. For aq. phase studies, the integral equation formalism polarized continuum model (IEF-PCM) was employed. From the outcomes, hydrogen atom transfer (HAT) was the most probable mechanism for the antioxidant action of this class of compds. Comparison of found results with exptl. data (available in literature), vitamin C possesses the lowest enthalpy values for both proton affinity (PA) and bond dissocn. energy (BDE)in the aq. phase, suggesting it as the most promising candidate as an antioxidant. Accordingly, these computational insights encourage the design of structurally novel, simple vitamins which will be more economical and beneficial in the pharmaceutical industry.
- 23Yamabe, S.; Tsuchida, N.; Yamazaki, S.; Sakaki, S. Frontier orbitals and transition states in the oxidation and degradation of l-ascorbic acid: a DFT study. Org. Biomol. Chem 2015, 13, 4002– 4015, DOI: 10.1039/C5OB00035A[Crossref], [PubMed], [CAS], Google Scholar23https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXjtVels74%253D&md5=bfc1f40f08d96be53563f78e4509085fFrontier orbitals and transition states in the oxidation and degradation of L-ascorbic acid: a DFT studyYamabe, Shinichi; Tsuchida, Noriko; Yamazaki, Shoko; Sakaki, ShigeyoshiOrganic & Biomolecular Chemistry (2015), 13 (13), 4002-4015CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)DFT calcns. were carried out to investigate reaction paths of L-ascorbic acid (AAH2), hydroxyl radicals and water clusters. Frontier-orbital analyses were also performed to examine the regioselectivity of the OH· addn. Transition states of the electrolytic dissocn. of AAH2 and intermediate carboxylic acids were found to have very small activation energies through proton transfers along hydrogen bonds. The ionized species (anions) are subject to the electrophilic attack of OH·. The elementary processes of AAH2 → A·- → dehydroascorbic acid → diketogulonic acid → threonic, oxalic, xylonic and lyxonic acids were investigated and discussed. The processes involved in the conversion of dehydroascorbic acid into a bicyclic hemiketal were also examd. as a side-chain participating reaction. The oxidn. and degrdn. of vitamin C up to threonic acid were described mainly as a donor (AAH2)-acceptor (OH·) reaction.
- 24Kumar, V.; Kishor, S.; Ramaniah, L. M. Understanding the antioxidant behavior of some vitamin molecules: a first-principles density functional approach. J. Mol. Model. 2013, 19, 3175– 3186, DOI: 10.1007/s00894-013-1836-6[Crossref], [PubMed], [CAS], Google Scholar24https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtFCru7jL&md5=6390909254b0a2869bcf20db32224aa4Understanding the antioxidant behavior of some vitamin molecules: a first-principles density functional approachKumar, Vipin; Kishor, Shyam; Ramaniah, Lavanya M.Journal of Molecular Modeling (2013), 19 (8), 3175-3186CODEN: JMMOFK; ISSN:0948-5023. (Springer)The structures, energetics, vertical and adiabatic ionization potentials, electron affinities, and global reactivity descriptors of antioxidant vitamins (both water- and fat-sol.) in neutral, pos. charged, and neg. charged states were studied theor. The authors worked within the framework of first-principles d. functional theory (DFT), using the B3LYP functional and both localized (6-311G+(d,p)) and plane-wave basis sets. Solvent effects were modeled via the polarizable continuum model (PCM), using the integral equation formalism variant (IEFPCM). From the computed structural parameters, ionization potentials, electron affinities, and spin densities, these vitamins prefer to lose electrons to neutral reactive oxygen species (·OH and ·OOH), making them good antioxidants. Conceptual DFT was used to det. global chem. reactivity parameters. The computed chem. hardnesses showed that these antioxidant vitamins are more reactive than neutral reactive oxygen species (ROS), thus supporting their antioxidant character towards these species. However, in the neutral state, these vitamins do not act as antioxidants for O-2. The reactivity of vitamins towards ROS depends on the nature of the solvent. Amongst the ROS, ·OH has the greatest propensity to attract electrons from a generic donor. The reactivities of fat-sol. vitamins towards neutral reactive oxygen species are larger than those of water-sol. vitamins towards these species, showing that the former are better antioxidants.
- 25Vo, Q. V.; Nam, P. C.; Van Bay, M.; Thong, N. M.; Cuong, N. D.; Mechler, A. Density functional theory study of the role of benzylic hydrogen atoms in the antioxidant properties of lignans. Sci. Rep. 2018, 8, 1– 10, DOI: 10.1038/s41598-018-30860-5[Crossref], [PubMed], [CAS], Google Scholar25https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhsVCisL8%253D&md5=888be3ba63cec65e57136aee5d293a83Effects of CRISPR/Cas9 dosage on TICAM1 and RBL gene mutation rate, embryonic development, hatchability and fry survival in channel catfishElaswad, Ahmed; Khalil, Karim; Ye, Zhi; Liu, Zhanjiang; Liu, Shikai; Peatman, Eric; Odin, Ramjie; Vo, Khoi; Drescher, David; Gosh, Kamal; Qin, Guyu; Bugg, William; Backenstose, Nathan; Dunham, RexScientific Reports (2018), 8 (1), 1-17CODEN: SRCEC3; ISSN:2045-2322. (Nature Research)The current study was conducted to assess the effects of microinjection of different dosages of guide RNA (gRNA)/Cas9 protein on the mutation rate, embryo survival, embryonic development, hatchability and early fry survival in channel catfish, Ictalurus punctatus. Guide RNAs targeting two of the channel catfish immune-related genes, toll/interleukin 1 receptor domain-contg. adapter mol. (TICAM 1) and rhamnose binding lectin (RBL) genes, were designed and prepd. Three dosages of gRNA/Cas9 protein (low, 2.5 ng gRNA/7.5 ng Cas9, medium, 5 ng gRNA/15 ng Cas9 and high, 7.5 ng gRNA/22.5 ng Cas9) were microinjected into the yolk of one-cell embryos. Mutation rate increased with higher dosages (p < 0.05). Higher dosages increased the mutation frequency in individual embryos where biallelic mutations were detected. For both genes, microinjection procedures increased the embryo mortality (p < 0.05). Increasing the dosage of gRNA/Cas9 protein increased the embryo mortality and reduced the hatching percent (p < 0.05). Embryonic development was delayed when gRNAs targeting RBL gene were injected. Means of fry survival time were similar for different dosages (p > 0.05). The current results lay the foundations for designing gene editing expts. in channel catfish and can be used as a guide for other fish species.
- 26Szerszunowicz, I.; Kłobukowski, J. Characteristics of Potential Protein Nutraceuticals of Plant Origin with Antioxidant Activity. Molecules 2020, 25, 1621, DOI: 10.3390/molecules25071621[Crossref], [CAS], Google Scholar26https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXpvVChu7Y%253D&md5=3f2e0e69b15055e457cabcb7df53f3ecCharacteristics of potential protein nutraceuticals of plant origin with antioxidant activitySzerszunowicz, Iwona; Klobukowski, JanMolecules (2020), 25 (7), 1621CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)This study used selected plant proteins and the tools available in the BIOPEP-UWM database to profile proteins and release antioxidant nutraceuticals from their primary structures. The frequency of the occurrence of fragments with antioxidant activity in a protein sequence (the A parameter) was detd. A simulated monocatalytic proteolysis was carried out using ficin or stem bromelain or pepsin (pH > 2), and the theor. degree of hydrolysis (DHt) and the frequency (including relative frequency) of the release of fragments with a particular antioxidant activity by a selected enzyme (the AE and W parameters, resp.). Both barley hordoindolines and the protein group of "actins and other rice proteins" were characterised by the best antioxidant potential. On the other hand, among the main analyzed cereal protein groups or species, the best nutraceutical sources included kafirins, rice glutelins and α-gliadins. Potentially the most nutraceutical mols. were released by pepsin (HL, VY, PHQ and PWQ biopeptides) from gliadins, but the most analyzed proteins were hydrolyzed (66% on av.) and the DHt for ficin and bromelain amounted to 27% and 31%, resp. However, based on the calcd. AE mean values, it can be concluded that nutraceuticals were more frequently released from rice protein structures (IY and VY biopeptides), and less frequently released from barley and other cereal protein species, which may be of significance in the context of designing nutraceutical food.
- 27Castro-González, L. M.; Alvarez-Idaboy, J. R.; Galano, A. Computationally Designed Sesamol Derivatives Proposed as Potent Antioxidants. ACS Omega 2020, 5, 9566– 9575, DOI: 10.1021/acsomega.0c00898[ACS Full Text
], [CAS], Google Scholar27https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXmvVCks74%253D&md5=e3eb7d8cfe31c2cdd86797b37408d186Computationally Designed Sesamol Derivatives Proposed as Potent AntioxidantsCastro-Gonzalez, Laura M.; Alvarez-Idaboy, Juan Raul; Galano, AnniaACS Omega (2020), 5 (16), 9566-9575CODEN: ACSODF; ISSN:2470-1343. (American Chemical Society)Oxidative stress has been recognized to play an important role in several diseases, such as Parkinson's and Alzheimer's disease, which justifies the beneficial effects of antioxidants in ameliorating the deleterious effects of these health disorders. Sesamol, in particular, has been investigated for the treatment of several conditions because of its antioxidant properties. This article reports a rational computational design of new sesamol derivs. They were constructed by adding four functional groups (-OH, -NH2, -COOH, and -SH) in three different positions of the sesamol mol. framework. A total of 50 derivs. between mono-, di-, and trisubstituted compds. were obtained. All the derivs. were evaluated and compared with a ref. set of com. neuroprotective drugs. The estd. properties are absorption, distribution, metab., excretion, toxicity, and synthetic accessibility. Selection and elimination scores were used to choose a first set of promising candidates. Acid-based properties and reactivity indexes were then estd. using the d. functional theory. Four sesamol derivs. were finally selected, which are hypothesized to be potent antioxidants, even better than sesamol and Trolox for that purpose. - 28Bichara, L. C.; Lanús, H. E.; Nieto, C. G.; Brandán, S. A. Density functional theory calculations of the molecular force field of L-ascorbic acid, vitamin C. J. Phys. Chem. A 2010, 114, 4997– 5004, DOI: 10.1021/jp912251g[ACS Full Text], [CAS], Google Scholar28https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXjsFOmsLg%253D&md5=7e4f3027202f0797860467ec0e75b13eDensity Functional Theory Calculations of the Molecular Force Field of L-Ascorbic Acid, Vitamin CBichara, Laura C.; Lanus, Hernan E.; Nieto, Carlos G.; Brandan, Silvia A.Journal of Physical Chemistry A (2010), 114 (14), 4997-5004CODEN: JPCAFH; ISSN:1089-5639. (American Chemical Society)We have studied L-ascorbic acid and characterized it by IR spectroscopy in solid and aq. soln. phases. The d. functional theory (DFT) method together with Pople's basis set show that three stable mols. for the compd. have been theor. detd. in the gas phase, and that an av. of only two more stable conformations are present in the solid phase, as it was exptl. obsd. The harmonic vibrational wavenumbers for the optimized geometries of both structures were calcd. at B3LYP/6-31G*and B3LYP/6-311++G** levels at the proximity of the isolated mol. For a complete assignment of the vibrational spectra in the compd. solid and aq. soln. phases, DFT calcns. were combined with Pulay's scaled quantum mechanics force field methodol. in order to fit the theor. wavenumber values to the exptl. ones. In this way, a complete assignment of all the obsd. bands in the IR spectrum for L-ascorbic acid was performed. The natural bond orbital study reveals the characteristics of the electronic delocalization of the three structures while the corresponding topol. properties of electronic charge d. are analyzed by employing Bader's atoms-in-mols. theory.
- 29Yadav, R.; Rani, P.; Kumar, M.; Singh, R.; Singh, P.; Singh, N. Experimental IR and Raman spectra and quantum chemical studies of molecular structures, conformers and vibrational characteristics of L-ascorbic acid and its anion and cation. Spectrochim. Acta, Part A 2011, 84, 6– 21, DOI: 10.1016/j.saa.2011.07.043[Crossref], [PubMed], [CAS], Google Scholar29https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtlGnsb3N&md5=d58117b76220729dd3e47b3d7237c17cExperimental IR and Raman spectra and quantum chemical studies of molecular structures, conformers and vibrational characteristics of L-ascorbic acid and its anion and cationYadav, R. A.; Rani, P.; Kumar, M.; Singh, R.; Singh, Priyanka; Singh, N. P.Spectrochimica Acta, Part A: Molecular and Biomolecular Spectroscopy (2011), 84 (1), 6-21CODEN: SAMCAS; ISSN:1386-1425. (Elsevier B.V.)IR and spectra of the L-ascorbic acid (L-AA) also known as vitamin C have been recorded in the region 4000-50 cm-1. In order to make vibrational assignments of the obsd. IR and Raman bands computations were carried out by employing the RHF and DFT methods to calc. the mol. geometries and harmonic vibrational frequencies along with other related parameters for the neutral L-AA and its singly charged anionic (L-AA-) and cationic (L-AA+) species. Significant changes have been found for different characteristics of a no. of vibrational modes. The four ν(O-H) modes of the L-AA mol. are found in the order ν(O9-H10) > ν(O19-H20) > ν(O7-H8) > ν(O14-H15) which could be due to complexity of hydrogen bonding in the lactone ring and the side chain. The C=O stretching wavenumber (ν 46) decreases by 151 cm-1 in going from the neutral to the anionic species whereas it increases by 151 cm-1 in going from the anionic to the cationic species. The anionic radicals have less kinetic stabilities and high chem. reactivity as compared to the neutral mol. It is found that the cationic radical of L-AA is kinetically least stable and chem. most reactive as compared to its neutral and anionic species.
- 30Mujika, J. I.; Matxain, J. M. Theoretical study of the pH-dependent antioxidant properties of vitamin C. J. Mol. Model. 2013, 19, 1945– 1952, DOI: 10.1007/s00894-012-1465-5[Crossref], [PubMed], [CAS], Google Scholar30https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXms1ymsbg%253D&md5=528f5ac4356bd515d5405006a7e978e9Theoretical study of the pH-dependent antioxidant properties of vitamin CMujika, Jon I.; Matxain, Jon M.Journal of Molecular Modeling (2013), 19 (5), 1945-1952CODEN: JMMOFK; ISSN:0948-5023. (Springer)Mols. acting as antioxidants capable of scavenging reactive oxygen species (ROS) are of utmost importance in the living cell. Vitamin C is known to be one of these mols. In this study we have analyzed the reactivity of vitamin C toward the and ROS species, in all acidic, neutral and basic media. In order to do so, d. functional theory (DFT) have been used. More concretely, the meta-GGA functional MPW1B95 have been used. Two reaction types have been studied in each case: addn. to the ring atoms, and hydrogen/proton abstraction. Our results show that is the most reactive species, while displays low reactivity. In all three media, vitamin C reactions with two hydroxyl radicals show a wide variety of possible products.
- 31Chen, L.; Liu, C.; Fang, H.; Xie, Q.; Kong, C.; Ji, G.; Xiang, Z. Periodic density functional theory study of the high-pressure behavior of crystalline l-serine-l-ascorbic acid. J. Mol. Model. 2016, 22, 19, DOI: 10.1007/s00894-015-2890-z[Crossref], [PubMed], [CAS], Google Scholar31https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28rls1CisA%253D%253D&md5=3a39805fd438a46879500913c1eae775Periodic density functional theory study of the high-pressure behavior of crystalline L-serine-L-ascorbic acidChen Limin; Liu Chunsheng; Fang Henan; Xie Qiyun; Kong Chengkai; Ji Guanghan; Xiang ZiyueJournal of molecular modeling (2016), 22 (1), 19 ISSN:.A detailed study of the structural, electronic and absorption properties of crystalline L-serine-L-ascorbic acid (SAA) in the pressure range of 0-300 GPa was performed by density-functional theory (DFT) calculations in this work. Our results show that the compressible crystal of SAA is anisotropic. Furthermore, specific analysis of the variation tendencies of bond lengths and bond angles under different pressures show that the main structural transformations occur at pressures of 40, 50, 70, 100, 130 and 150 GPa, accompanied by repeated formations and disconnections of covalent bonds between O2(P1) and C2(P2) as well as C3(P1) and O1(P2), and a newly formed five-atom ring at 100 GPa. In addition, from 40 to 230 GPa, complex hydrogen bond transformations occur in SAA under compression, while from 240 to 300 GPa, the curve of lattice constants, bond lengths and bond angles of SAA barely changes, suggesting structural stability after 230 GPa. Then, by analyzing the band gap and density of states of SAA, it was found that the crystal undergoes a phase transformation from insulator to semiconductor at 150 GPa and it becomes more sensitive under compression. In addition, a relatively high optical activity with the pressure increases of SAA was seen from the absorption spectra, and two obvious changes of absorption coefficients were also observed at 50 GPa and 130 GPa, respectively, indicating that structural transformations occur here. Graphical abstract Structural formation and breaking of the five-atom ring O1(P2)-C2(P2)-O2(P1)-C2(P1)-C3(P1) with increasing pressure.
- 32Chen, Q.; Espey, M. G.; Sun, A. Y.; Pooput, C.; Kirk, K. L.; Krishna, M. C.; Khosh, D. B.; Drisko, J.; Levine, M. Pharmacologic doses of ascorbate act as a prooxidant and decrease growth of aggressive tumor xenografts in mice. Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 11105– 11109, DOI: 10.1073/pnas.0804226105[Crossref], [PubMed], [CAS], Google Scholar32https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtVSnsLzF&md5=c89873f5c235d3c5ce3a4f6f36d5398bPharmacologic doses of ascorbate act as a prooxidant and decrease growth of aggressive tumor xenografts in miceChen, Qi; Espey, Michael Graham; Sun, Andrew Y.; Pooput, Chaya; Kirk, Kenneth L.; Krishna, Murali C.; Khosh, Deena Beneda; Drisko, Jeanne; Leven, MarkProceedings of the National Academy of Sciences of the United States of America (2008), 105 (32), 11105-11109CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Ascorbic acid is an essential nutrient commonly regarded as an antioxidant. In this study, we showed that ascorbate at pharmacol. concns. was a prooxidant, generating hydrogen-peroxide-dependent cytotoxicity toward a variety of cancer cells in vitro without adversely affecting normal cells. To test this action in vivo, normal oral tight control was bypassed by parenteral ascorbate administration. Real-time microdialysis sampling in mice bearing glioblastoma xenografts showed that a single pharmacol. dose of ascorbate produced sustained ascorbate radical and hydrogen peroxide formation selectively within interstitial fluids of tumors but not in blood. Moreover, a regimen of daily pharmacol. ascorbate treatment significantly decreased growth rates of ovarian (P < 0.005), pancreatic (P < 0.05), and glioblastoma (P < 0.001) tumors established in mice. Similar pharmacol. concns. were readily achieved in humans given ascorbate i.v. These data suggest that ascorbate as a prodrug may have benefits in cancers with poor prognosis and limited therapeutic options.
- 33Berger, M. M.; Oudemans-van Straaten, H. M. Vitamin C supplementation in the critically ill patient. Curr. Opin. Clin. Nutr. Metab. Care 2015, 18, 193– 201, DOI: 10.1097/MCO.0000000000000148[Crossref], [PubMed], [CAS], Google Scholar33https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXitl2msbc%253D&md5=4fda0a9a40ba0bce86366c782aa242c5Vitamin C supplementation in the critically ill patientBerger, Mette M.; Oudemans-van Straaten, Heleen M.Current Opinion in Clinical Nutrition and Metabolic Care (2015), 18 (2), 193-201CODEN: COCMF3; ISSN:1363-1950. (Lippincott Williams & Wilkins)Purpose of review: Vitamin C is not only an essential nutrient involved in many anabolic pathways, but also an important player of the endogenous antioxidant defense. Low plasma levels are very common in crit. care patients and may reflect severe deficiency states. Recent findings: Vitamin C scavenges reactive oxygen species such as superoxide and peroxynitrite in plasma and cells (preventing damage to proteins, lipids and DNA), prevents occludin dephosphorylation and loosening of the tight junctions. Ascorbate improves microcirculatory flow impairment by inhibiting tumor-necrosis-factor-induced intracellular adhesion mol. expression, which triggers leukocyte stickiness and slugging. Clin. trials in sepsis, trauma and major burns testing high-dose vitamin C show clin. benefit. Restoration of normal plasma levels in inflammatory patients requires the administration of 3g/day for several days, which is 30 times the daily recommended dose. Summary: The recent research on the modulation of oxidative stress and endothelial protection offer interesting therapeutic perspectives, based on the biochem. evidence, with limited or even absent side-effects.
- 34Taira, N.; Katsuyama, Y.; Yoshioka, M.; Okano, Y.; Masaki, H. 3-O-Glyceryl-2-O-hexyl ascorbate suppresses melanogenesis by interfering with intracellular melanosome transport and suppressing tyrosinase protein synthesis. J. Cosmet. Dermatol. 2018, 17, 1209– 1215, DOI: 10.1111/jocd.12451[Crossref], [PubMed], [CAS], Google Scholar34https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1M7ovFCqsQ%253D%253D&md5=2fd97f8c6a36908146bebc5b2edfd6623-O-Glyceryl-2-O-hexyl ascorbate suppresses melanogenesis by interfering with intracellular melanosome transport and suppressing tyrosinase protein synthesisTaira Norihisa; Katsuyama Yushi; Yoshioka Masato; Okano Yuri; Masaki HitoshiJournal of cosmetic dermatology (2018), 17 (6), 1209-1215 ISSN:.BACKGROUND: Ascorbic acid (AsA) has multifunctional benefits on skin beauty, such as the reduction in oxidative stress and the induction of collagen production. Among them, the prevention and improvement of skin pigmentation by AsA is a most important benefit for people. However, it is well known that AsA not only is quite unstable in formulations but it also has a low capability of skin penetration due to its hydrophilic property. In addition, existing water-soluble AsA derivatives that were developed to improve its stability also have low skin penetration. AIM: To investigate the potential of a newly synthesized amphiphilic derivative of AsA, 3-O-Glyceryl-2-O-hexyl ascorbate (VC-HG), which has an added glyceryl group and a hexyl group, on skin beauty focusing on its skin lightening/whitening effects. METHODS: DNA microarray analysis and real-time PCR were used to clarify the effects of VC-HG on melanogenesis using B16 mouse melanoma cells. The effects of VC-HG on melanin synthesis, tyrosinase protein levels, and the inhibition of tyrosinase activity were evaluated. RESULTS: DNA microarray analysis revealed that treatment with VC-HG downregulated the expression of genes encoding tyrosinase and MyosinVa. Further, real-time PCR analysis showed the downregulation of tyrosinase, MyosinVa, Rab27a, and Kinesin mRNAs following VC-HG treatment. In addition, VC-HG caused decreases in tyrosinase protein levels and melanin synthesis. CONCLUSION: We conclude that VC-HG has an impact on skin lightening/whitening by inhibiting tyrosinase protein synthesis and interfering with intracellular melanosome transport.
- 35Frei, B.; Lawson, S. Vitamin C and cancer revisited. Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 11037– 11038, DOI: 10.1073/pnas.0806433105[Crossref], [PubMed], [CAS], Google Scholar35https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtVSnsL%252FJ&md5=ee09e48da5fd31e0fbc0f5e1ba52ccc8Vitamin C and cancer revisitedFrei, Balz; Lawson, StephenProceedings of the National Academy of Sciences of the United States of America (2008), 105 (32), 11037-11038CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)A review. Antitumor effects of Vitamin C is discussed.
- 36Chen, X.; Liu, R.; Liu, X.; Xu, C.; Wang, X. L-ascorbic Acid-2-Glucoside inhibits Helicobacter pylori-induced apoptosis through mitochondrial pathway in Gastric Epithelial cells. Biomed. Pharmacother. 2018, 97, 75– 81, DOI: 10.1016/j.biopha.2017.10.030[Crossref], [PubMed], [CAS], Google Scholar36https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhslGhtrnF&md5=6147747df685be77da670195a3c35b53L-ascorbic Acid-2-Glucoside inhibits Helicobacter pylori-induced apoptosis through mitochondrial pathway in Gastric Epithelial cellsChen, Xiong; Liu, Rui; Liu, Xiaoming; Xu, Canxia; Wang, XiaoyanBiomedicine & Pharmacotherapy (2018), 97 (), 75-81CODEN: BIPHEX; ISSN:0753-3322. (Elsevier Masson SAS)Helicobacter pylori (H. pylori) infection is the major cause for gastritis, peptic ulcer, and gastric cancer. Elevated oxidative stress, mitochondrial dysfunction and apoptotic death of gastric epithelial cells are typical hallmarks of H. pylori infection. Ascorbic Acid 2-Glucoside (AA2G) is a stable version of Vitamin C, that binds glucose to conventional vitamin C. AA2G has free radical scavenging activities and anti-apoptotic abilities. However, the protective effect of AA2G against H. pylori-infection in gastric epithelial cells is yet unknown. In this study, we investigated the effects of AA2G in human H. pylori-infected gastric epithelial cells. AA2G could remarkably ameliorate H. pylori-induced oxidative stress, including the levels of intracellular reactive oxygen species (ROS) and 4-hydroxynonenal (4-HNE). Importantly, AA2G treatment also improved mitochondrial function by restoring the level of ATP and mitochondrial membrane potential (MMP). Furthermore, AA2G reduced apoptosis induced by H. pylori through modulation of mitochondria-dependent apoptotic pathways. Our findings suggest that AA2G has a protective effect against H. pylori infection in gastric epithelial cells.
- 37Iliopoulos, F.; Sil, B. C.; Moore, D. J.; Lucas, R. A.; Lane, M. E. 3-O-ethyl-l-ascorbic acid: Characterisation and investigation of single solvent systems for delivery to the skin. Int. J. Pharm. X. 2019, 1, 100025 DOI: 10.1016/j.ijpx.2019.100025[Crossref], [PubMed], [CAS], Google Scholar37https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3Mrotl2kug%253D%253D&md5=f2036ee3f939861a42899b0c366415f43-O-ethyl-l-ascorbic acid: Characterisation and investigation of single solvent systems for delivery to the skinIliopoulos Fotis; Lane Majella E; Sil Bruno C; Moore David J; Lucas Robert AInternational journal of pharmaceutics: X (2019), 1 (), 100025 ISSN:.l-ascorbic acid (AA), commonly known as vitamin C, has been widely used in topical formulations for many years as an antioxidant and anti-aging ingredient. However, the physicochemical properties of AA are not optimal for skin uptake and the molecule is also unstable, readily undergoing oxidation on exposure to air. The compound 3-o-ethyl-l-ascorbic acid (EA) has been developed as a stable vitamin C derivative and has been used in topical products. The aims of this work were to conduct a comprehensive characterisation of physicochemical properties of EA as well as to investigate the influence of various neat solvents on EA skin delivery. Nuclear magnetic resonance (NMR), mass spectroscopy, differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) were used to characterise the molecule. The pKa of the compound and the partition coefficient logP(o/w) were experimentally determined. A new HPLC method for analysis of the molecule was also developed and validated. A number of solvents for topical preparations were selected based on their wide use as excipients in topical formulations, their potential to act as skin penetration enhancers and their favourable safety profiles. The solubility and stability of EA was examined. Skin permeation of the molecule in full thickness porcine skin in vitro was investigated using Franz-type diffusion cells. The melting point, log P(o/w) value and pKa value of EA were determined to be 114.39 ± 0.5 °C, -1.07 ± 0.03 and 7.72 ± 0.01 respectively. Skin penetration of EA was evident for the following vehicles 1,2 hexanediol (HEX), glycerol (GLY), propylene glycol (PG), 1,2 pentanediol (1-2P), isopropyl alcohol (IPA), propylene glycol monolaurate (PGML) and propylene glycol monocaprylate (PGMC). Skin uptake but no permeation through the skin was observed for Transcutol® (TC) and dipropylene glycol (DiPG), while no penetration was observed for the solvents 1,5 pentanediol (1-5P) and tripropylene glycol (TriPG). The findings of the permeation experiments confirm the potential of simple formulations to deliver EA to the skin. Studies are ongoing to identify complex vehicles for synergistic enhancement of EA skin penetration. To our knowledge this is the first study to conduct a comprehensive characterization of EA and examine its skin uptake and permeation properties in porcine skin.
- 38Jain, R.; Ahuja, B.; Sharma, B. Density-Functional Thermochemistry. III. The Role of Exact Exchange. Indian J. Pure Appl. Phys. 2004, 42, 43– 48[CAS], Google Scholar38https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXpvVCktw%253D%253D&md5=6600f589db6c62e6debfb1febbc3ad1bElectronic state in α-gallium using Compton scattering techniqueJain, Rajesh; Ahuja, B. L.; Sharma, B. K.Indian Journal of Pure and Applied Physics (2004), 42 (1), 43-48CODEN: IJOPAU; ISSN:0019-5596. (National Institute of Science Communication and Information Resources)Study of the electronic state in α-Ga using Compton scattering technique is reported in this paper. The isotropic Compton profile has been measured using a γ-ray Compton spectrometer, which employs a 5 Ci annular 241Am source. The measurement is compared with the available augmented plane-wave (APW) and non-local model potential calcns. Comparison with the present calcns. based on renormalized-free-atom (RFA) model for 4s and 4p electrons is also made. It is seen that APW (with Lam-Platzman electron-electron correlation) calcn. is in better agreement with the expt. The Fourier transform of exptl. Compton profile confirms the free-electron like behavior of Ga.
- 39Grimme, S.; Antony, J.; Ehrlich, S.; Krieg, H. A consistent and accurate ab initio parametrization of density functional dispersion correction (DFT-D) for the 94 elements H-Pu. J. Chem. Phys. 2010, 132, 154104 DOI: 10.1063/1.3382344[Crossref], [PubMed], [CAS], Google Scholar39https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXkvVyks7o%253D&md5=2bca89d904579d5565537a0820dc2ae8A consistent and accurate ab initio parametrization of density functional dispersion correction (DFT-D) for the 94 elements H-PuGrimme, Stefan; Antony, Jens; Ehrlich, Stephan; Krieg, HelgeJournal of Chemical Physics (2010), 132 (15), 154104/1-154104/19CODEN: JCPSA6; ISSN:0021-9606. (American Institute of Physics)The method of dispersion correction as an add-on to std. Kohn-Sham d. functional theory (DFT-D) has been refined regarding higher accuracy, broader range of applicability, and less empiricism. The main new ingredients are atom-pairwise specific dispersion coeffs. and cutoff radii that are both computed from first principles. The coeffs. for new eighth-order dispersion terms are computed using established recursion relations. System (geometry) dependent information is used for the first time in a DFT-D type approach by employing the new concept of fractional coordination nos. (CN). They are used to interpolate between dispersion coeffs. of atoms in different chem. environments. The method only requires adjustment of two global parameters for each d. functional, is asymptotically exact for a gas of weakly interacting neutral atoms, and easily allows the computation of at. forces. Three-body nonadditivity terms are considered. The method has been assessed on std. benchmark sets for inter- and intramol. noncovalent interactions with a particular emphasis on a consistent description of light and heavy element systems. The mean abs. deviations for the S22 benchmark set of noncovalent interactions for 11 std. d. functionals decrease by 15%-40% compared to the previous (already accurate) DFT-D version. Spectacular improvements are found for a tripeptide-folding model and all tested metallic systems. The rectification of the long-range behavior and the use of more accurate C6 coeffs. also lead to a much better description of large (infinite) systems as shown for graphene sheets and the adsorption of benzene on an Ag(111) surface. For graphene it is found that the inclusion of three-body terms substantially (by about 10%) weakens the interlayer binding. We propose the revised DFT-D method as a general tool for the computation of the dispersion energy in mols. and solids of any kind with DFT and related (low-cost) electronic structure methods for large systems. (c) 2010 American Institute of Physics.
- 40Grimme, S.; Ehrlich, S.; Goerigk, L. Effect of the damping function in dispersion corrected density functional theory. J. Comput. Chem. 2011, 32, 1456– 1465, DOI: 10.1002/jcc.21759[Crossref], [PubMed], [CAS], Google Scholar40https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXjsF2isL0%253D&md5=370c4fe3164f548718b4bfcf22d1c753Effect of the damping function in dispersion corrected density functional theoryGrimme, Stefan; Ehrlich, Stephan; Goerigk, LarsJournal of Computational Chemistry (2011), 32 (7), 1456-1465CODEN: JCCHDD; ISSN:0192-8651. (John Wiley & Sons, Inc.)It is shown by an extensive benchmark on mol. energy data that the math. form of the damping function in DFT-D methods has only a minor impact on the quality of the results. For 12 different functionals, a std. "zero-damping" formula and rational damping to finite values for small interat. distances according to Becke and Johnson (BJ-damping) has been tested. The same (DFT-D3) scheme for the computation of the dispersion coeffs. is used. The BJ-damping requires one fit parameter more for each functional (three instead of two) but has the advantage of avoiding repulsive interat. forces at shorter distances. With BJ-damping better results for nonbonded distances and more clear effects of intramol. dispersion in four representative mol. structures are found. For the noncovalently-bonded structures in the S22 set, both schemes lead to very similar intermol. distances. For noncovalent interaction energies BJ-damping performs slightly better but both variants can be recommended in general. The exception to this is Hartree-Fock that can be recommended only in the BJ-variant and which is then close to the accuracy of cor. GGAs for non-covalent interactions. According to the thermodn. benchmarks BJ-damping is more accurate esp. for medium-range electron correlation problems and only small and practically insignificant double-counting effects are obsd. It seems to provide a phys. correct short-range behavior of correlation/dispersion even with unmodified std. functionals. In any case, the differences between the two methods are much smaller than the overall dispersion effect and often also smaller than the influence of the underlying d. functional. © 2011 Wiley Periodicals, Inc.; J. Comput. Chem., 2011.
- 41Neese, F. The ORCA program system. Wiley Interdiscip. Rev.: Comput. Mol. Sci. 2012, 2, 73– 78, DOI: 10.1002/wcms.81[Crossref], [CAS], Google Scholar41https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhvFGls7s%253D&md5=a753e33a6f9a326553295596f5c754e5The ORCA program systemNeese, FrankWiley Interdisciplinary Reviews: Computational Molecular Science (2012), 2 (1), 73-78CODEN: WIRCAH; ISSN:1759-0884. (Wiley-Blackwell)A review. ORCA is a general-purpose quantum chem. program package that features virtually all modern electronic structure methods (d. functional theory, many-body perturbation and coupled cluster theories, and multireference and semiempirical methods). It is designed with the aim of generality, extendibility, efficiency, and user friendliness. Its main field of application is larger mols., transition metal complexes, and their spectroscopic properties. ORCA uses std. Gaussian basis functions and is fully parallelized. The article provides an overview of its current possibilities and documents its efficiency.
- 42Goerigk, L.; Grimme, S. Efficient and Accurate Double-Hybrid-Meta-GGA Density Functionals Evaluation with the Extended GMTKN30 Database for General Main Group Thermochemistry, Kinetics, and Noncovalent Interactions. J. Chem. Theory Comput. 2011, 7, 291– 309, DOI: 10.1021/ct100466k[ACS Full Text], [CAS], Google Scholar42https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhs1Srsb7N&md5=bd9fde6f59698f9f9f7a41195e6ad144Efficient and Accurate Double-Hybrid-Meta-GGA Density Functionals-Evaluation with the Extended GMTKN30 Database for General Main Group Thermochemistry, Kinetics, and Noncovalent InteractionsGoerigk, Lars; Grimme, StefanJournal of Chemical Theory and Computation (2011), 7 (2), 291-309CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)We present an extended and improved version of our recently published database for general main group thermochem., kinetics, and noncovalent interactions, which is dubbed GMTKN30. Furthermore, we suggest and investigate two new double-hybrid-meta-GGA d. functionals called PTPSS-D3 and PWPB95-D3. PTPSS-D3 is based on reparameterized TPSS exchange and correlation contributions; PWPB95-D3 contains reparameterized PW exchange and B95 parts. Both functionals contain fixed amts. of 50% Fock-exchange. Furthermore, they include a spin-opposite scaled perturbative contribution and are combined with our latest atom-pairwise London-dispersion correction. When evaluated with the help of the Laplace transformation algorithm, both methods scale as N4 with system size. The functionals are compared with the double hybrids B2PLYP-D3, B2GPPLYP-D3, DSD-BLYP-D3, and XYG3 for GMTKN30 with a quadruple-ζ basis set. PWPB95-D3 and DSD-BLYP-D3 are the best functionals in our study and turned out to be more robust than B2PLYP-D3 and XYG3. Furthermore, PWPB95-D3 is the least basis set dependent and the best functional at the triple-ζ level. For the example of transition metal carbonyls, it is shown that, mainly due to the lower amt. of Fock-exchange, PWPB95-D3 and PTPSS-D3 are better applicable than the other double hybrids. Finally, we discuss in some detail the XYG3 functional, which makes use of B3LYP orbitals and electron densities. We show that it is basically a highly nonlocal variant of B2PLYP and that its partially good performance is mainly due to a larger effective amt. of perturbative correlation compared to other double hybrids. We finally recommend the PWPB95-D3 functional in general chem. applications.
- 43Amorati, R.; Pedulli, G. F.; Valgimigli, L. Kinetic and thermodynamic aspects of the chain-breaking antioxidant activity of ascorbic acid derivatives in non-aqueous media. Org. Biomol. Chem. 2011, 9, 3792– 3800, DOI: 10.1039/c1ob05334e[Crossref], [PubMed], [CAS], Google Scholar43https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXlt1GhtL4%253D&md5=1025149786ed77319da8471d41ff5d96Kinetic and thermodynamic aspects of the chain-breaking antioxidant activity of ascorbic acid derivatives in non-aqueous mediaAmorati, Riccardo; Pedulli, Gian Franco; Valgimigli, LucaOrganic & Biomolecular Chemistry (2011), 9 (10), 3792-3800CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)Ascorbic acid (vitamin C) is a cofactor whose reactivity toward peroxyl and other radical species has a key-role in its biol. function. At physiol. pH it is dissocd. to the corresponding anion. Derivs. of ascorbic acid, like ascorbyl palmitate, are widely employed in food or in cosmetics and pharmaceuticals. While the aq. chem. of ascorbate has long been investigated, in non-aq. media it is largely unexplored. In this work oxygen-uptake kinetics, EPR and computational methods were combined to study the reaction of peroxyl radicals with two lipid-sol. derivs.: ascorbyl palmitate and 5,6-isopropylidene-l-ascorbic acid in non-aq. solvents. In acetonitrile at 303 K the undissociated AscH2 form of the two derivs. trapped peroxyl radicals with kinh of (8.4 ± 1.0) × 104 M-1/s-1, with stoichiometric factor of ca. 1 and isotope effect kH/kD = 3.0 ± 0.6, while in the presence of bases the anionic AscH- form had kinh of (5.0 ± 3.3) × 107 M-1/s-1. Reactivity was also enhanced in the presence of acetic acid and the mechanism is discussed. The difference in reactivity between the AscH2/AscH- forms was paralleled by a difference in O-H bond dissocn. enthalpy, which was detd. by EPR equilibrations as 81.0 ± 0.4 and 72.2 ± 0.4 kcal/mol-1 resp. for AscH2 and AscH- in tert-butanol at 298 K. Gas-phase calcns. for the neutral/anionic forms were in good agreement yielding 80.1/69.0 kcal/mol-1 using B3LYP/6-31+g(d,p) and 79.0/67.8 kcal/mol-1 at CBS-QB3 level. EPR spectra of ascorbyl palmitate in tBuOH consisted of a doublet with HSC = 0.45 G centered at g = 2.0050 for the neutral radical AscH· and a doublet of triplets with HSCs of 1.85 G, 0.18 G and 0.16 G centered at g = 2.0054 for Asc·- radical anion.
- 44Anouar, E. H.; Shah, S. A. A.; Hassan, N. B.; Moussaoui, N. E.; Ahmad, R.; Zulkefeli, M.; Weber, J.-F. F. Antioxidant activity of hispidin oligomers from medicinal fungi: A DFT study. Molecules 2014, 19, 3489– 3507, DOI: 10.3390/molecules19033489[Crossref], [PubMed], [CAS], Google Scholar44https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXos1Ojuro%253D&md5=8c85f32533a6bebe4deb0d01f4665a58Antioxidant activity of hispidin oligomers from medicinal fungi: a DFT studyAnouar, El Hassane; Ali Shah, Syed Adnan; Binti Hassan, Normahanim; El Moussaoui, Najoua; Ahmad, Rohaya; Zulkefeli, Mohd.; Weber, Jean-Frederic F.Molecules (2014), 19 (3), 3489-3507, 19 pp.CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)Hispidin oligomers are styrylpyrone pigments isolated from the medicinal fungi Inonotus xeranticus and Phellinus linteus. They exhibit diverse biol. activities and strong free radical scavenging activity. To rationalize the antioxidant activity of a series of four hispidin oligomers and det. the favored mechanism involved in free radical scavenging, DFT calcns. were carried out at the B3P86/6-31 + G (d, p) level of theory in gas and solvent. The results showed that bond dissocn. enthalpies of OH groups of hispidin oligomers (ArOH) and spin d. delocalization of related radicals (ArO•) are the appropriate parameters to clarify the differences between the obsd. antioxidant activities for the four oligomers. The effect of the no. of hydroxyl groups and presence of a catechol moiety conjugated to a double bond on the antioxidant activity were detd. Thermodn. and kinetic studies showed that the PC-ET mechanism is the main mechanism involved in free radical scavenging. The spin d. distribution over phenoxyl radicals allows a better understanding of the hispidin oligomers formation.
- 45Takebayashi, J.; Tai, A.; Gohda, E.; Yamamoto, I. Characterization of the radical-scavenging reaction of 2-O-substituted ascorbic acid derivatives, AA-2G, AA-2P, and AA-2S: a kinetic and stoichiometric study. Biol. Pharm. Bull. 2006, 29, 766– 771, DOI: 10.1248/bpb.29.766[Crossref], [PubMed], [CAS], Google Scholar45https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XkslOit7g%253D&md5=a97c0b143fc36973a462c9a139ac5f92Characterization of the radical-scavenging reaction of 2-O-substituted ascorbic acid derivatives, AA-2G, AA-2P, and AA-2S: a kinetic and stoichiometric studyTakebayashi, Jun; Tai, Akihiro; Gohda, Eiichi; Yamamoto, ItaruBiological & Pharmaceutical Bulletin (2006), 29 (4), 766-771CODEN: BPBLEO; ISSN:0918-6158. (Pharmaceutical Society of Japan)The aim of this study was to characterize the antioxidant activity of three ascorbic acid (AA) derivs. O-substituted at the C-2 position of AA: ascorbic acid 2-glucoside (AA-2G), ascorbic acid 2-phosphate (AA-2P), and ascorbic acid 2-sulfate (AA-2S). The radical-scavenging activities of these AA derivs. and some common low mol.-wt. antioxidants such as uric acid or glutathione against 1,1-diphenyl-picrylhydrazyl (DPPH) radical, 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) radical cation (ABTS·+), or galvinoxyl radical were kinetically and stoichiometrically evaluated under pH-controlled conditions. Those AA derivs. slowly and continuously reacted with DPPH radical and ABTS·+, but not with galvinoxyl radical. They effectively reacted with DPPH radical under acidic conditions and with ABTS·+ under neutral conditions. In contrast, AA immediately quenched all species of radicals tested at all pH values investigated. The reactivity of Trolox, a water-sol. vitamin E analog, was comparable to that of AA in terms of kinetics and stoichiometrics. Uric acid and glutathione exhibited long-lasting radical-scavenging activity against these radicals under certain pH conditions. The radical-scavenging profiles of AA derivs. were closer to those of uric acid and glutathione rather than to that of AA. The no. of radicals scavenged by one mol. of AA derivs., uric acid, or glutathione was equal to or greater than that by AA or Trolox under the appropriate conditions. These data suggest the potential usage of AA derivs. as radical scavengers.
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- 48Bannwarth, C.; Ehlert, S.; Grimme, S. GFN2-xTBAn accurate and broadly parametrized self-consistent tight-binding quantum chemical method with multipole electrostatics and density-dependent dispersion contributions. J. Chem. Theory Comput. 2019, 15, 1652– 1671, DOI: 10.1021/acs.jctc.8b01176[ACS Full Text], [CAS], Google Scholar48https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXis1entL0%253D&md5=e0862761437cd9ff1e57b3afe30bac21GFN2-xTB-An Accurate and Broadly Parametrized Self-Consistent Tight-Binding Quantum Chemical Method with Multipole Electrostatics and Density-Dependent Dispersion ContributionsBannwarth, Christoph; Ehlert, Sebastian; Grimme, StefanJournal of Chemical Theory and Computation (2019), 15 (3), 1652-1671CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)An extended semiempirical tight-binding model is presented, which is primarily designed for the fast calcn. of structures and noncovalent interactions energies for mol. systems with roughly 1000 atoms. The essential novelty in this so-called GFN2-xTB method is the inclusion of anisotropic second order d. fluctuation effects via short-range damped interactions of cumulative at. multipole moments. Without noticeable increase in the computational demands, this results in a less empirical and overall more phys. sound method, which does not require any classical halogen or hydrogen bonding corrections and which relies solely on global and element-specific parameters (available up to radon, Z = 86). Moreover, the at. partial charge dependent D4 London dispersion model is incorporated self-consistently, which can be naturally obtained in a tight-binding picture from second order d. fluctuations. Fully anal. and numerically precise gradients (nuclear forces) are implemented. The accuracy of the method is benchmarked for a wide variety of systems and compared with other semiempirical methods. Along with excellent performance for the "target" properties, we also find lower errors for "off-target" properties such as barrier heights and mol. dipole moments. High computational efficiency along with the improved physics compared to it precursor GFN-xTB makes this method well-suited to explore the conformational space of mol. systems. Significant improvements are furthermore obsd. for various benchmark sets, which are prototypical for biomol. systems in aq. soln.
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- 50Lu, T.; Chen, F. Multiwfn: a multifunctional wavefunction analyzer. J. Comput. Chem. 2012, 33, 580– 592, DOI: 10.1002/jcc.22885[Crossref], [PubMed], [CAS], Google Scholar50https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsFykurjN&md5=deb758db27c2d0c4df698db0a3fd066fMultiwfn: A multifunctional wavefunction analyzerLu, Tian; Chen, FeiwuJournal of Computational Chemistry (2012), 33 (5), 580-592CODEN: JCCHDD; ISSN:0192-8651. (John Wiley & Sons, Inc.)Multiwfn is a multifunctional program for wavefunction anal. Its main functions are: (1) Calcg. and visualizing real space function, such as electrostatic potential and electron localization function at point, in a line, in a plane or in a spatial scope. (2) Population anal. (3) Bond order anal. (4) Orbital compn. anal. (5) Plot d.-of-states and spectrum. (6) Topol. anal. for electron d. Some other useful utilities involved in quantum chem. studies are also provided. The built-in graph module enables the results of wavefunction anal. to be plotted directly or exported to high-quality graphic file. The program interface is very user-friendly and suitable for both research and teaching purpose. The code of Multiwfn is substantially optimized and parallelized. Its efficiency is demonstrated to be significantly higher than related programs with the same functions. Five practical examples involving a wide variety of systems and anal. methods are given to illustrate the usefulness of Multiwfn. The program is free of charge and open-source. Its precompiled file and source codes are available from http://multiwfn.codeplex.com. © 2011 Wiley Periodicals, Inc. J Comput Chem, 2011.
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Abstract
Scheme 1
Scheme 1. Antioxidant Reaction Mechanism and Corresponding Enthalpy Symbols of VC and Its DerivativesFigure 1
Figure 1. Schematic structures of VC and its derivatives.
Figure 2
Figure 2. Optimized structure of VC (a), AA2G (b), AAE (c), and AA6P (d) in the gas phase.
Figure 3
Figure 3. Comparison of bond dissociation enthalpies (BDEs) of VC and its derivatives.
Figure 4
Figure 4. Spin population distribution in the radical species of AA. (a, b) Spin population distribution of the radicals formed by the cleavage of O7–H bond in the gas phase and the water phase, respectively. (c, d) Spin population distribution of the radicals formed by the cleavage of O8–H bond in the gas phase and the water phase, respectively. Red and blue indicate two spins in different directions.
Figure 5
Figure 5. Comparison of the adiabatic ionization potentials (IPs) of VC and its derivatives.
Figure 6
Figure 6. Comparison of the proton dissociation enthalpies (PDEs) of VC and its derivatives.
Figure 7
Figure 7. Comparison of the sum of IP and PDE values for VC and its derivatives.
Figure 8
Figure 8. Comparison of the proton affinities (PAs) of VC and its derivatives.
Figure 9
Figure 9. Comparison of the electron transfer enthalpies (ETEs) of VC and its derivatives.
Figure 10
Figure 10. Comparison of the sum of PA and ETE for VC and its derivatives.
Figure 11
Figure 11. Surface plot of the Fukui function of f0(r) of VC (a), AA2G (b), AAE (c), and AA6P (d).
Figure 12
Figure 12. Potential energy surfaces (PES) of the reaction between VC and its derivatives with the HO• group in water.
References
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- 1Masaki, H. Role of antioxidants in the skin: anti-aging effects. J. Dermatol. Sci. 2010, 58, 85– 90[Crossref], [PubMed], [CAS], Google Scholar1https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXlt1GjsLk%253D&md5=525c0ac25312b1662055b3afa8cac6acRole of antioxidants in the skin: Anti-aging effectsMasaki, HitoshiJournal of Dermatological Science (2010), 58 (2), 85-90CODEN: JDSCEI; ISSN:0923-1811. (Elsevier Ltd.)A review. Intracellular and extracellular oxidative stress initiated by reactive oxygen species (ROS) advance skin aging, which is characterized by wrinkles and atypical pigmentation. Because UV enhances ROS generation in cells, skin aging is usually discussed in relation to UV exposure. The use of antioxidants is an effective approach to prevent symptoms related to photo-induced aging of the skin. In this review, the mechanisms of ROS generation and ROS elimination in the body are summarized. The effects of ROS generated in the skin and the roles of ROS in altering the skin are also discussed. In addn., the effects of representative antioxidants on the skin are summarized with a focus on skin aging.
- 2Di Meo, S.; Reed, T. T.; Venditti, P.; Victor, V. M. Role of ROS and RNS sources in physiological and pathological conditions. Oxid. Med. Cell. Longevity 2016, 2016, 1245049, DOI: 10.1155/2016/1245049[Crossref], [PubMed], [CAS], Google Scholar2https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2s3msFGgtQ%253D%253D&md5=be8eed0d2ba3d2f97566f70e5f7878bbRole of ROS and RNS Sources in Physiological and Pathological ConditionsDi Meo Sergio; Venditti Paola; Reed Tanea T; Victor Victor ManuelOxidative medicine and cellular longevity (2016), 2016 (), 1245049 ISSN:.There is significant evidence that, in living systems, free radicals and other reactive oxygen and nitrogen species play a double role, because they can cause oxidative damage and tissue dysfunction and serve as molecular signals activating stress responses that are beneficial to the organism. Mitochondria have been thought to both play a major role in tissue oxidative damage and dysfunction and provide protection against excessive tissue dysfunction through several mechanisms, including stimulation of opening of permeability transition pores. Until recently, the functional significance of ROS sources different from mitochondria has received lesser attention. However, the most recent data, besides confirming the mitochondrial role in tissue oxidative stress and protection, show interplay between mitochondria and other ROS cellular sources, so that activation of one can lead to activation of other sources. Thus, it is currently accepted that in various conditions all cellular sources of ROS provide significant contribution to processes that oxidatively damage tissues and assure their survival, through mechanisms such as autophagy and apoptosis.
- 3Wadhwa, R.; Gupta, R.; Maurya, P. K. Oxidative stress and accelerated aging in neurodegenerative and neuropsychiatric disorder. Curr. Pharm. Des. 2018, 24, 4711– 4725, DOI: 10.2174/1381612825666190115121018[Crossref], [PubMed], [CAS], Google Scholar3https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXmsV2gtLs%253D&md5=7185dd651d136a99c3d9ee406e047c52Oxidative Stress and Accelerated Aging in Neurodegenerative and Neuropsychiatric DisorderWadhwa, Ridhima; Gupta, Riya; Maurya, Pawan K.Current Pharmaceutical Design (2018), 24 (40), 4711-4725CODEN: CPDEFP; ISSN:1381-6128. (Bentham Science Publishers Ltd.)Background: Neurodegenerative diseases are becoming more and more common in today's world. As people are continuously being exposed to exogenous factors like UV radiations, gamma rays, X-Rays, environmental pollutants and heavy metals, the cases of increased oxidative damage are increasing. Even though some amt. of oxidative damage occurs in all metabolic reactions but their increase from the normal level in organisms causes neurodegenerative diseases. These neurodegenerative disorders like Alzheimer disease, Parkinson disease and neuropsychiatric disorders such as schizophrenia, bipolar, depression are caused due to the decline in physiol. and psychol. functions caused by ROS and RNS. These ROS and RNS are formed as the result of excess oxidative damage in the system. Methods: The following article goes into detail explaining all the effects caused by excess oxidative damage like ROS/RNS formation and telomere shortening. Further, it explains the pathways of neurodegenerative diseases and neuropsychiatric diseases. This article also sheds light on the effective treatments of such disorders by changing lifestyle and activating antioxidant pathways. Conclusion: It is clear that neurodegenerative diseases are caused due to excess oxidative stress and alter the functioning of the central nervous system. The central nervous system undergoes neurodegenerative or neuropsychiatric changes.
- 4Liguori, I.; Russo, G.; Curcio, F.; Bulli, G.; Aran, L.; Della-Morte, D.; Gargiulo, G.; Testa, G.; Cacciatore, F.; Bonaduce, D. Oxidative stress, aging, and diseases. Clin. Interventions Aging 2018, 13, 757, DOI: 10.2147/CIA.S158513[Crossref], [PubMed], [CAS], Google Scholar4https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtlCmtrrL&md5=d41718641bd2744185e1eeccd4758ccdOxidative stress, aging, and diseasesLiguori, Ilaria; Russo, Gennaro; Curcio, Francesco; Bulli, Giulia; Aran, Luisa; Della-Morte, David; Gargiulo, Gaetano; Testa, Gianluca; Cacciatore, Francesco; Bonaduce, Domenico; Abete, PasqualeClinical Interventions in Aging (2018), 13 (), 757-772CODEN: CIALBC; ISSN:1178-1998. (Dove Medical Press Ltd.)Reactive oxygen and nitrogen species (RONS) are produced by several endogenous and exogenous processes, and their neg. effects are neutralized by antioxidant defenses. Oxidative stress occurs from the imbalance between RONS prodn. and these antioxidant defenses. Aging is a process characterized by the progressive loss of tissue and organ function. The oxidative stress theory of aging is based on the hypothesis that age-assocd. functional losses are due to the accumulation of RONS-induced damages. At the same time, oxidative stress is involved in several age-related conditions (ie, cardiovascular diseases [CVDs], chronic obstructive pulmonary disease, chronic kidney disease, neurodegenerative diseases, and cancer), including sarcopenia and frailty. Different types of oxidative stress biomarkers have been identified and may provide important information about the efficacy of the treatment, guiding the selection of the most effective drugs/dose regimens for patients and, if particularly relevant from a pathophysiol. point of view, acting on a specific therapeutic target. Given the important role of oxidative stress in the pathogenesis of many clin. conditions and aging, antioxidant therapy could pos. affect the natural history of several diseases, but further investigation is needed to evaluate the real efficacy of these therapeutic interventions. The purpose of this paper is to provide a review of literature on this complex topic of ever increasing interest.
- 5Esfandi, R.; Walters, M. E.; Tsopmo, A. Antioxidant properties and potential mechanisms of hydrolyzed proteins and peptides from cereals. Heliyon 2019, 5, e01538 DOI: 10.1016/j.heliyon.2019.e01538
- 6Brand, M. D. The sites and topology of mitochondrial superoxide production. Exp. Gerontol. 2010, 45, 466– 472, DOI: 10.1016/j.exger.2010.01.003[Crossref], [PubMed], [CAS], Google Scholar6https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXmslGjt70%253D&md5=bdf5ea100a6ccb83d791d0f8b36ffa3aThe sites and topology of mitochondrial superoxide productionBrand, Martin D.Experimental Gerontology (2010), 45 (7-8), 466-472CODEN: EXGEAB; ISSN:0531-5565. (Elsevier)A review. Mitochondrial superoxide prodn. is an important source of reactive oxygen species in cells, and may cause or contribute to ageing and the diseases of ageing. Seven major sites of superoxide prodn. in mammalian mitochondria are known and widely accepted. In descending order of max. capacity they are the ubiquinone-binding sites in complex I (site IQ) and complex III (site IIIQo), glycerol 3-phosphate dehydrogenase, the flavin in complex I (site IF), the electron transferring flavoprotein:Q oxidoreductase (ETFQOR) of fatty acid beta-oxidn., and pyruvate and 2-oxoglutarate dehydrogenases. None of these sites is fully characterized and for some we only have sketchy information. The topol. of the sites is important because it dets. whether or not a site will produce superoxide in the mitochondrial matrix and be able to damage mitochondrial DNA. All sites produce superoxide in the matrix; site IIIQo and glycerol 3-phosphate dehydrogenase also produce superoxide to the intermembrane space. The relative contribution of each site to mitochondrial reactive oxygen species generation in the absence of electron transport inhibitors is unknown in isolated mitochondria, in cells or in vivo, and may vary considerably with species, tissue, substrate, energy demand and oxygen tension.
- 7Pan, Y.; Lin, Z. Anti-aging Effect of Ganoderma (Lingzhi) with Health and Fitness; Springer, 2019; Vol. 1182, pp 299– 309.
- 8Frei, B.; England, L.; Ames, B. N. Ascorbate is an outstanding antioxidant in human blood plasma. Proc. Natl. Acad. Sci. U.S.A. 1989, 86, 6377– 6381, DOI: 10.1073/pnas.86.16.6377[Crossref], [PubMed], [CAS], Google Scholar8https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL1MXltlWrsb4%253D&md5=9fc1ad7b2617d2673dae4cb9e9fb75baAscorbate is an outstanding antioxidant in human blood plasmaFrei, Balz; England, Laura; Ames, Bruce N.Proceedings of the National Academy of Sciences of the United States of America (1989), 86 (16), 6377-81CODEN: PNASA6; ISSN:0027-8424.The temporal order of antioxidant consumption in human blood plasma exposed to a const. flux of aq. peroxyl radicals is ascorbate = protein thiols > bilirubin > urate > α-tocopherol, and detectable lipid peroxidn. starts only after ascorbate has been consumed completely. Ascorbate completely protected plasma lipids against detectable peroxidative damage induced by aq. peroxyl radicals and ascorbate was the only plasma antioxidant that can do so. Plasma devoid of ascorbate, but no other endogenous antioxidant, was extremely vulnerable to oxidant stress and susceptible to peroxidative damage to lipids. The plasma protein's thiols, although they became oxidized immediately upon exposure to aq. peroxyl radicals, were inefficient radical scavengers and appeared to be consumed mainly by autoxidn. Ascorbate in the most effective aq.-phase antioxidant in human blood plasma and, in humans, ascorbate is a physiol. antioxidant of major importance for protection against diseases and degenerative processes caused by oxidant stress.
- 9Chen, Q.; Espey, M. G.; Sun, A. Y.; Lee, J.-H.; Krishna, M. C.; Shacter, E.; Choyke, P. L.; Pooput, C.; Kirk, K. L.; Buettner, G. R. Ascorbate in pharmacologic concentrations selectively generates ascorbate radical and hydrogen peroxide in extracellular fluid in vivo. Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 8749– 8754, DOI: 10.1073/pnas.0702854104[Crossref], [PubMed], [CAS], Google Scholar9https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXmt1aktbo%253D&md5=07ab8305b9c3e577515ede9cbb1f5d6fAscorbate in pharmacologic concentrations selectively generates ascorbate radical and hydrogen peroxide in extracellular fluid in vivoChen, Qi; Espey, Michael Graham; Sun, Andrew Y.; Lee, Je-Hyuk; Krishna, Murali C.; Shacter, Emily; Choyke, Peter L.; Pooput, Chaya; Kirk, Kenneth L.; Buettner, Garry R.; Levine, MarkProceedings of the National Academy of Sciences of the United States of America (2007), 104 (21), 8749-8754CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Ascorbate (ascorbic acid, vitamin C), in pharmacol. concns. easily achieved in humans by i.v. administration, selectively kills some cancer cells but not normal cells. We proposed that pharmacol. ascorbate is a prodrug for preferential steady-state formation of ascorbate radical (Asc•-) and H2O2 in the extracellular space compared with blood. Here we test this hypothesis in vivo. Rats were administered parenteral (i.v. or i.p.) or oral ascorbate in typical human pharmacol. doses (≈0.25-0.5 mg per g of body wt.). After i.v. injection, ascorbate baseline concns. of 50-100 μM in blood and extracellular fluid increased to peaks of >8 mM. After i.p. injection, peaks approached 3 mM in both fluids. By gavage, the same doses produced ascorbate concns. of <150 μM in both fluids. In blood, Asc•- concns. measured by EPR were undetectable with oral administration and always <50 nM with parenteral administration, even when corresponding ascorbate concns. were >8 mM. After parenteral dosing, Asc•- concns. in extracellular fluid were 4- to 12-fold higher than those in blood, were as high as 250 nM, and were a function of ascorbate concns. By using the synthesized probe peroxyxanthone, H2O2 in extracellular fluid was detected only after parenteral administration of ascorbate and when Asc•- concns. in extracellular fluid exceeded 100 nM. The data show that pharmacol. ascorbate is a prodrug for preferential steady-state formation of Asc•- and H2O2 in the extracellular space but not blood. These data provide a foundation for pursuing pharmacol. ascorbate as a prooxidant therapeutic agent in cancer and infections.
- 10Elmore, A. R. Final report of the safety assessment of L-Ascorbic Acid, Calcium Ascorbate, Magnesium Ascorbate, Magnesium Ascorbyl Phosphate, Sodium Ascorbate, and Sodium Ascorbyl Phosphate as used in cosmetics. Int. J. Toxicol. 2005, 24, 51– 111, DOI: 10.1080/10915810590953851[Crossref], [PubMed], [CAS], Google Scholar10https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2Mrit1Gjsw%253D%253D&md5=64c3eb96fd44600d0075ea8350fb0d4eFinal report of the safety assessment of L-Ascorbic Acid, Calcium Ascorbate, Magnesium Ascorbate, Magnesium Ascorbyl Phosphate, Sodium Ascorbate, and Sodium Ascorbyl Phosphate as used in cosmeticsElmore Amy RInternational journal of toxicology (2005), 24 Suppl 2 (), 51-111 ISSN:1091-5818.L-Ascorbic Acid, Calcium Ascorbate, Magnesium Ascorbate, Magnesium Ascorbyl Phosphate, Sodium Ascorbate, and Sodium Ascorbyl Phosphate function in cosmetic formulations primarily as antioxidants. Ascorbic Acid is commonly called Vitamin C. Ascorbic Acid is used as an antioxidant and pH adjuster in a large variety of cosmetic formulations, over 3/4 of which were hair dyes and colors at concentrations between 0.3% and 0.6%. For other uses, the reported concentrations were either very low (<0.01%) or in the 5% to 10% range. Calcium Ascorbate and Magnesium Ascorbate are described as antioxidants and skin conditioning agents--miscellaneous for use in cosmetics, but are not currently used. Sodium Ascorbyl Phosphate functions as an antioxidant in cosmetic products and is used at concentrations ranging from 0.01% to 3%. Magnesium Ascorbyl Phosphate functions as an antioxidant in cosmetics and was reported being used at concentrations from 0.001% to 3%. Sodium Ascorbate also functions as an antioxidant in cosmetics at concentrations from 0.0003% to 0.3%. Related ingredients (Ascorbyl Palmitate, Ascorbyl Dipalmitate, Ascorbyl Stearate, Erythorbic Acid, and Sodium Erythorbate) have been previously reviewed by the Cosmetic Ingredient Review (CIR) Expert Panel and found "to be safe for use as cosmetic ingredients in the present practices of good use." Ascorbic Acid is a generally recognized as safe (GRAS) substance for use as a chemical preservative in foods and as a nutrient and/or dietary supplement. Calcium Ascorbate and Sodium Ascorbate are listed as GRAS substances for use as chemical preservatives. L-Ascorbic Acid is readily and reversibly oxidized to L-dehydroascorbic acid and both forms exist in equilibrium in the body. Permeation rates of Ascorbic Acid through whole and stripped mouse skin were 3.43 +/- 0.74 microg/cm(2)/h and 33.2 +/- 5.2 microg/cm(2)/h. Acute oral and parenteral studies in mice, rats, rabbits, guinea pigs, dogs, and cats demonstrated little toxicity. Ascorbic Acid and Sodium Ascorbate acted as a nitrosation inhibitor in several food and cosmetic product studies. No compound-related clinical signs or gross or microscopic pathological effects were observed in either mice, rats, or guinea pigs in short-term studies. Male guinea pigs fed a control basal diet and given up to 250 mg Ascorbic Acid orally for 20 weeks had similar hemoglobin, blood glucose, serum iron, liver iron, and liver glycogen levels compared to control values. Male and female F344/N rats and B6C3F(1) mice were fed diets containing up to 100,000 ppm Ascorbic Acid for 13 weeks with little toxicity. Chronic Ascorbic Acid feeding studies showed toxic effects at dosages above 25 mg/kg body weight (bw) in rats and guinea pigs. Groups of male and female rats given daily doses up to 2000 mg/kg bw Ascorbic Acid for 2 years had no macro- or microscopically detectable toxic lesions. Mice given Ascorbic Acid subcutaneous and intravenous daily doses (500 to 1000 mg/kg bw) for 7 days had no changes in appetite, weight gain, and general behavior; and histological examination of various organs showed no changes. Ascorbic Acid was a photoprotectant when applied to mice and pig skin before exposure to ultraviolet (UV) radiation. The inhibition of UV-induced suppression of contact hypersensitivity was also noted. Magnesium Ascorbyl Phosphate administration immediately after exposure in hairless mice significantly delayed skin tumor formation and hyperplasia induced by chronic exposure to UV radiation. Pregnant mice and rats were given daily oral doses of Ascorbic Acid up to 1000 mg/kg bw with no indications of adult-toxic, teratogenic, or fetotoxic effects. Ascorbic Acid and Sodium Ascorbate were not genotoxic in several bacterial and mammalian test systems, consistent with the antioxidant properties of these chemicals. In the presence of certain enzyme systems or metal ions, evidence of genotoxicity was seen. The National Toxicology Program (NTP) conducted a 2-year oral carcinogenesis bioassay of Ascorbic Acid (25,000 and 50,000 ppm) in F344/N rats and B6C3F(1) mice. Ascorbic Acid was not carcinogenic in either sex of both rats and mice. Inhibition of carcinogenesis and tumor growth related to Ascorbic Acid's antioxidant properties has been reported. Sodium Ascorbate has been shown to promote the development of urinary carcinomas in two-stage carcinogenesis studies. Dermal application of Ascorbic Acid to patients with radiation dermatitis and burn victims had no adverse effects. Ascorbic Acid was a photoprotectant in clinical human UV studies at doses well above the minimal erythema dose (MED). An opaque cream containing 5% Ascorbic Acid did not induce dermal sensitization in 103 human subjects. A product containing 10% Ascorbic Acid was nonirritant in a 4-day minicumulative patch assay on human skin and a facial treatment containing 10% Ascorbic Acid was not a contact sensitizer in a maximization assay on 26 humans. Because of the structural and functional similarities of these ingredients, the Panel believes that the data on one ingredient can be extrapolated to all of them. The Expert Panel attributed the finding that Ascorbic Acid was genotoxic in these few assay systems due to the presence of other chemicals, e.g., metals, or certain enzyme systems, which effectively convert Ascorbic Acid's antioxidant action to that of a pro-oxidant. When Ascorbic Acid acts as an antioxidant, the Panel concluded that Ascorbic Acid is not genotoxic. Supporting this view were the carcinogenicity studies conducted by the NTP, which demonstrated no evidence of carcinogenicity. Ascorbic Acid was found to effectively inhibit nitrosamine yield in several test systems. The Panel did review studies in which Sodium Ascorbate acted as a tumor promoter in animals. These results were considered to be related to the concentration of sodium ions and the pH of urine in the test animals. Similar effects were seen with sodium bicarbonate. Because of the concern that certain metal ions may combine with these ingredients to produce pro-oxidant activity, the Panel cautioned formulators to be certain that these ingredients are acting as antioxidants in cosmetic formulations. The Panel believed that the clinical experience in which Ascorbic Acid was used on damaged skin with no adverse effects and the repeat-insult patch test (RIPT) using 5% Ascorbic Acid with negative results supports the finding that this group of ingredients does not present a risk of skin sensitization. These data coupled with an absence of reports in the clinical literature of Ascorbic Acid sensitization strongly support the safety of these ingredients.
- 11Mohamed, R.; Tarannum, S.; Yariswamy, M.; Vivek, H. K.; Siddesha, J. M.; Angaswamy, N.; Vishwanath, B. S. Ascorbic acid 6-palmitate: a potent inhibitor of human and soybean lipoxygenase-dependent lipid peroxidation. J. Pharm. Pharmacol. 2014, 66, 769– 778, DOI: 10.1111/jphp.12200[Crossref], [PubMed], [CAS], Google Scholar11https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXns1Sru7k%253D&md5=c9c3f943899899ce9e8096f0aa511e49Ascorbic acid 6-palmitate: a potent inhibitor of human and soybean lipoxygenase-dependent lipid peroxidationMohamed, Riyaz; Tarannum, Shaista; Yariswamy, Manjunath; Vivek, Hamse K.; Siddesha, Jalahalli M.; Angaswamy, Nataraju; Vishwanath, Bannikuppe S.Journal of Pharmacy and Pharmacology (2014), 66 (6), 769-778CODEN: JPPMAB; ISSN:0022-3573. (John Wiley & Sons Ltd.)Lipoxygenases (LOX) are the key enzymes involved in the biosynthesis of leukotrienes and reactive oxygen species, which are implicated in pathophysiol. of inflammatory disorders. This study was conducted to evaluate the inhibitory effect of water-sol. antioxidant ascorbic acid and its lipophilic deriv., ascorbic acid 6-palmitate (Vcpal) on polymorphonuclear lymphocyte 5-LOX and soybean 15-LOX (sLOX) in vitro. LOX activity was detd. by measuring the end products, 5-hydroperoxy eicosatetraenoic acid (5-HETE) and lipid hydroperoxides, by spectrophotometric and high performance liq. chromatog. methods. The substrate-dependent enzyme kinetics and docking studies were carried out to understand the nature of inhibition. Vcpal potently inhibited 5-LOX when compared with its inhibitory effect on sLOX (IC50; 2.5 and 10.3 μm resp.). Further, Vcpal inhibited 5-LOX more strongly than the known synthetic drugs: phenidone and nordihydroguaiaretic acid. Enzyme kinetic studies demonstrated Vcpal as a non-competitive reversible inhibitor of 5-LOX. In-silico mol. docking revealed high MolDock and Rerank score for Vcpal than ascorbic acid, complementing in-vitro results. Both in-vitro and docking studies demonstrated Vcpal but not ascorbic acid as a non-competitive inhibitor of 5-LOX- and sLOX-induced lipid peroxidn., suggesting a key role for lipophilic nature in bringing about inhibition.
- 12Amirlak, B.; Mahedia, M.; Shah, N. A clinical evaluation of efficacy and safety of hyaluronan sponge with vitamin C versus placebo for scar reduction. Plast. Reconstr. Surg. Glob. Open 2016, 4 (7), e792 DOI: 10.1097/GOX.0000000000000734
- 13Hill, A.; Wendt, S.; Benstoem, C.; Neubauer, C.; Meybohm, P.; Langlois, P.; Adhikari, N. K.; Heyland, D. K.; Stoppe, C. Vitamin C to improve organ dysfunction in cardiac surgery patientsreview and pragmatic approach. Nutrients 2018, 10, 974, DOI: 10.3390/nu10080974[Crossref], [CAS], Google Scholar13https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXisFKmt7vN&md5=1c7175759721cbf7271c6f65eb58c91eVitamin C to improve organ dysfunction in cardiac surgery patients-review and pragmatic approachHill, Aileen; Wendt, Sebastian; Benstoem, Carina; Neubauer, Christina; Meybohm, Patrick; Langlois, Pascal; Adhikari, Neill K. J.; Heyl, Daren K.; Stoppe, ChristianNutrients (2018), 10 (8), 974/1-974/29CODEN: NUTRHU; ISSN:2072-6643. (MDPI AG)A review. The pleiotropic biochem. and antioxidant functions of vitamin C have sparked recent interest in its application in intensive care. Vitamin C protects important organ systems (cardiovascular, neurol. and renal systems) during inflammation and oxidative stress. It also influences coagulation and inflammation; its application might prevent organ damage. The current evidence of vitamin C's effect on pathophysiol. reactions during various acute stress events (such as sepsis, shock, trauma, burn and ischemia-reperfusion injury) questions whether the application of vitamin Cmight be esp. beneficial for cardiac surgery patientswho are routinely exposed to ischemia/reperfusion and subsequent inflammation, systematically affecting different organ systems. This review covers current knowledge about the role of vitamin C in cardiac surgery patients with focus on its influence on organ dysfunctions. The relationships between vitamin C and clin. health outcomes are reviewed with special emphasis on its application in cardiac surgery. Addnl., this review pragmatically discusses evidence on the administration of vitamin C in every day clin. practice, tackling the issues of safety,monitoring, dosage, and appropriate application strategy.
- 14Nauman, G.; Gray, J. C.; Parkinson, R.; Levine, M.; Paller, C. J. Systematic review of intravenous ascorbate in cancer clinical trials. Antioxidants 2018, 7, 89, DOI: 10.3390/antiox7070089[Crossref], [CAS], Google Scholar14https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhvFGhtLzI&md5=a30c975f696436d1b75751b23c314178Systematic review of intravenous ascorbate in cancer clinical trialsNauman, Gina; Gray, Javaughn Corey; Parkinson, Rose; Levine, Mark; Paller, Channing J.Antioxidants (2018), 7 (7), 89/1-89/22CODEN: ANTIGE; ISSN:2076-3921. (MDPI AG)A review. Background: Ascorbate (vitamin C) has been evaluated as a potential treatment for cancer as an independent agent and in combination with std. chemotherapies. This review assesses the evidence for safety and clin. effectiveness of i.v. (IV) ascorbate in treating various types of cancer. Methods: Single arm and randomized Phase I/II trials were included in this review. The PubMed, MEDLINE, and Cochrane databases were searched. Results were screened by three of the authors (GN, RP, and CJP) to det. if they met inclusion criteria, and then summarized using a narrative approach. Results: A total of 23 trials involving 385 patients met the inclusion criteria. Only one trial, in ovarian cancer, randomized patients to receive vitamin C or std. of care (chemotherapy). That trial reported an 8.75 mo increase in progression-free survival (PFS) and an improved trend in overall survival (OS) in the vitamin C treated arm. Conclusion: Overall, vitamin C has been shown to be safe in nearly all patient populations, alone and in combination with chemotherapies. The promising results support the need for randomized placebo-controlled trials such as the ongoing placebo-controlled trials of vitamin C and chemotherapy in prostate cancer.
- 15Taira, N.; Katsuyama, Y.; Yoshioka, M.; Muraoka, O.; Morikawa, T. Structural requirements of alkylglyceryl-L-ascorbic acid derivatives for melanogenesis inhibitory activity. Int. J. Mol. Sci. 2018, 19, 1144, DOI: 10.3390/ijms19041144[Crossref], [CAS], Google Scholar15https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXisVOqurfK&md5=de1be49d36505658c02db86c8031d534Structural requirements of alkylglyceryl-L-ascorbic acid derivatives for melanogenesis inhibitory activityTaira, Norihisa; Katsuyama, Yushi; Yoshioka, Masato; Muraoka, Osamu; Morikawa, ToshioInternational Journal of Molecular Sciences (2018), 19 (4), 1144/1-1144/22CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)L-Ascorbic acid has multifunctional benefits on skin aesthetics, including inhibition of melanin prodn., and is widely used in cosmetics. It, however, has low stability and poor skin penetration. We hypothesize that alkylglyceryl-L-ascorbic acid derivs., highly stable vitamin C-alkylglycerol conjugates, would have similar anti-melanogenic activity with better stability and penetration. We test 28 alkylglyceryl-L-ascorbic acid derivs. (1-28) on theophylline-stimulated B16 melanoma 4A5 cells to det. if they inhibit melanogenesis and establish any structure-function relationships. Although not the most potent inhibitors, 3-O-(2,3-dihydroxypropyl)-2-O-hexyl-L-ascorbic acid (6, IC50 = 81.4μM) and 2-O-(2,3-dihydroxypropyl)-3-O-hexyl-L-ascorbic acid (20, IC50 = 117μM) are deemed the best candidate derivs. based on their inhibitory activities and low toxicities. These derivs. are also found to be more stable than L-ascorbic acid and to have favorable characteristics for skin penetration. The following structural requirements for inhibitory activity of alkylglyceryl-L-ascorbic acid derivs. are also detd.: (i) alkylation of glyceryl-L-ascorbic acid is essential for inhibitory activity; (ii) the 3-O-alkyl-derivs. (2-14) exhibit stronger inhibitory activity than the corresponding 2-O-alkyl-derivs. (16-28); and (iii) derivs. with longer alkyl chains have stronger inhibitory activities. Mechanistically, our studies suggest that L-ascorbic acid derivs. exert their effects by suppressing the mRNA expression of tyrosinase and tyrosine-related protein-1.
- 16Isola, G.; Polizzi, A.; Muraglie, S.; Leonardi, R.; Lo Giudice, A. Assessment of vitamin C and antioxidant profiles in saliva and serum in patients with periodontitis and ischemic heart disease. Nutrients 2019, 11, 2956, DOI: 10.3390/nu11122956
- 17Meščić Macan, A.; Gazivoda Kraljević, T.; Raić-Malić, S. Therapeutic perspective of vitamin C and its derivatives. Antioxidants 2019, 8, 247, DOI: 10.3390/antiox8080247
- 18Miao, F.; Su, M.-Y.; Jiang, S.; Luo, L.-F.; Shi, Y.; Lei, T.-C. Intramelanocytic acidification plays a role in the antimelanogenic and antioxidative properties of vitamin C and its derivatives. Oxid. Med. Cell. Longevity 2019, 2019, 1– 14, DOI: 10.1155/2019/2084805
- 19Maekawa, T.; Uchida, T.; Nakata-Horiuchi, Y.; Kobayashi, H.; Kawauchi, S.; Kinoshita, M.; Saitoh, D.; Sato, S. Oral ascorbic acid 2-glucoside prevents coordination disorder induced via laser-induced shock waves in rat brain. PLoS One 2020, 15, e0230774 DOI: 10.1371/journal.pone.0230774[Crossref], [PubMed], [CAS], Google Scholar19https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXnvVGnsrw%253D&md5=a3a5ce53948182c6281724d42049d059Oral ascorbic acid 2-glucoside prevents coordination disorder induced via laser-induced shock waves in rat brainMaekawa, Takaaki; Uchida, Takahiro; Nakata-Horiuchi, Yuka; Kobayashi, Hiroaki; Kawauchi, Satoko; Kinoshita, Manabu; Saitoh, Daizoh; Sato, ShunichiPLoS One (2020), 15 (4), e0230774CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)Oxidative stress is considered to be involved in the pathogenesis of primary blast-related traumatic brain injury (bTBI). We evaluated the effects of ascorbic acid 2-glucoside (AA2G), a well-known antioxidant, to control oxidative stress in rat brain exposed to laser-induced shock waves (LISWs). The design consisted of a controlled animal study using male 10-wk-old Sprague-Dawley rats. The study was conducted at the University research lab. Low-impulse (54 Pa•s) LISWs were transcranially applied to rat brain. Rats were randomized to control group (anesthesia and head shaving, n = 10), LISW group (anesthesia, head shaving and LISW application, n = 10) or LISW + post AA2G group (AA2G administration after LISW application, n = 10) in the first study. In another study, rats were randomized to control group (n = 10), LISW group (n = 10) or LISW + pre and post AA2G group (AA2G administration before and after LISW application, n = 10). The measured outcomes were as follows: (i) motor function assessed by accelerating rotarod test; (ii) levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG), an oxidative stress marker; (iii) ascorbic acid in each group of rats. Ascorbic acid levels were significantly decreased and 8-OHdG levels were significantly increased in the cerebellum of the LISW group. Motor coordination disorder was also obsd. in the group. Prophylactic AA2G administration significantly increased the ascorbic acid levels, reduced oxidative stress and mitigated the motor dysfunction. In contrast, the effects of therapeutic AA2G administration alone were limited. The results suggest that the prophylactic administration of ascorbic acid can reduce shock wave-related oxidative stress and prevented motor dysfunction in rats.
- 20Gašperlin, M.; Gosenca, M. Main approaches for delivering antioxidant vitamins through the skin to prevent skin ageing. Expert Opin. Drug Delivery 2011, 8, 905– 919, DOI: 10.1517/17425247.2011.581657[Crossref], [PubMed], [CAS], Google Scholar20https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3MngvVWjsw%253D%253D&md5=c9bb3ac0d877a86dae48f79a120f8d54Main approaches for delivering antioxidant vitamins through the skin to prevent skin ageingGasperlin Mirjana; Gosenca MirjamExpert opinion on drug delivery (2011), 8 (7), 905-19 ISSN:.INTRODUCTION: One of the major contributions to skin photoageing and diseases is oxidative stress, caused by UV radiation inducing reactive oxygen and nitrogen species. Successful prophylaxis and therapy would necessitate control of the oxidant/antioxidant balance at the affected site, which can be achieved through the external supply of endogenous antioxidants. AREAS COVERED: This review discusses possible strategies for dermal delivery of the antioxidant vitamins E and C, as oral supplementation has proved insufficient. These antioxidants have low skin bioavailability, owing to their poor solubility, inefficient skin permeability, or instability during storage. These drawbacks can be overcome by various approaches, such as chemical modification of the vitamins and the use of new colloidal drug delivery systems. New knowledge is included about the importance of: enhancing the endogenous skin antioxidant defense through external supply; the balance between various skin antioxidants; factors that can improve the skin bioavailability of antioxidants; and new delivery systems, such as microemulsions, used to deliver vitamins C and E into the skin simultaneously. EXPERT OPINION: A promising strategy for enhancing skin protection from oxidative stress is to support the endogenous antioxidant system, with antioxidants containing products that are normally present in the skin.
- 21Yim, S.; Lee, J.; Jo, H.; Scholten, J.; Willingham, R.; Nicoll, J.; Baswan, S. M. Chrysanthemum morifolium extract and Ascorbic Acid-2-Glucoside (AA2G) blend inhibits UVA-induced delayed cyclobutane pyrimidine dimer (CPD) production in melanocytes. Clin., Cosmet. Invest. Dermatol. 2019, 12, 823, DOI: 10.2147/CCID.S223802[Crossref], [PubMed], [CAS], Google Scholar21https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXns1Gitbk%253D&md5=a41c0709afdd3619c5cb7de1af997a97Chrysanthemum Morifolium extract and Ascorbic Acid-2-Glucoside (AA2G) blend inhibits UVA-induced delayed cyclobutane pyrimidine dimer (CPD) Production In MelanocytesYim, Sunghan; Lee, Jeesun; Jo, Hae; Scholten, Jeff; Willingham, Ryan; Nicoll, Jim; Baswan, Sudhir M.Clinical, Cosmetic and Investigational Dermatology (2019), 12 (), 823-832CODEN: CCIDCL; ISSN:1178-7015. (Dove Medical Press Ltd.)Background: Solar UV radiation (UV) induces DNA damages in skin via direct absorption of UVB or indirectly by photosensitization mediated through UVA. Recent findings have revealed that UVA induces cyclobutane pyrimidine dimer (CPD) generation via chemiexcitation in melanocytes hours after the exposure. This UVA-induced delayed CPD (dark CPD) constitutes the majority of CPD in melanocytes. These findings indicate that sun light can damage the skin hours after the exposure, suggesting the need for skin care products post sun exposure. The main objective of this study was to investigate whether a blend of Chrysanthemum Morifolium flower ext. (Chrys) and vitamin C deriv., Ascorbic Acid-2-Glucoside (AA2G), can provide protective effects against reactive oxygen species, melanin formation and UVA-induced dark CPD. Methods: Intracellular ROS levels were measured in epidermal keratinocytes using DHR123 dye. Melanogenesis inhibition efficacy was detd. using B16 cells. As for the dark CPD measurement, Melan-a cells were treated with or without actives for 6 days, then irradiated with UVA at various doses. Cells were exposed with anti-CPD mAb followed by secondary Ab. CPD levels were detd. by measuring fluorescent intensity using a high content imaging anal. Results: Chrys, AA2G and their blend at various concns. demonstrated ROS scavenging activity. Though Chrys alone did not show significant melanogenesis inhibition in B16 assay, the blend of Chrys with AA2G demonstrated additive effects in comparison with AA2G alone. The blend of AA2G and Chrys at various concns. exhibited enhanced efficacy for inhibiting dark CPD compared to AA2G alone. Conclusion: The results from this study indicate that the use of natural antioxidant, Chrys in combination with AA2G, provides protection against UVA-induced delayed CPD formation by enhancing ROS scavenging activity and melanogenesis inhibition. These findings could potentially be applied for formulating post-sun exposure skin care products, possibly extending to evening-after care products.
- 22Pandithavidana, D. R.; Jayawardana, S. B. Comparative Study of Antioxidant Potential of Selected Dietary Vitamins; Computational Insights. Molecules 2019, 24, 1646, DOI: 10.3390/molecules24091646[Crossref], [CAS], Google Scholar22https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtF2jtLnI&md5=e6f1b3bf185104529e1bed5c3543fcd0Comparative study of antioxidant potential of selected dietary vitamins; computational insightsPandithavidana, Dinesh R.; Jayawardana, Samith B.Molecules (2019), 24 (9), 1646CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)D. functional theory (DFT) was used to explore the antioxidant properties of some naturally occurring dietary vitamins, and the reaction enthalpies related to various mechanisms of primary antioxidant action, i.e., hydrogen atom transfer, single electron transfer-proton transfer, and sequential proton loss-electron transfer were discussed in detail. B3LYP, M05-2X, and M06-2X functionals were utilized in this work. For aq. phase studies, the integral equation formalism polarized continuum model (IEF-PCM) was employed. From the outcomes, hydrogen atom transfer (HAT) was the most probable mechanism for the antioxidant action of this class of compds. Comparison of found results with exptl. data (available in literature), vitamin C possesses the lowest enthalpy values for both proton affinity (PA) and bond dissocn. energy (BDE)in the aq. phase, suggesting it as the most promising candidate as an antioxidant. Accordingly, these computational insights encourage the design of structurally novel, simple vitamins which will be more economical and beneficial in the pharmaceutical industry.
- 23Yamabe, S.; Tsuchida, N.; Yamazaki, S.; Sakaki, S. Frontier orbitals and transition states in the oxidation and degradation of l-ascorbic acid: a DFT study. Org. Biomol. Chem 2015, 13, 4002– 4015, DOI: 10.1039/C5OB00035A[Crossref], [PubMed], [CAS], Google Scholar23https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXjtVels74%253D&md5=bfc1f40f08d96be53563f78e4509085fFrontier orbitals and transition states in the oxidation and degradation of L-ascorbic acid: a DFT studyYamabe, Shinichi; Tsuchida, Noriko; Yamazaki, Shoko; Sakaki, ShigeyoshiOrganic & Biomolecular Chemistry (2015), 13 (13), 4002-4015CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)DFT calcns. were carried out to investigate reaction paths of L-ascorbic acid (AAH2), hydroxyl radicals and water clusters. Frontier-orbital analyses were also performed to examine the regioselectivity of the OH· addn. Transition states of the electrolytic dissocn. of AAH2 and intermediate carboxylic acids were found to have very small activation energies through proton transfers along hydrogen bonds. The ionized species (anions) are subject to the electrophilic attack of OH·. The elementary processes of AAH2 → A·- → dehydroascorbic acid → diketogulonic acid → threonic, oxalic, xylonic and lyxonic acids were investigated and discussed. The processes involved in the conversion of dehydroascorbic acid into a bicyclic hemiketal were also examd. as a side-chain participating reaction. The oxidn. and degrdn. of vitamin C up to threonic acid were described mainly as a donor (AAH2)-acceptor (OH·) reaction.
- 24Kumar, V.; Kishor, S.; Ramaniah, L. M. Understanding the antioxidant behavior of some vitamin molecules: a first-principles density functional approach. J. Mol. Model. 2013, 19, 3175– 3186, DOI: 10.1007/s00894-013-1836-6[Crossref], [PubMed], [CAS], Google Scholar24https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtFCru7jL&md5=6390909254b0a2869bcf20db32224aa4Understanding the antioxidant behavior of some vitamin molecules: a first-principles density functional approachKumar, Vipin; Kishor, Shyam; Ramaniah, Lavanya M.Journal of Molecular Modeling (2013), 19 (8), 3175-3186CODEN: JMMOFK; ISSN:0948-5023. (Springer)The structures, energetics, vertical and adiabatic ionization potentials, electron affinities, and global reactivity descriptors of antioxidant vitamins (both water- and fat-sol.) in neutral, pos. charged, and neg. charged states were studied theor. The authors worked within the framework of first-principles d. functional theory (DFT), using the B3LYP functional and both localized (6-311G+(d,p)) and plane-wave basis sets. Solvent effects were modeled via the polarizable continuum model (PCM), using the integral equation formalism variant (IEFPCM). From the computed structural parameters, ionization potentials, electron affinities, and spin densities, these vitamins prefer to lose electrons to neutral reactive oxygen species (·OH and ·OOH), making them good antioxidants. Conceptual DFT was used to det. global chem. reactivity parameters. The computed chem. hardnesses showed that these antioxidant vitamins are more reactive than neutral reactive oxygen species (ROS), thus supporting their antioxidant character towards these species. However, in the neutral state, these vitamins do not act as antioxidants for O-2. The reactivity of vitamins towards ROS depends on the nature of the solvent. Amongst the ROS, ·OH has the greatest propensity to attract electrons from a generic donor. The reactivities of fat-sol. vitamins towards neutral reactive oxygen species are larger than those of water-sol. vitamins towards these species, showing that the former are better antioxidants.
- 25Vo, Q. V.; Nam, P. C.; Van Bay, M.; Thong, N. M.; Cuong, N. D.; Mechler, A. Density functional theory study of the role of benzylic hydrogen atoms in the antioxidant properties of lignans. Sci. Rep. 2018, 8, 1– 10, DOI: 10.1038/s41598-018-30860-5[Crossref], [PubMed], [CAS], Google Scholar25https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhsVCisL8%253D&md5=888be3ba63cec65e57136aee5d293a83Effects of CRISPR/Cas9 dosage on TICAM1 and RBL gene mutation rate, embryonic development, hatchability and fry survival in channel catfishElaswad, Ahmed; Khalil, Karim; Ye, Zhi; Liu, Zhanjiang; Liu, Shikai; Peatman, Eric; Odin, Ramjie; Vo, Khoi; Drescher, David; Gosh, Kamal; Qin, Guyu; Bugg, William; Backenstose, Nathan; Dunham, RexScientific Reports (2018), 8 (1), 1-17CODEN: SRCEC3; ISSN:2045-2322. (Nature Research)The current study was conducted to assess the effects of microinjection of different dosages of guide RNA (gRNA)/Cas9 protein on the mutation rate, embryo survival, embryonic development, hatchability and early fry survival in channel catfish, Ictalurus punctatus. Guide RNAs targeting two of the channel catfish immune-related genes, toll/interleukin 1 receptor domain-contg. adapter mol. (TICAM 1) and rhamnose binding lectin (RBL) genes, were designed and prepd. Three dosages of gRNA/Cas9 protein (low, 2.5 ng gRNA/7.5 ng Cas9, medium, 5 ng gRNA/15 ng Cas9 and high, 7.5 ng gRNA/22.5 ng Cas9) were microinjected into the yolk of one-cell embryos. Mutation rate increased with higher dosages (p < 0.05). Higher dosages increased the mutation frequency in individual embryos where biallelic mutations were detected. For both genes, microinjection procedures increased the embryo mortality (p < 0.05). Increasing the dosage of gRNA/Cas9 protein increased the embryo mortality and reduced the hatching percent (p < 0.05). Embryonic development was delayed when gRNAs targeting RBL gene were injected. Means of fry survival time were similar for different dosages (p > 0.05). The current results lay the foundations for designing gene editing expts. in channel catfish and can be used as a guide for other fish species.
- 26Szerszunowicz, I.; Kłobukowski, J. Characteristics of Potential Protein Nutraceuticals of Plant Origin with Antioxidant Activity. Molecules 2020, 25, 1621, DOI: 10.3390/molecules25071621[Crossref], [CAS], Google Scholar26https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXpvVChu7Y%253D&md5=3f2e0e69b15055e457cabcb7df53f3ecCharacteristics of potential protein nutraceuticals of plant origin with antioxidant activitySzerszunowicz, Iwona; Klobukowski, JanMolecules (2020), 25 (7), 1621CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)This study used selected plant proteins and the tools available in the BIOPEP-UWM database to profile proteins and release antioxidant nutraceuticals from their primary structures. The frequency of the occurrence of fragments with antioxidant activity in a protein sequence (the A parameter) was detd. A simulated monocatalytic proteolysis was carried out using ficin or stem bromelain or pepsin (pH > 2), and the theor. degree of hydrolysis (DHt) and the frequency (including relative frequency) of the release of fragments with a particular antioxidant activity by a selected enzyme (the AE and W parameters, resp.). Both barley hordoindolines and the protein group of "actins and other rice proteins" were characterised by the best antioxidant potential. On the other hand, among the main analyzed cereal protein groups or species, the best nutraceutical sources included kafirins, rice glutelins and α-gliadins. Potentially the most nutraceutical mols. were released by pepsin (HL, VY, PHQ and PWQ biopeptides) from gliadins, but the most analyzed proteins were hydrolyzed (66% on av.) and the DHt for ficin and bromelain amounted to 27% and 31%, resp. However, based on the calcd. AE mean values, it can be concluded that nutraceuticals were more frequently released from rice protein structures (IY and VY biopeptides), and less frequently released from barley and other cereal protein species, which may be of significance in the context of designing nutraceutical food.
- 27Castro-González, L. M.; Alvarez-Idaboy, J. R.; Galano, A. Computationally Designed Sesamol Derivatives Proposed as Potent Antioxidants. ACS Omega 2020, 5, 9566– 9575, DOI: 10.1021/acsomega.0c00898[ACS Full Text], [CAS], Google Scholar27https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXmvVCks74%253D&md5=e3eb7d8cfe31c2cdd86797b37408d186Computationally Designed Sesamol Derivatives Proposed as Potent AntioxidantsCastro-Gonzalez, Laura M.; Alvarez-Idaboy, Juan Raul; Galano, AnniaACS Omega (2020), 5 (16), 9566-9575CODEN: ACSODF; ISSN:2470-1343. (American Chemical Society)Oxidative stress has been recognized to play an important role in several diseases, such as Parkinson's and Alzheimer's disease, which justifies the beneficial effects of antioxidants in ameliorating the deleterious effects of these health disorders. Sesamol, in particular, has been investigated for the treatment of several conditions because of its antioxidant properties. This article reports a rational computational design of new sesamol derivs. They were constructed by adding four functional groups (-OH, -NH2, -COOH, and -SH) in three different positions of the sesamol mol. framework. A total of 50 derivs. between mono-, di-, and trisubstituted compds. were obtained. All the derivs. were evaluated and compared with a ref. set of com. neuroprotective drugs. The estd. properties are absorption, distribution, metab., excretion, toxicity, and synthetic accessibility. Selection and elimination scores were used to choose a first set of promising candidates. Acid-based properties and reactivity indexes were then estd. using the d. functional theory. Four sesamol derivs. were finally selected, which are hypothesized to be potent antioxidants, even better than sesamol and Trolox for that purpose.
- 28Bichara, L. C.; Lanús, H. E.; Nieto, C. G.; Brandán, S. A. Density functional theory calculations of the molecular force field of L-ascorbic acid, vitamin C. J. Phys. Chem. A 2010, 114, 4997– 5004, DOI: 10.1021/jp912251g[ACS Full Text], [CAS], Google Scholar28https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXjsFOmsLg%253D&md5=7e4f3027202f0797860467ec0e75b13eDensity Functional Theory Calculations of the Molecular Force Field of L-Ascorbic Acid, Vitamin CBichara, Laura C.; Lanus, Hernan E.; Nieto, Carlos G.; Brandan, Silvia A.Journal of Physical Chemistry A (2010), 114 (14), 4997-5004CODEN: JPCAFH; ISSN:1089-5639. (American Chemical Society)We have studied L-ascorbic acid and characterized it by IR spectroscopy in solid and aq. soln. phases. The d. functional theory (DFT) method together with Pople's basis set show that three stable mols. for the compd. have been theor. detd. in the gas phase, and that an av. of only two more stable conformations are present in the solid phase, as it was exptl. obsd. The harmonic vibrational wavenumbers for the optimized geometries of both structures were calcd. at B3LYP/6-31G*and B3LYP/6-311++G** levels at the proximity of the isolated mol. For a complete assignment of the vibrational spectra in the compd. solid and aq. soln. phases, DFT calcns. were combined with Pulay's scaled quantum mechanics force field methodol. in order to fit the theor. wavenumber values to the exptl. ones. In this way, a complete assignment of all the obsd. bands in the IR spectrum for L-ascorbic acid was performed. The natural bond orbital study reveals the characteristics of the electronic delocalization of the three structures while the corresponding topol. properties of electronic charge d. are analyzed by employing Bader's atoms-in-mols. theory.
- 29Yadav, R.; Rani, P.; Kumar, M.; Singh, R.; Singh, P.; Singh, N. Experimental IR and Raman spectra and quantum chemical studies of molecular structures, conformers and vibrational characteristics of L-ascorbic acid and its anion and cation. Spectrochim. Acta, Part A 2011, 84, 6– 21, DOI: 10.1016/j.saa.2011.07.043[Crossref], [PubMed], [CAS], Google Scholar29https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtlGnsb3N&md5=d58117b76220729dd3e47b3d7237c17cExperimental IR and Raman spectra and quantum chemical studies of molecular structures, conformers and vibrational characteristics of L-ascorbic acid and its anion and cationYadav, R. A.; Rani, P.; Kumar, M.; Singh, R.; Singh, Priyanka; Singh, N. P.Spectrochimica Acta, Part A: Molecular and Biomolecular Spectroscopy (2011), 84 (1), 6-21CODEN: SAMCAS; ISSN:1386-1425. (Elsevier B.V.)IR and spectra of the L-ascorbic acid (L-AA) also known as vitamin C have been recorded in the region 4000-50 cm-1. In order to make vibrational assignments of the obsd. IR and Raman bands computations were carried out by employing the RHF and DFT methods to calc. the mol. geometries and harmonic vibrational frequencies along with other related parameters for the neutral L-AA and its singly charged anionic (L-AA-) and cationic (L-AA+) species. Significant changes have been found for different characteristics of a no. of vibrational modes. The four ν(O-H) modes of the L-AA mol. are found in the order ν(O9-H10) > ν(O19-H20) > ν(O7-H8) > ν(O14-H15) which could be due to complexity of hydrogen bonding in the lactone ring and the side chain. The C=O stretching wavenumber (ν 46) decreases by 151 cm-1 in going from the neutral to the anionic species whereas it increases by 151 cm-1 in going from the anionic to the cationic species. The anionic radicals have less kinetic stabilities and high chem. reactivity as compared to the neutral mol. It is found that the cationic radical of L-AA is kinetically least stable and chem. most reactive as compared to its neutral and anionic species.
- 30Mujika, J. I.; Matxain, J. M. Theoretical study of the pH-dependent antioxidant properties of vitamin C. J. Mol. Model. 2013, 19, 1945– 1952, DOI: 10.1007/s00894-012-1465-5[Crossref], [PubMed], [CAS], Google Scholar30https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXms1ymsbg%253D&md5=528f5ac4356bd515d5405006a7e978e9Theoretical study of the pH-dependent antioxidant properties of vitamin CMujika, Jon I.; Matxain, Jon M.Journal of Molecular Modeling (2013), 19 (5), 1945-1952CODEN: JMMOFK; ISSN:0948-5023. (Springer)Mols. acting as antioxidants capable of scavenging reactive oxygen species (ROS) are of utmost importance in the living cell. Vitamin C is known to be one of these mols. In this study we have analyzed the reactivity of vitamin C toward the and ROS species, in all acidic, neutral and basic media. In order to do so, d. functional theory (DFT) have been used. More concretely, the meta-GGA functional MPW1B95 have been used. Two reaction types have been studied in each case: addn. to the ring atoms, and hydrogen/proton abstraction. Our results show that is the most reactive species, while displays low reactivity. In all three media, vitamin C reactions with two hydroxyl radicals show a wide variety of possible products.
- 31Chen, L.; Liu, C.; Fang, H.; Xie, Q.; Kong, C.; Ji, G.; Xiang, Z. Periodic density functional theory study of the high-pressure behavior of crystalline l-serine-l-ascorbic acid. J. Mol. Model. 2016, 22, 19, DOI: 10.1007/s00894-015-2890-z[Crossref], [PubMed], [CAS], Google Scholar31https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28rls1CisA%253D%253D&md5=3a39805fd438a46879500913c1eae775Periodic density functional theory study of the high-pressure behavior of crystalline L-serine-L-ascorbic acidChen Limin; Liu Chunsheng; Fang Henan; Xie Qiyun; Kong Chengkai; Ji Guanghan; Xiang ZiyueJournal of molecular modeling (2016), 22 (1), 19 ISSN:.A detailed study of the structural, electronic and absorption properties of crystalline L-serine-L-ascorbic acid (SAA) in the pressure range of 0-300 GPa was performed by density-functional theory (DFT) calculations in this work. Our results show that the compressible crystal of SAA is anisotropic. Furthermore, specific analysis of the variation tendencies of bond lengths and bond angles under different pressures show that the main structural transformations occur at pressures of 40, 50, 70, 100, 130 and 150 GPa, accompanied by repeated formations and disconnections of covalent bonds between O2(P1) and C2(P2) as well as C3(P1) and O1(P2), and a newly formed five-atom ring at 100 GPa. In addition, from 40 to 230 GPa, complex hydrogen bond transformations occur in SAA under compression, while from 240 to 300 GPa, the curve of lattice constants, bond lengths and bond angles of SAA barely changes, suggesting structural stability after 230 GPa. Then, by analyzing the band gap and density of states of SAA, it was found that the crystal undergoes a phase transformation from insulator to semiconductor at 150 GPa and it becomes more sensitive under compression. In addition, a relatively high optical activity with the pressure increases of SAA was seen from the absorption spectra, and two obvious changes of absorption coefficients were also observed at 50 GPa and 130 GPa, respectively, indicating that structural transformations occur here. Graphical abstract Structural formation and breaking of the five-atom ring O1(P2)-C2(P2)-O2(P1)-C2(P1)-C3(P1) with increasing pressure.
- 32Chen, Q.; Espey, M. G.; Sun, A. Y.; Pooput, C.; Kirk, K. L.; Krishna, M. C.; Khosh, D. B.; Drisko, J.; Levine, M. Pharmacologic doses of ascorbate act as a prooxidant and decrease growth of aggressive tumor xenografts in mice. Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 11105– 11109, DOI: 10.1073/pnas.0804226105[Crossref], [PubMed], [CAS], Google Scholar32https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtVSnsLzF&md5=c89873f5c235d3c5ce3a4f6f36d5398bPharmacologic doses of ascorbate act as a prooxidant and decrease growth of aggressive tumor xenografts in miceChen, Qi; Espey, Michael Graham; Sun, Andrew Y.; Pooput, Chaya; Kirk, Kenneth L.; Krishna, Murali C.; Khosh, Deena Beneda; Drisko, Jeanne; Leven, MarkProceedings of the National Academy of Sciences of the United States of America (2008), 105 (32), 11105-11109CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Ascorbic acid is an essential nutrient commonly regarded as an antioxidant. In this study, we showed that ascorbate at pharmacol. concns. was a prooxidant, generating hydrogen-peroxide-dependent cytotoxicity toward a variety of cancer cells in vitro without adversely affecting normal cells. To test this action in vivo, normal oral tight control was bypassed by parenteral ascorbate administration. Real-time microdialysis sampling in mice bearing glioblastoma xenografts showed that a single pharmacol. dose of ascorbate produced sustained ascorbate radical and hydrogen peroxide formation selectively within interstitial fluids of tumors but not in blood. Moreover, a regimen of daily pharmacol. ascorbate treatment significantly decreased growth rates of ovarian (P < 0.005), pancreatic (P < 0.05), and glioblastoma (P < 0.001) tumors established in mice. Similar pharmacol. concns. were readily achieved in humans given ascorbate i.v. These data suggest that ascorbate as a prodrug may have benefits in cancers with poor prognosis and limited therapeutic options.
- 33Berger, M. M.; Oudemans-van Straaten, H. M. Vitamin C supplementation in the critically ill patient. Curr. Opin. Clin. Nutr. Metab. Care 2015, 18, 193– 201, DOI: 10.1097/MCO.0000000000000148[Crossref], [PubMed], [CAS], Google Scholar33https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXitl2msbc%253D&md5=4fda0a9a40ba0bce86366c782aa242c5Vitamin C supplementation in the critically ill patientBerger, Mette M.; Oudemans-van Straaten, Heleen M.Current Opinion in Clinical Nutrition and Metabolic Care (2015), 18 (2), 193-201CODEN: COCMF3; ISSN:1363-1950. (Lippincott Williams & Wilkins)Purpose of review: Vitamin C is not only an essential nutrient involved in many anabolic pathways, but also an important player of the endogenous antioxidant defense. Low plasma levels are very common in crit. care patients and may reflect severe deficiency states. Recent findings: Vitamin C scavenges reactive oxygen species such as superoxide and peroxynitrite in plasma and cells (preventing damage to proteins, lipids and DNA), prevents occludin dephosphorylation and loosening of the tight junctions. Ascorbate improves microcirculatory flow impairment by inhibiting tumor-necrosis-factor-induced intracellular adhesion mol. expression, which triggers leukocyte stickiness and slugging. Clin. trials in sepsis, trauma and major burns testing high-dose vitamin C show clin. benefit. Restoration of normal plasma levels in inflammatory patients requires the administration of 3g/day for several days, which is 30 times the daily recommended dose. Summary: The recent research on the modulation of oxidative stress and endothelial protection offer interesting therapeutic perspectives, based on the biochem. evidence, with limited or even absent side-effects.
- 34Taira, N.; Katsuyama, Y.; Yoshioka, M.; Okano, Y.; Masaki, H. 3-O-Glyceryl-2-O-hexyl ascorbate suppresses melanogenesis by interfering with intracellular melanosome transport and suppressing tyrosinase protein synthesis. J. Cosmet. Dermatol. 2018, 17, 1209– 1215, DOI: 10.1111/jocd.12451[Crossref], [PubMed], [CAS], Google Scholar34https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1M7ovFCqsQ%253D%253D&md5=2fd97f8c6a36908146bebc5b2edfd6623-O-Glyceryl-2-O-hexyl ascorbate suppresses melanogenesis by interfering with intracellular melanosome transport and suppressing tyrosinase protein synthesisTaira Norihisa; Katsuyama Yushi; Yoshioka Masato; Okano Yuri; Masaki HitoshiJournal of cosmetic dermatology (2018), 17 (6), 1209-1215 ISSN:.BACKGROUND: Ascorbic acid (AsA) has multifunctional benefits on skin beauty, such as the reduction in oxidative stress and the induction of collagen production. Among them, the prevention and improvement of skin pigmentation by AsA is a most important benefit for people. However, it is well known that AsA not only is quite unstable in formulations but it also has a low capability of skin penetration due to its hydrophilic property. In addition, existing water-soluble AsA derivatives that were developed to improve its stability also have low skin penetration. AIM: To investigate the potential of a newly synthesized amphiphilic derivative of AsA, 3-O-Glyceryl-2-O-hexyl ascorbate (VC-HG), which has an added glyceryl group and a hexyl group, on skin beauty focusing on its skin lightening/whitening effects. METHODS: DNA microarray analysis and real-time PCR were used to clarify the effects of VC-HG on melanogenesis using B16 mouse melanoma cells. The effects of VC-HG on melanin synthesis, tyrosinase protein levels, and the inhibition of tyrosinase activity were evaluated. RESULTS: DNA microarray analysis revealed that treatment with VC-HG downregulated the expression of genes encoding tyrosinase and MyosinVa. Further, real-time PCR analysis showed the downregulation of tyrosinase, MyosinVa, Rab27a, and Kinesin mRNAs following VC-HG treatment. In addition, VC-HG caused decreases in tyrosinase protein levels and melanin synthesis. CONCLUSION: We conclude that VC-HG has an impact on skin lightening/whitening by inhibiting tyrosinase protein synthesis and interfering with intracellular melanosome transport.
- 35Frei, B.; Lawson, S. Vitamin C and cancer revisited. Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 11037– 11038, DOI: 10.1073/pnas.0806433105[Crossref], [PubMed], [CAS], Google Scholar35https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtVSnsL%252FJ&md5=ee09e48da5fd31e0fbc0f5e1ba52ccc8Vitamin C and cancer revisitedFrei, Balz; Lawson, StephenProceedings of the National Academy of Sciences of the United States of America (2008), 105 (32), 11037-11038CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)A review. Antitumor effects of Vitamin C is discussed.
- 36Chen, X.; Liu, R.; Liu, X.; Xu, C.; Wang, X. L-ascorbic Acid-2-Glucoside inhibits Helicobacter pylori-induced apoptosis through mitochondrial pathway in Gastric Epithelial cells. Biomed. Pharmacother. 2018, 97, 75– 81, DOI: 10.1016/j.biopha.2017.10.030[Crossref], [PubMed], [CAS], Google Scholar36https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhslGhtrnF&md5=6147747df685be77da670195a3c35b53L-ascorbic Acid-2-Glucoside inhibits Helicobacter pylori-induced apoptosis through mitochondrial pathway in Gastric Epithelial cellsChen, Xiong; Liu, Rui; Liu, Xiaoming; Xu, Canxia; Wang, XiaoyanBiomedicine & Pharmacotherapy (2018), 97 (), 75-81CODEN: BIPHEX; ISSN:0753-3322. (Elsevier Masson SAS)Helicobacter pylori (H. pylori) infection is the major cause for gastritis, peptic ulcer, and gastric cancer. Elevated oxidative stress, mitochondrial dysfunction and apoptotic death of gastric epithelial cells are typical hallmarks of H. pylori infection. Ascorbic Acid 2-Glucoside (AA2G) is a stable version of Vitamin C, that binds glucose to conventional vitamin C. AA2G has free radical scavenging activities and anti-apoptotic abilities. However, the protective effect of AA2G against H. pylori-infection in gastric epithelial cells is yet unknown. In this study, we investigated the effects of AA2G in human H. pylori-infected gastric epithelial cells. AA2G could remarkably ameliorate H. pylori-induced oxidative stress, including the levels of intracellular reactive oxygen species (ROS) and 4-hydroxynonenal (4-HNE). Importantly, AA2G treatment also improved mitochondrial function by restoring the level of ATP and mitochondrial membrane potential (MMP). Furthermore, AA2G reduced apoptosis induced by H. pylori through modulation of mitochondria-dependent apoptotic pathways. Our findings suggest that AA2G has a protective effect against H. pylori infection in gastric epithelial cells.
- 37Iliopoulos, F.; Sil, B. C.; Moore, D. J.; Lucas, R. A.; Lane, M. E. 3-O-ethyl-l-ascorbic acid: Characterisation and investigation of single solvent systems for delivery to the skin. Int. J. Pharm. X. 2019, 1, 100025 DOI: 10.1016/j.ijpx.2019.100025[Crossref], [PubMed], [CAS], Google Scholar37https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3Mrotl2kug%253D%253D&md5=f2036ee3f939861a42899b0c366415f43-O-ethyl-l-ascorbic acid: Characterisation and investigation of single solvent systems for delivery to the skinIliopoulos Fotis; Lane Majella E; Sil Bruno C; Moore David J; Lucas Robert AInternational journal of pharmaceutics: X (2019), 1 (), 100025 ISSN:.l-ascorbic acid (AA), commonly known as vitamin C, has been widely used in topical formulations for many years as an antioxidant and anti-aging ingredient. However, the physicochemical properties of AA are not optimal for skin uptake and the molecule is also unstable, readily undergoing oxidation on exposure to air. The compound 3-o-ethyl-l-ascorbic acid (EA) has been developed as a stable vitamin C derivative and has been used in topical products. The aims of this work were to conduct a comprehensive characterisation of physicochemical properties of EA as well as to investigate the influence of various neat solvents on EA skin delivery. Nuclear magnetic resonance (NMR), mass spectroscopy, differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) were used to characterise the molecule. The pKa of the compound and the partition coefficient logP(o/w) were experimentally determined. A new HPLC method for analysis of the molecule was also developed and validated. A number of solvents for topical preparations were selected based on their wide use as excipients in topical formulations, their potential to act as skin penetration enhancers and their favourable safety profiles. The solubility and stability of EA was examined. Skin permeation of the molecule in full thickness porcine skin in vitro was investigated using Franz-type diffusion cells. The melting point, log P(o/w) value and pKa value of EA were determined to be 114.39 ± 0.5 °C, -1.07 ± 0.03 and 7.72 ± 0.01 respectively. Skin penetration of EA was evident for the following vehicles 1,2 hexanediol (HEX), glycerol (GLY), propylene glycol (PG), 1,2 pentanediol (1-2P), isopropyl alcohol (IPA), propylene glycol monolaurate (PGML) and propylene glycol monocaprylate (PGMC). Skin uptake but no permeation through the skin was observed for Transcutol® (TC) and dipropylene glycol (DiPG), while no penetration was observed for the solvents 1,5 pentanediol (1-5P) and tripropylene glycol (TriPG). The findings of the permeation experiments confirm the potential of simple formulations to deliver EA to the skin. Studies are ongoing to identify complex vehicles for synergistic enhancement of EA skin penetration. To our knowledge this is the first study to conduct a comprehensive characterization of EA and examine its skin uptake and permeation properties in porcine skin.
- 38Jain, R.; Ahuja, B.; Sharma, B. Density-Functional Thermochemistry. III. The Role of Exact Exchange. Indian J. Pure Appl. Phys. 2004, 42, 43– 48[CAS], Google Scholar38https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXpvVCktw%253D%253D&md5=6600f589db6c62e6debfb1febbc3ad1bElectronic state in α-gallium using Compton scattering techniqueJain, Rajesh; Ahuja, B. L.; Sharma, B. K.Indian Journal of Pure and Applied Physics (2004), 42 (1), 43-48CODEN: IJOPAU; ISSN:0019-5596. (National Institute of Science Communication and Information Resources)Study of the electronic state in α-Ga using Compton scattering technique is reported in this paper. The isotropic Compton profile has been measured using a γ-ray Compton spectrometer, which employs a 5 Ci annular 241Am source. The measurement is compared with the available augmented plane-wave (APW) and non-local model potential calcns. Comparison with the present calcns. based on renormalized-free-atom (RFA) model for 4s and 4p electrons is also made. It is seen that APW (with Lam-Platzman electron-electron correlation) calcn. is in better agreement with the expt. The Fourier transform of exptl. Compton profile confirms the free-electron like behavior of Ga.
- 39Grimme, S.; Antony, J.; Ehrlich, S.; Krieg, H. A consistent and accurate ab initio parametrization of density functional dispersion correction (DFT-D) for the 94 elements H-Pu. J. Chem. Phys. 2010, 132, 154104 DOI: 10.1063/1.3382344[Crossref], [PubMed], [CAS], Google Scholar39https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXkvVyks7o%253D&md5=2bca89d904579d5565537a0820dc2ae8A consistent and accurate ab initio parametrization of density functional dispersion correction (DFT-D) for the 94 elements H-PuGrimme, Stefan; Antony, Jens; Ehrlich, Stephan; Krieg, HelgeJournal of Chemical Physics (2010), 132 (15), 154104/1-154104/19CODEN: JCPSA6; ISSN:0021-9606. (American Institute of Physics)The method of dispersion correction as an add-on to std. Kohn-Sham d. functional theory (DFT-D) has been refined regarding higher accuracy, broader range of applicability, and less empiricism. The main new ingredients are atom-pairwise specific dispersion coeffs. and cutoff radii that are both computed from first principles. The coeffs. for new eighth-order dispersion terms are computed using established recursion relations. System (geometry) dependent information is used for the first time in a DFT-D type approach by employing the new concept of fractional coordination nos. (CN). They are used to interpolate between dispersion coeffs. of atoms in different chem. environments. The method only requires adjustment of two global parameters for each d. functional, is asymptotically exact for a gas of weakly interacting neutral atoms, and easily allows the computation of at. forces. Three-body nonadditivity terms are considered. The method has been assessed on std. benchmark sets for inter- and intramol. noncovalent interactions with a particular emphasis on a consistent description of light and heavy element systems. The mean abs. deviations for the S22 benchmark set of noncovalent interactions for 11 std. d. functionals decrease by 15%-40% compared to the previous (already accurate) DFT-D version. Spectacular improvements are found for a tripeptide-folding model and all tested metallic systems. The rectification of the long-range behavior and the use of more accurate C6 coeffs. also lead to a much better description of large (infinite) systems as shown for graphene sheets and the adsorption of benzene on an Ag(111) surface. For graphene it is found that the inclusion of three-body terms substantially (by about 10%) weakens the interlayer binding. We propose the revised DFT-D method as a general tool for the computation of the dispersion energy in mols. and solids of any kind with DFT and related (low-cost) electronic structure methods for large systems. (c) 2010 American Institute of Physics.
- 40Grimme, S.; Ehrlich, S.; Goerigk, L. Effect of the damping function in dispersion corrected density functional theory. J. Comput. Chem. 2011, 32, 1456– 1465, DOI: 10.1002/jcc.21759[Crossref], [PubMed], [CAS], Google Scholar40https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXjsF2isL0%253D&md5=370c4fe3164f548718b4bfcf22d1c753Effect of the damping function in dispersion corrected density functional theoryGrimme, Stefan; Ehrlich, Stephan; Goerigk, LarsJournal of Computational Chemistry (2011), 32 (7), 1456-1465CODEN: JCCHDD; ISSN:0192-8651. (John Wiley & Sons, Inc.)It is shown by an extensive benchmark on mol. energy data that the math. form of the damping function in DFT-D methods has only a minor impact on the quality of the results. For 12 different functionals, a std. "zero-damping" formula and rational damping to finite values for small interat. distances according to Becke and Johnson (BJ-damping) has been tested. The same (DFT-D3) scheme for the computation of the dispersion coeffs. is used. The BJ-damping requires one fit parameter more for each functional (three instead of two) but has the advantage of avoiding repulsive interat. forces at shorter distances. With BJ-damping better results for nonbonded distances and more clear effects of intramol. dispersion in four representative mol. structures are found. For the noncovalently-bonded structures in the S22 set, both schemes lead to very similar intermol. distances. For noncovalent interaction energies BJ-damping performs slightly better but both variants can be recommended in general. The exception to this is Hartree-Fock that can be recommended only in the BJ-variant and which is then close to the accuracy of cor. GGAs for non-covalent interactions. According to the thermodn. benchmarks BJ-damping is more accurate esp. for medium-range electron correlation problems and only small and practically insignificant double-counting effects are obsd. It seems to provide a phys. correct short-range behavior of correlation/dispersion even with unmodified std. functionals. In any case, the differences between the two methods are much smaller than the overall dispersion effect and often also smaller than the influence of the underlying d. functional. © 2011 Wiley Periodicals, Inc.; J. Comput. Chem., 2011.
- 41Neese, F. The ORCA program system. Wiley Interdiscip. Rev.: Comput. Mol. Sci. 2012, 2, 73– 78, DOI: 10.1002/wcms.81[Crossref], [CAS], Google Scholar41https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhvFGls7s%253D&md5=a753e33a6f9a326553295596f5c754e5The ORCA program systemNeese, FrankWiley Interdisciplinary Reviews: Computational Molecular Science (2012), 2 (1), 73-78CODEN: WIRCAH; ISSN:1759-0884. (Wiley-Blackwell)A review. ORCA is a general-purpose quantum chem. program package that features virtually all modern electronic structure methods (d. functional theory, many-body perturbation and coupled cluster theories, and multireference and semiempirical methods). It is designed with the aim of generality, extendibility, efficiency, and user friendliness. Its main field of application is larger mols., transition metal complexes, and their spectroscopic properties. ORCA uses std. Gaussian basis functions and is fully parallelized. The article provides an overview of its current possibilities and documents its efficiency.
- 42Goerigk, L.; Grimme, S. Efficient and Accurate Double-Hybrid-Meta-GGA Density Functionals Evaluation with the Extended GMTKN30 Database for General Main Group Thermochemistry, Kinetics, and Noncovalent Interactions. J. Chem. Theory Comput. 2011, 7, 291– 309, DOI: 10.1021/ct100466k[ACS Full Text], [CAS], Google Scholar42https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhs1Srsb7N&md5=bd9fde6f59698f9f9f7a41195e6ad144Efficient and Accurate Double-Hybrid-Meta-GGA Density Functionals-Evaluation with the Extended GMTKN30 Database for General Main Group Thermochemistry, Kinetics, and Noncovalent InteractionsGoerigk, Lars; Grimme, StefanJournal of Chemical Theory and Computation (2011), 7 (2), 291-309CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)We present an extended and improved version of our recently published database for general main group thermochem., kinetics, and noncovalent interactions, which is dubbed GMTKN30. Furthermore, we suggest and investigate two new double-hybrid-meta-GGA d. functionals called PTPSS-D3 and PWPB95-D3. PTPSS-D3 is based on reparameterized TPSS exchange and correlation contributions; PWPB95-D3 contains reparameterized PW exchange and B95 parts. Both functionals contain fixed amts. of 50% Fock-exchange. Furthermore, they include a spin-opposite scaled perturbative contribution and are combined with our latest atom-pairwise London-dispersion correction. When evaluated with the help of the Laplace transformation algorithm, both methods scale as N4 with system size. The functionals are compared with the double hybrids B2PLYP-D3, B2GPPLYP-D3, DSD-BLYP-D3, and XYG3 for GMTKN30 with a quadruple-ζ basis set. PWPB95-D3 and DSD-BLYP-D3 are the best functionals in our study and turned out to be more robust than B2PLYP-D3 and XYG3. Furthermore, PWPB95-D3 is the least basis set dependent and the best functional at the triple-ζ level. For the example of transition metal carbonyls, it is shown that, mainly due to the lower amt. of Fock-exchange, PWPB95-D3 and PTPSS-D3 are better applicable than the other double hybrids. Finally, we discuss in some detail the XYG3 functional, which makes use of B3LYP orbitals and electron densities. We show that it is basically a highly nonlocal variant of B2PLYP and that its partially good performance is mainly due to a larger effective amt. of perturbative correlation compared to other double hybrids. We finally recommend the PWPB95-D3 functional in general chem. applications.
- 43Amorati, R.; Pedulli, G. F.; Valgimigli, L. Kinetic and thermodynamic aspects of the chain-breaking antioxidant activity of ascorbic acid derivatives in non-aqueous media. Org. Biomol. Chem. 2011, 9, 3792– 3800, DOI: 10.1039/c1ob05334e[Crossref], [PubMed], [CAS], Google Scholar43https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXlt1GhtL4%253D&md5=1025149786ed77319da8471d41ff5d96Kinetic and thermodynamic aspects of the chain-breaking antioxidant activity of ascorbic acid derivatives in non-aqueous mediaAmorati, Riccardo; Pedulli, Gian Franco; Valgimigli, LucaOrganic & Biomolecular Chemistry (2011), 9 (10), 3792-3800CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)Ascorbic acid (vitamin C) is a cofactor whose reactivity toward peroxyl and other radical species has a key-role in its biol. function. At physiol. pH it is dissocd. to the corresponding anion. Derivs. of ascorbic acid, like ascorbyl palmitate, are widely employed in food or in cosmetics and pharmaceuticals. While the aq. chem. of ascorbate has long been investigated, in non-aq. media it is largely unexplored. In this work oxygen-uptake kinetics, EPR and computational methods were combined to study the reaction of peroxyl radicals with two lipid-sol. derivs.: ascorbyl palmitate and 5,6-isopropylidene-l-ascorbic acid in non-aq. solvents. In acetonitrile at 303 K the undissociated AscH2 form of the two derivs. trapped peroxyl radicals with kinh of (8.4 ± 1.0) × 104 M-1/s-1, with stoichiometric factor of ca. 1 and isotope effect kH/kD = 3.0 ± 0.6, while in the presence of bases the anionic AscH- form had kinh of (5.0 ± 3.3) × 107 M-1/s-1. Reactivity was also enhanced in the presence of acetic acid and the mechanism is discussed. The difference in reactivity between the AscH2/AscH- forms was paralleled by a difference in O-H bond dissocn. enthalpy, which was detd. by EPR equilibrations as 81.0 ± 0.4 and 72.2 ± 0.4 kcal/mol-1 resp. for AscH2 and AscH- in tert-butanol at 298 K. Gas-phase calcns. for the neutral/anionic forms were in good agreement yielding 80.1/69.0 kcal/mol-1 using B3LYP/6-31+g(d,p) and 79.0/67.8 kcal/mol-1 at CBS-QB3 level. EPR spectra of ascorbyl palmitate in tBuOH consisted of a doublet with HSC = 0.45 G centered at g = 2.0050 for the neutral radical AscH· and a doublet of triplets with HSCs of 1.85 G, 0.18 G and 0.16 G centered at g = 2.0054 for Asc·- radical anion.
- 44Anouar, E. H.; Shah, S. A. A.; Hassan, N. B.; Moussaoui, N. E.; Ahmad, R.; Zulkefeli, M.; Weber, J.-F. F. Antioxidant activity of hispidin oligomers from medicinal fungi: A DFT study. Molecules 2014, 19, 3489– 3507, DOI: 10.3390/molecules19033489[Crossref], [PubMed], [CAS], Google Scholar44https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXos1Ojuro%253D&md5=8c85f32533a6bebe4deb0d01f4665a58Antioxidant activity of hispidin oligomers from medicinal fungi: a DFT studyAnouar, El Hassane; Ali Shah, Syed Adnan; Binti Hassan, Normahanim; El Moussaoui, Najoua; Ahmad, Rohaya; Zulkefeli, Mohd.; Weber, Jean-Frederic F.Molecules (2014), 19 (3), 3489-3507, 19 pp.CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)Hispidin oligomers are styrylpyrone pigments isolated from the medicinal fungi Inonotus xeranticus and Phellinus linteus. They exhibit diverse biol. activities and strong free radical scavenging activity. To rationalize the antioxidant activity of a series of four hispidin oligomers and det. the favored mechanism involved in free radical scavenging, DFT calcns. were carried out at the B3P86/6-31 + G (d, p) level of theory in gas and solvent. The results showed that bond dissocn. enthalpies of OH groups of hispidin oligomers (ArOH) and spin d. delocalization of related radicals (ArO•) are the appropriate parameters to clarify the differences between the obsd. antioxidant activities for the four oligomers. The effect of the no. of hydroxyl groups and presence of a catechol moiety conjugated to a double bond on the antioxidant activity were detd. Thermodn. and kinetic studies showed that the PC-ET mechanism is the main mechanism involved in free radical scavenging. The spin d. distribution over phenoxyl radicals allows a better understanding of the hispidin oligomers formation.
- 45Takebayashi, J.; Tai, A.; Gohda, E.; Yamamoto, I. Characterization of the radical-scavenging reaction of 2-O-substituted ascorbic acid derivatives, AA-2G, AA-2P, and AA-2S: a kinetic and stoichiometric study. Biol. Pharm. Bull. 2006, 29, 766– 771, DOI: 10.1248/bpb.29.766[Crossref], [PubMed], [CAS], Google Scholar45https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XkslOit7g%253D&md5=a97c0b143fc36973a462c9a139ac5f92Characterization of the radical-scavenging reaction of 2-O-substituted ascorbic acid derivatives, AA-2G, AA-2P, and AA-2S: a kinetic and stoichiometric studyTakebayashi, Jun; Tai, Akihiro; Gohda, Eiichi; Yamamoto, ItaruBiological & Pharmaceutical Bulletin (2006), 29 (4), 766-771CODEN: BPBLEO; ISSN:0918-6158. (Pharmaceutical Society of Japan)The aim of this study was to characterize the antioxidant activity of three ascorbic acid (AA) derivs. O-substituted at the C-2 position of AA: ascorbic acid 2-glucoside (AA-2G), ascorbic acid 2-phosphate (AA-2P), and ascorbic acid 2-sulfate (AA-2S). The radical-scavenging activities of these AA derivs. and some common low mol.-wt. antioxidants such as uric acid or glutathione against 1,1-diphenyl-picrylhydrazyl (DPPH) radical, 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) radical cation (ABTS·+), or galvinoxyl radical were kinetically and stoichiometrically evaluated under pH-controlled conditions. Those AA derivs. slowly and continuously reacted with DPPH radical and ABTS·+, but not with galvinoxyl radical. They effectively reacted with DPPH radical under acidic conditions and with ABTS·+ under neutral conditions. In contrast, AA immediately quenched all species of radicals tested at all pH values investigated. The reactivity of Trolox, a water-sol. vitamin E analog, was comparable to that of AA in terms of kinetics and stoichiometrics. Uric acid and glutathione exhibited long-lasting radical-scavenging activity against these radicals under certain pH conditions. The radical-scavenging profiles of AA derivs. were closer to those of uric acid and glutathione rather than to that of AA. The no. of radicals scavenged by one mol. of AA derivs., uric acid, or glutathione was equal to or greater than that by AA or Trolox under the appropriate conditions. These data suggest the potential usage of AA derivs. as radical scavengers.
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- 48Bannwarth, C.; Ehlert, S.; Grimme, S. GFN2-xTBAn accurate and broadly parametrized self-consistent tight-binding quantum chemical method with multipole electrostatics and density-dependent dispersion contributions. J. Chem. Theory Comput. 2019, 15, 1652– 1671, DOI: 10.1021/acs.jctc.8b01176[ACS Full Text], [CAS], Google Scholar48https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXis1entL0%253D&md5=e0862761437cd9ff1e57b3afe30bac21GFN2-xTB-An Accurate and Broadly Parametrized Self-Consistent Tight-Binding Quantum Chemical Method with Multipole Electrostatics and Density-Dependent Dispersion ContributionsBannwarth, Christoph; Ehlert, Sebastian; Grimme, StefanJournal of Chemical Theory and Computation (2019), 15 (3), 1652-1671CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)An extended semiempirical tight-binding model is presented, which is primarily designed for the fast calcn. of structures and noncovalent interactions energies for mol. systems with roughly 1000 atoms. The essential novelty in this so-called GFN2-xTB method is the inclusion of anisotropic second order d. fluctuation effects via short-range damped interactions of cumulative at. multipole moments. Without noticeable increase in the computational demands, this results in a less empirical and overall more phys. sound method, which does not require any classical halogen or hydrogen bonding corrections and which relies solely on global and element-specific parameters (available up to radon, Z = 86). Moreover, the at. partial charge dependent D4 London dispersion model is incorporated self-consistently, which can be naturally obtained in a tight-binding picture from second order d. fluctuations. Fully anal. and numerically precise gradients (nuclear forces) are implemented. The accuracy of the method is benchmarked for a wide variety of systems and compared with other semiempirical methods. Along with excellent performance for the "target" properties, we also find lower errors for "off-target" properties such as barrier heights and mol. dipole moments. High computational efficiency along with the improved physics compared to it precursor GFN-xTB makes this method well-suited to explore the conformational space of mol. systems. Significant improvements are furthermore obsd. for various benchmark sets, which are prototypical for biomol. systems in aq. soln.
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- 50Lu, T.; Chen, F. Multiwfn: a multifunctional wavefunction analyzer. J. Comput. Chem. 2012, 33, 580– 592, DOI: 10.1002/jcc.22885[Crossref], [PubMed], [CAS], Google Scholar50https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsFykurjN&md5=deb758db27c2d0c4df698db0a3fd066fMultiwfn: A multifunctional wavefunction analyzerLu, Tian; Chen, FeiwuJournal of Computational Chemistry (2012), 33 (5), 580-592CODEN: JCCHDD; ISSN:0192-8651. (John Wiley & Sons, Inc.)Multiwfn is a multifunctional program for wavefunction anal. Its main functions are: (1) Calcg. and visualizing real space function, such as electrostatic potential and electron localization function at point, in a line, in a plane or in a spatial scope. (2) Population anal. (3) Bond order anal. (4) Orbital compn. anal. (5) Plot d.-of-states and spectrum. (6) Topol. anal. for electron d. Some other useful utilities involved in quantum chem. studies are also provided. The built-in graph module enables the results of wavefunction anal. to be plotted directly or exported to high-quality graphic file. The program interface is very user-friendly and suitable for both research and teaching purpose. The code of Multiwfn is substantially optimized and parallelized. Its efficiency is demonstrated to be significantly higher than related programs with the same functions. Five practical examples involving a wide variety of systems and anal. methods are given to illustrate the usefulness of Multiwfn. The program is free of charge and open-source. Its precompiled file and source codes are available from http://multiwfn.codeplex.com. © 2011 Wiley Periodicals, Inc. J Comput Chem, 2011.
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ARTICLE SECTIONSThe Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.0c04318.
Values of thermodynamic parameters related to the antioxidant mechanism of VC and its derivatives calculated in the water and gas phases at the B3LYP/6-31G* level; and optimized geometries of TS in the reaction between VC and its derivatives with OH• (PDF)
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