Calculations based on the density functional theory, with the B3LYP functional and the 6-311++G(d,p) basis set, were performed with the aim of confirming the molecular structure and spectroscopic characteristics of kaempferol, a naturally occurring flavonoid molecule. The electronic structure of kaempferol was examined using NBO analysis. The assigning of the experimentally obtained IR and Raman spectra was performed after the best-fit-based comparison with theoretical spectra. The C-13 and H-1 NMR experimental spectra were related to the theoretically obtained values of the chemical shifts determined by the GIAO method. The correlation coefficient and the average absolute error values proved B3LYP-D3 to be an adequate method in describing the NMR parameters of kaempferol. Molecular docking analysis was carried out in order to identify the potency of inhibition of the title molecule against human procalcitonin. The inhibition activity was obtained for 10 conformations of ligand inside the protein.

Flavylium salts substituted at 4-position with hydroxyphenyl substituents were synthesized by acidic condensation according to a slightly modified procedure described by Robinson and Walker. Their thermodynamic properties and conformational analysis have been studied at DFT level.

Reaction energetics of the double (2H(+)/2e(-)), i.e., the first 1H(+)/1e(-) (catechol -> phenoxyl radical) and the second 1H(+)/1e(-) (phenoxyl radical -> quinone) free radical scavenging mechanisms of quercetin and its six colonic catecholic metabolites (caffeic acid, hydrocaffeic acid, homoprotocatechuic acid, protocatechuic acid, 4-methylcatechol, and catechol) were computationally studied using density functional theory, with the aim to estimate the antiradical potency of these molecules. We found that second hydrogen atom transfer (HAT) and second sequential proton loss electron transfer (SPLET) mechanisms are less energy demanding than the first ones indicating 2H(+)/2e(-) processes as inherent to catechol moiety. The Gibbs free energy change for reactions of inactivation of selected free radicals indicate that catecholic colonic metabolites constitute an efficient group of more potent scavengers than quercetin itself, able to deactivate various free radicals, under different biological conditions. They could be responsible for the health benefits associated with regular intake of flavonoid-rich diet. (C) 2016 Elsevier Ltd. All rights reserved.

Phloretic acid is one of the most abundant colon catabolites of various classes of polyphenols (e.g., polymeric proanthocyanidins, tea catechins, and ellagitannins). In this paper thermodynamics of 2H(+)/2e(-) radical scavenging mechanisms of phloretic acid was studied. For the first time the involvement of carboxyl group in double hydrogen atom transfer (dHAT), double electron transfer-proton transfer (dET-PT) and sequential double proton loss double electron transfer (SdPLdET) processes was investigated. Obtained results indicate that phloretic acid possesses potential for inactivating radicals of different characteristics (HO center dot, HOO center dot, CH3O center dot, CH3OO center dot, CH2=CH-O-O-center dot, PhO center dot, Cl3COO center dot etc.) via dHAT and SdPLdET mechanisms. Because phloretic acid is usually better absorbed than its precursor molecules, it may contribute to health benefits associated with regular intake of polyphenol-rich diet by direct scavenging of radicals.

Free radical scavenging and inhibitory potency against cyclooxygenase-2 (COX-2) by two abundant colon metabolites of polyphenols, i.e., 3-hydroxyphenylacetic acid (3-HPAA) and 4-hydroxyphenylpropionic acid (4-HPPA) were theoretically studied. Different free radical scavenging mechanisms are investigated in water and pentyl ethanoate as a solvent. By considering electronic properties of scavenged free radicals, hydrogen atom transfer (HAT) and sequential proton loss electron transfer (SPLET) mechanisms are found to be thermodynamically probable and competitive processes in both media. The Gibbs free energy change for reaction of inactivation of free radicals indicates 3-HPAA and 4-HPPA as potent scavengers. Their reactivity toward free radicals was predicted to decrease as follows: hydroxyl >> alkoxyls > phenoxyl ≈ peroxyls >> superoxide. Shown free radical scavenging potency of 3-HPAA and 4-HPPA along with their high μM concentration produced by microbial colon degradation of polyphenols could enable at least in situ inactivation of free radicals. Docking analysis with structural forms of 3-HPAA and 4-HPPA indicates dianionic ligands as potent inhibitors of COX-2, an inducible enzyme involved in colon carcinogenesis. Obtained results suggest that suppressing levels of free radicals and COX-2 could be achieved by 3-HPAA and 4-HPPA indicating that these compounds may contribute to reduced risk of colon cancer development.

Naturally occurring flavonoids, delphinidin, pelargonidin and malvin, were investigated experimentally and theoretically for their ability to scavenge hydroxyl and nitric oxide radicals. Electron spin resonance (ESR) spectroscopy was used to determine antiradical activity of the selected compounds and M05-2X/6-311+G(d,p) level of theory for the calculation of reaction enthalpies related to three possible mechanisms of free radical scavenging activity, namely HAT, SET-PT and SPLET. The results obtained show that the molecules investigated reacted with hydroxyl radical via both HAT and SPLET in the solvents investigated. These results point to HAT as implausible for the reaction with nitric oxide radical in all the solvents investigated. SET-PT also proved to be thermodynamically unfavourable for all three molecules in the solvents considered.

Hydroxybenzoic acids (HBAs) and their anions play an important role in the food and pharmaceutical industries because of their antioxidant activity. In this study, we examined the mechanisms of the free radical scavenging action of HBAs and their anions using density functional theory (DFT) methods. Reaction enthalpies related to the mechanisms of free radical scavenging by the investigated species were calculated by DFT methods in water, DMSO, pentylethanoate, and benzene. Hydrogen atom transfer (HAT) is a preferred reaction pathway in benzene, while sequential proton loss electron transfer (SPLET) is a predominant reaction pathway in polar solvents, water, and DMSO for all species. For anions of HBAs, HAT and SPLET mechanisms in pentylethanoate are competitive, while SPLET is the most probable pathway in the case of HBAs.

The antioxidant activity of chrysophanol (CH), emodin (EM), aloe-emodin (AE), and 1,3,8-trihydroxyanthraquinone (THA) was examined in water and pentyl ethanoate by using the M052X/6-311++G(d,p) level of theory. It was shown that hydrogen bonds are of significant importance for the stability of the radical and anionic species obtained in the HAT and SPLET mechanisms. Consequently, all radicals and anions formed with retention of 09 center dot center dot center dot H1-O1 and 09 center dot center dot center dot H8-O8 hydrogen bonds are more stable than those where the hydrogen bonds are disturbed. The exceptions are the radical and anion of AE, the unpaired electron or negative charge is poorly delocalized.The high IP values for all investigated compounds undoubtedly discredit the SET-PT mechanism. Since the PA values are notably lower than the BDE values, one can conclude that SPLET is more favorable reaction pathway than the HAT mechanism in both solvents. In the case of CH and AE 1-OH and 8-OH are the most reactive sites for radical inactivation, while 3-OH is the most reactive site for EM and THA. The examined compounds are moderate antioxidants. (C) 2015 Elsevier B.V. All rights reserved.

3-Hydroxyphenylacetic acid (3-HPA) is one of the colon microbial metabolites of flavonoids produced in high concentrations (∼300 μM). In this work potency of direct inactivating of selected set of free radicals by 3-HPA was computationally investigated. All calculations were carried out using M05-2X functional with 6-311++G(d, p) basis set coupled with the SMD solvation model. Thermodynamics of three free radical scavenging mechanisms were studied considering electronic properties of 3-HPA and scavenged free radicals. On the basis of obtained results it can be safety predicted that 3-HPA is able to at least in situ effectively scavenge free radicals of different nature, thus contributing to protection from diseases mediated by oxidative stress.

Double (2H(+)2e(-)) free radical scavenging mechanisms of the most abundant endogenous plasma antioxidant uric acid were theoretically studied using DFT method M05-2X/6-311++G(d,p) coupled with SMD solvation model. Calculations were performed for double, two sequential 1H(+)/1e(-) hydrogen atom transfer (HAT), double electron transfer followed by proton transfer (ET-PT) and double sequential proton loss electron transfer (SPLET) mechanisms in water as a solvent. It was found that inactivation of the first free radical by uric acid (the first 1H(+)+/1e(-) mechanism) occurs at its 3-N site and inactivation of another one (the second 1H(+)+/1e(-) mechanism) occurs at 7-N site of uric acid 3-N-center dot radical. The final product of all studied 2H(+)/2e(-) pathways is uric acid quinonoid diimine. Obtained results point to the SPLET mechanism as the favorable free radical scavenging mechanism by uric acid. Taking into account electronic properties of scavenged free radicals, double HAT mechanism is found to be competitive to double SPLET mechanism. Second mechanisms are less energy demanding than the first ones indicating 2H(+)/2e(-) processes as plausible. On the basis of exergonicity of the calculated reaction free energies, the reactivity of uric acid toward free radicals was predicted to decrease as follows: HO center dot and Cl3COO center dot > alkoxyl, peroxyl >> superoxide radical. (C) 2015 Elsevier B.V. All rights reserved.

Various plant polyphenols have been recognized as redox active molecules. This review discusses some aspects of polyphenols' modes of redox action, corresponding structure-activity relationships and their potential to be applied as adjuvants to conventional cytostatic drugs. Polyphenols' antioxidative capacity has been discussed as the basis for targeting oxidative stress and, consequently, for their chemopreventive and anti-inflammatory activities, which may alleviate side-effects on normal cells arising from oxidative stress caused by cytostatics. Some polyphenols may scavenge various free radicals directly, and some of them are found to suppress free radical production through inhibiting NADPH oxidases and xanthine oxidase. Additionally, polyphenols may increase antioxidative defense in normal cells by increasing the activity of NRF2, transcription factor for many protective proteins. The activation of the NRF2-mediated signaling pathways in cancer cells results in chemoresistance. Luteolin, apigenin and chrysin reduce NRF2 expression and increase the chemosensitivity of cancer cells to cytostatic drugs. Their common 5,7-dihydroxy-4H-chromen-4-one moiety, may represent a starting pharmacophore model for designing novel, non-toxic compounds for overcoming chemoresistance. However, prooxidative activity of some polyphenols (quercetin, EGCG) may also provide a basis for their use as chemotherapeutic adjuvants since they may enhance cytotoxic effects of cytostatics selectively on cancer cells. However, considerable caution is needed in applying polyphenols to anticancer therapy, since their effects greatly depend on the applied dose, the cell type, exposure time and environmental conditions.