Chromanol Ring Research Articles

Synthesis of 2-aminopropyl benzopyran derivatives as potential agents against triple-negative breast cancer.

Synthesis of three series of 2-aminopropyl derivatives containing a benzopyran nucleus was performed to evaluate their performance against triple-negative breast cancer cell lines (MDA-MB-231 and MDA-MB-436) and normal breast epithelial cells (MCF10A). For the three series, the cytotoxic activity was as follows: N-methylated derivatives (tertiary amines) 5b, 6b, and 7b > secondary amine benzopyrans 5, 6, and 7 > quaternary amine salts 5c, 6c, and 7c > free phenolic derivatives 5a, 6a, and 7a. The structure-activity relationship showed the importance of the presence of an amine group and a p-fluorobenzyloxy substituent in the chromanol ring (IC50 values from 1.5 μM to 58.4 μM). In addition, 5a, 5b, 6a, and 7b displayed slight selectivity towards tumor cells. Compounds 5, 5a, 5b, 6, 6a, 6c, 7, and 7b showed apoptotic/necrotic effects due to, at least in part, an increase in reactive oxygen species generation, whereas 5b, 5c, 6b, 7a, and 7c caused cell cycle arrest in the G1 phase. Further cell-based mechanistic studies revealed that 5a, 6a, and 7b, which were the most promising compounds, downregulated the expression of Bcl-2, while 5b downregulated the expression of cyclins CCND1 and CCND2. Therefore, 2-aminopropyl benzopyran derivatives emerge as new hits and potential leads for developing useful agents against breast cancer.

Phase Transitions and Structural Changes in DPPC Liposomes Induced by a 1-Carba-Alpha-Tocopherol Analogue.

Steady-state emission spectroscopy of 1-anilino-8- naphthalene sulfonate (ANS) and 1,6-diphenyl-1,3,5-hexatriene (DPH), fluorescence anisotropy, and DSC methods were used to characterize the interactions of the newly synthesized 1-carba-alpha-tocopherol (CT) with a 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) membrane. The DSC results showed significant perturbations in the DPPC structure for CT concentrations as low as 2 mol%. The main phase transition peak was broadened and shifted to lower temperatures in a concentration-dependent manner, and pretransition was abolished. Increasing CT concentrations induced the formation of new phases in the DPPC structure, leading to melting at lower temperatures and, finally, disruption of the ordered DPPC structure. Hydration and structural changes of the DPPC liposomes using ANS and DPH fluorescent probes, which are selectively located at different places in the bilayer, were studied. With the increased concentration of CT molecules in the DPPC liposomes, structural changes with the simultaneous formation of different phases of such mixture were observed. Temperature studies of such mixtures revealed a decrease in the temperature of the main phase transition and fluidization at decreasing temperatures related to increasing hydration in the bilayer. Contour plots obtained from concentration–temperature data with fluorescent probes allowed for identification of different phases, such as gel, ordered liquid, disordered liquid, and liquid crystalline phases. The CT molecule with a modified chromanol ring embedded in the bilayer led to H-bonding interactions, expelling water molecules from the interphase, thus introducing disorder and structural changes to the highly ordered gel phase.

Spectroscopic Evidence for Photooxidation of Tocopherols in n-Hexane.

This paper presents the results of an investigation into the photooxidation of tocopherols (Tocs) dissolved in argonated and non-argonated n-hexane. During irradiation, steady-state absorption and fluorescence spectra as well as lifetimes were measured. In all experiments, the photoreactions were of the first order type. The reaction rate was higher for all Tocs in argonated solvent. A new emission band with a maximum at 298 nm as well as new absorption and fluorescence bands beyond the 300 nm connected with charge-transfer (C-T) complexes for all Tocs appeared during the irradiation of γ- and δ-Toc. The above results indicate that the photooxidation process is very complex and that the observed phenomena strongly depend on the number and position of methyl groups in the chromanol ring.

A computational study of effects on membrane recruitment of the polar linkers in Vitamin E derivatives

BackgroundPrevious studies found that Vitamin E (VE) could recruit protein kinase B (Akt1) to the membrane by targeting its unconventional lipid-binding site, which led to the dephosphorylation of Akt1 at Ser473, eventually deactivating the enzyme. MethodsA series of VE-like compounds with varying types and lengths of the linker groups are designed to study the VE-driven membrane recruitment of Akt1 using a combined molecular docking and molecular dynamics (MD) simulation approach. ResultsWe find that the linker groups with only one methylene linker and multiple hydrogen bond donors are optimal for achieving a balance between binding to the protein and partitioning into the membrane to form a stable protein-ligand-membrane ternary complex. These polar linkers are found to form stable hydrogen bonds with the lipid head groups during the MD simulations, which turns out critical for ensuring that the chromanol ring of the VE-like compounds resides above the membrane surface to fully engage in the protein. ConclusionsOur results reveal the molecular determinants of the linker groups for VE derivatives' ability to anchor Akt1 to the membrane. General significanceThese findings will facilitate the design of membrane interfacial compounds to recruit specific proteins to the membrane to modulate the protein function.

Vitamin E in Plants: Biosynthesis, Transport, and Function.

Vitamin E, which includes both tocopherols and tocotrienols, comprises lipid-soluble antioxidants that modulate lipid peroxidation. Recently, significant advances have been made in our understanding of vitamin E biosynthesis, transport, and function. The phytyl moiety from chlorophyll degradation is used for tocopherol biosynthesis. An α-tocopherol-binding protein (TBP) has been identified in tomato (SlTBP) serving in intraorganellar vitamin E transport in plants. Moreover, α-tocopherol not only scavenges free radicals through flip-flop movements in the lipid bilayer, but may also contribute to fine-tuning the transmission of specific signals outside chloroplasts. Vitamin E, and α-tocopherol in particular, appear to be essential for plant development and help to provide the most suitable response to a number of environmental stresses.

Mode of action of tocotrienol as anticancer

Tocotrienols are fat soluble substances members of the vitamin E family with the main properties of antioxidant. They are composed of the chiral center of chromanol ring with polypreniyl side chains. Research suggests that tocotrienols have a number of health benefit, and one of them as an anticancer agent. As an anticancer, tocotrienols could perform in different processes of the multi stages of cancer development and interact with other anticancer medicines and other bioactive substances, suchs geneistein, lovastin, hydroxychavicol, 6- gingerol and sesamin. The anticancer activities occur through their roles as antioxidant, coenzyme, gene expression regulator, and preventing cholesterol synthesis by inhibiting the expression of HMGCR enzyme after transcription, through this method, tocotrienols could control the cholesterol level of cancer cells and prevent the growth of the cancer. Tocotrienols target several signalling pathways at cellular and molecular levels.

α-Tocopherol transfer protein does not regulate the cellular uptake and intracellular distribution of α- and γ-tocopherols and -tocotrienols in cultured liver cells

Liver cells express a cytosolic α-tocopherol transfer protein (αTTP) with high binding affinity for α-tocopherol (αT) and much lower affinities for the non-αT congeners. The role of αTTP in the intracellular distribution of the different vitamin E forms is currently unknown. We therefore investigated the intracellular localization of αT, γ-tocopherol (γT), α-tocotrienol (αT3), and γ-tocotrienol (γT3) in cultured hepatic cells with and without stable expression of αTTP. We first determined cellular uptake of the four congeners and found the methylation of the chromanol ring and saturation of the sidechain to be important factors, with tocotrienols being taken up more efficiently than tocopherols and the γ-congeners more than the α-congeners, irrespective of the expression of αTTP. This, however, could perhaps also be due to an observed higher stability of tocotrienols, compared to tocopherols, in culture media rather than a higher absorption. We then incubated HepG2 cells and αTTP-expressing HepG2 cells with αT, γT, αT3, or γT3, isolated organelle fractions by density gradient centrifugation, and determined the concentrations of the congeners in the subcellular fractions. All four congeners were primarily associated with the lysosomes, endoplasmic reticulum, and plasma membrane, whereas only αT correlated with mitochondria. Neither the chromanol ring methylation or sidechain saturation, nor the expression of αTTP were important factors for the intracellular distribution of vitamin E. In conclusion, αTTP does not appear to regulate the uptake and intracellular localization of different vitamin E congeners in cultured liver cells.

Phenolic Group of α-Tocopherol Anchors at the Lipid-Water Interface of Fully Saturated Membranes.

α-Tocopherol is considered to carry on a very important role as an antioxidant for membranes and lipoproteins and other biological roles as membrane stabilizers and bioactive lipids. Given its essential role, it is very important to fully understand its location in the membrane. In this work, the vertical location of vitamin E in saturated membranes has been studied using biophysical techniques. Small- and wide-angle X-ray diffraction experiments show that α-tocopherol alters the water layer between bilayers in both 1,2-dimyristoyl- sn-glycero-3-phosphocholine (DMPC) and 1,2-dipalmitoyl- sn-glycero-3-phosphocholine (DPPC), indicating its proximity to this surface. The quenching of the intrinsic fluorescence of α-tocopherol indicates a low quenching efficiency by acrylamide and a higher quenching by 5-doxyl-PC than by 9- and 16-doxyl-PC. These results suggest that in both DMPC and DPPC membranes, the chromanol ring is not far away from the surface of the membrane but within the bilayer. 1H nuclear Overhauser enhancement spectroscopy magic-angle spinning-nuclear magnetic resonance studies showed that α-tocopherol is localized in a similar manner in DMPC and DPPC membranes, with the chromanol ring embedded in the upper part of the hydrophobic bilayer. Using attenuated total reflection-Fourier transform infrared spectroscopy, it was observed that the tail chain of α-tocopherol lies nearly parallel to the acyl chains of DMPC and DPPC. Taking these results together, it was concluded that in both DMPC and DPPC, the hydroxyl group of the chromanol ring will establish hydrogen bonding with water on the membrane surface, and the main axis of the α-tocopherol molecule will be perpendicular to the bilayer plane.

Theoretical Insights into the Switching Off/On of 1 O2 Photosensitization in Chemicontrolled Photodynamic Therapy.

Density Functional Theory and time-dependent (TD) DFT calculations were carried out for recently reported 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY)-based photosensitizers (PSs) that could be activated by reactive oxygen species (ROS) to generate 1 O2 specifically in target tissues. To assess the applicability of the compounds as activatable PSs (a-PSs) in photodynamic therapy, absorption wavelengths; singlet-triplet energy gaps; and spin-orbit matrix elements for the radiationless transition, Sn →Tm , were investigated. A TD-DFT qualitative analysis indicated that only a Br-substituted BODIPY derivative with the chromanol ring of α-tocopherol linked by methylene functioned as an a-PS. The chromanol ring promotes photoinduced electron transfer to the BODIPY unit that reduces the probability of intersystem crossing and triplet-state population, and can turn off 1 O2 photosensitization. Therefore, 1 O2 photosensitization can be switched on only in target cells in which the chromanol ring is oxidized by ROS. The oxidation reaction pathways of the most promising derivative, by either 1 O2 or cumyloxyl radical as typical ROS, have been examined to reveal that oxidation by the cumyloxyl radical is more effective than that by 1 O2 .

Structure-Function Relationship Studies In Vitro Reveal Distinct and Specific Effects of Long-Chain Metabolites of Vitamin E.

Cytochrome-dependent metabolism of vitamin E initially forms the long-chain metabolites (LCM) 13'-hydroxychromanols (13'-OH) and 13'-carboxychromanols (13'-COOH), which occur in human blood. Little is known about their biological functions. A structure-activity relationship study using α- and δ-tocopherol (TOH), their LCM (α-13'-OH, δ-13'-OH, α-13'-COOH, and δ-13'-COOH) and representatives of their substructures (α-carboxyethylhydroxychromanol and pristanic acid) is performed to unravel critical structural elements of the LCM for biological activity. Prominent effects are mediated by α- and δ-LCM, as scavenger receptor cluster of differentiation 36 (CD36) expression is induced in human THP-1 macrophages and lipopolysaccharide-stimulated inducible nitric oxide synthase (iNos) expression is inhibited in murine RAW264.7 macrophages, while the other molecules are less or not effective. The LCM effects depend on the presence of the chromanol ring system and on the modification of the side-chain but not on the substitution pattern of the chromanol ring. Therefore, it can be concluded that for mediation of effects by LCM the entire molecule is needed and that the effects are specific. We propose the LCM of the micronutrient vitamin E as a new class of regulatory metabolites, but further studies are needed to corroborate this hypothesis.

Chromatographic Separation of Vitamin E Enantiomers.

Vitamin E is recognized as an essential vitamin since its discovery in 1922. Most vegetable oils contain a mixture of tocopherols and tocotrienols in the vitamin E composition. Structurally, tocopherols and tocotrienols share a similar chromanol ring and a side chain at the C-2 position. Owing to the three chiral centers in tocopherols, they can appear as eight different stereoisomers. Plant sources of tocopherol are naturally occurring in the form of RRR while synthetic tocopherols are usually in the form of all-racemic mixture. Similarly, with only one chiral center, natural tocotrienols occur as the R-isoform. In this review, we aim to discuss a few chromatographic methods that had been used to separate the stereoisomers of tocopherols and tocotrienols. These methods include high performance liquid chromatography, gas chromatography and combination of both. The review will focus on method development including selection of chiral columns, detection method and choice of elution solvent in the context of separation efficiency, resolution and chiral purity. The applications for separation of enantiomers in vitamin E will also be discussed especially in terms of the distinctive biological potency among the stereoisoforms.

Separation of Vitamin E on a 100-Å Phenogel Column

The effect of π-electrons and hydroxyl group on the separations of vitamin E on a swelling-controlled polystyrene-divinylbenzene (Phenogel) column using toluene/isooctane as the mobile phase was investigated. The effect of the π-electrons was demonstrated in the baseline separation of α-tocopherol and α-tocotrienol on a 100-Å Phenogel column. In addition, baseline separation of α-, (β-+γ-)- and δ-tocopherol could be achieved on this column. The separation mechanism of these isomers are due to the difference in the interactions between the hydroxyl group on the chromanol ring of each tocopherol and the gel matrix caused by the steric hindrance of methyl group(s). It was concluded that solutes of the same molecular size but different in the polar groups could be separated on a high performance size-exclusion chromatography by controlling the swelling of the gel matrix via modification of the mobile phase.

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Oxidative stress, a state characterized by imbalance between pro-oxidant molecules comprising reactive oxygen and nitrogen species, and antioxidant defences, has been found to play an important in poultry reproduction in both male and female Increasing evidence suggests that vitamin E plays an important role in normal reproduction in animals and humans, and vitamin E supplementation is now recommended. Vitamin E comprises eight molecules composed by a chromanol ring and a phytol side chain having same functions: four tocopherols (α, β, γ, and δ) and four tocotrienols (α, β, γ, and δ). This article reports an overview on the currently available literature on the role of reactive species and oxidative stress in avian reproductive processes. Current evidences demonstrate that dietary vitamin E supplementation may be effective in controlling the production of reactive oxygen species and continue to be explored as a potential feeding strategy to support avian reproduction.

The rise, the fall and the renaissance of vitamin E

This review deals with the expectations of vitamin E ability of preventing or curing, as a potent antioxidant, alleged oxidative stress based ailments including cardiovascular disease, cancer, neurodegenerative diseases, cataracts, macular degeneration and more. The results obtained with clinical intervention studies have highly restricted the range of effectiveness of this vitamin. At the same time, new non-antioxidant mechanisms have been proposed. The new functions of vitamin E have been shown to affect cell signal transduction and gene expression, both in vitro and in vivo. Phosphorylation of vitamin E, which takes place in vivo, results in a molecule provided with functions that are in part stronger and in part different from those of the non-phosphorylate compound. The in vivo documented functions of vitamin E preventing the vitamin E deficiency ataxia (AVED), slowing down the progression of non-alcoholic steato-hepatitis (NASH), decreasing inflammation and potentiating the immune response are apparently based on these new molecular mechanisms. It should be stressed however that vitamin E, when present at higher concentrations in the body, should exert antioxidant properties to the extent that its chromanol ring is unprotected or un-esterified.

Reactive Oxygen Species Mediated Activation of a Dormant Singlet Oxygen Photosensitizer: From Autocatalytic Singlet Oxygen Amplification to Chemicontrolled Photodynamic Therapy.

Here we show the design, preparation, and characterization of a dormant singlet oxygen ((1)O2) photosensitizer that is activated upon its reaction with reactive oxygen species (ROS), including (1)O2 itself, in what constitutes an autocatalytic process. The compound is based on a two segment photosensitizer-trap molecule where the photosensitizer segment consists of a Br-substituted boron-dipyrromethene (BODIPY) dye. The trap segment consists of the chromanol ring of α-tocopherol, the most potent naturally occurring lipid soluble antioxidant. Time-resolved absorption, fluorescence, and (1)O2 phosphorescence studies together with fluorescence and (1)O2 phosphorescence emission quantum yields collected on Br2B-PMHC and related bromo and iodo-substituted BODIPY dyes show that the trap segment provides a total of three layers of intramolecular suppression of (1)O2 production. Oxidation of the trap segment with ROS restores the sensitizing properties of the photosensitizer segment resulting in ∼40-fold enhancement in (1)O2 production. The juxtaposed antioxidant (chromanol) and prooxidant (Br-BODIPY) antagonistic chemical activities of the two-segment compound enable the autocatalytic, and in general ROS-mediated, activation of (1)O2 sensitization providing a chemical cue for the spatiotemporal control of (1)O2.The usefulness of this approach to selectively photoactivate the production of singlet oxygen in ROS stressed vs regular cells was successfully tested via the photodynamic inactivation of a ROS stressed Gram negative Escherichia coli strain.

Complexity of vitamin E metabolism.

Bioavailability of vitamin E is influenced by several factors, most are highlighted in this review. While gender, age and genetic constitution influence vitamin E bioavailability but cannot be modified, life-style and intake of vitamin E can be. Numerous factors must be taken into account however, i.e., when vitamin E is orally administrated, the food matrix may contain competing nutrients. The complex metabolic processes comprise intestinal absorption, vascular transport, hepatic sorting by intracellular binding proteins, such as the significant α-tocopherol-transfer protein, and hepatic metabolism. The coordinated changes involved in the hepatic metabolism of vitamin E provide an effective physiological pathway to protect tissues against the excessive accumulation of, in particular, non-α-tocopherol forms. Metabolism of vitamin E begins with one cycle of CYP4F2/CYP3A4-dependent ω-hydroxylation followed by five cycles of subsequent β-oxidation, and forms the water-soluble end-product carboxyethylhydroxychroman. All known hepatic metabolites can be conjugated and are excreted, depending on the length of their side-chain, either via urine or feces. The physiological handling of vitamin E underlies kinetics which vary between the different vitamin E forms. Here, saturation of the side-chain and also substitution of the chromanol ring system are important. Most of the metabolic reactions and processes that are involved with vitamin E are also shared by other fat soluble vitamins. Influencing interactions with other nutrients such as vitamin K or pharmaceuticals are also covered by this review. All these processes modulate the formation of vitamin E metabolites and their concentrations in tissues and body fluids. Differences in metabolism might be responsible for the discrepancies that have been observed in studies performed in vivo and in vitro using vitamin E as a supplement or nutrient. To evaluate individual vitamin E status, the analytical procedures used for detecting and quantifying vitamin E and its metabolites are crucial. The latest methods in analytics are presented.

Vitamin E therapy beyond cancer: Tocopherol versus tocotrienol.

The discovery of vitamin E (α-tocopherol) began in 1922 as a vital component required in reproduction. Today, there are eight naturally occurring vitamin E isoforms, namely α-, β-, γ- and δ-tocopherol and α-, β-, γ- and δ-tocotrienol. Vitamin E is potent antioxidants, capable of neutralizing free radicals directly by donating hydrogen from its chromanol ring. α-Tocopherol is regarded the dominant form in vitamin E as the α-tocopherol transfer protein in the liver binds mainly α-tocopherol, thus preventing its degradation. That contributed to the oversight of tocotrienols and resulted in less than 3% of all vitamin E publications studying tocotrienols. Nevertheless, tocotrienols have been shown to possess superior antioxidant and anti-inflammatory properties over α-tocopherol. In particular, inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase to lower cholesterol, attenuating inflammation via downregulation of transcription factor NF-κB activation, and potent radioprotectant against radiation damage are some properties unique to tocotrienols, not tocopherols. Aside from cancer, vitamin E has also been shown protective in bone, cardiovascular, eye, nephrological and neurological diseases. In light of the different pharmacological properties of tocopherols and tocotrienols, it becomes critical to specify which vitamin E isoform(s) are being studied in any future vitamin E publications. This review provides an update on vitamin E therapeutic potentials, protective effects and modes of action beyond cancer, with comparison of tocopherols against tocotrienols. With the concerted efforts in synthesizing novel vitamin E analogs and clinical pharmacology of vitamin E, it is likely that certain vitamin E isoform(s) will be therapeutic agents against human diseases besides cancer.

OP41 - Methylation at positon 7’ but not 5’ and the isoprenoid chain are required for vitamin E to induce P-glycoprotein protein expression and activity in the human colon carcinoma cell line LS180

The eight congeners of vitamin E differ in their methylation pattern and either possess an alkyl (tocopherols, T) or an isoprenoid (tocotrienols, T3) side chain. The different chemical structures influence the biological activity of the vitamin, like the binding to the nuclear pregnane X receptor (PXR). P-glycoprotein (P-gp), a PXR target gene, is an efflux transporter expressed at various barriers in the body including small intestine, bile ducts and the blood-brain-barrier. We therefore investigated the impact of methylation of the chromanol ring (position 5’ and 7’ = α; position 7’ = γ) and the structure of the side chain on the expression and activity of P-gp. LS180 cells, which have a low basal P-gp expression, are a good model to study the induction of P-gp protein expression and activity. LS180 cells were either treated with the positive control rifampicin (25 µmol/L), a known P-gp inducer, the appropriate solvent control, or the respective vitamin E congener for 48 hours. αT was investigated in the range of 10–100 µmol/L, γT 10-50 µmol/L, αT3 5-50 µmol/L and γT 5-25 µmol/L due to differences in cell toxicity. Protein expression was determined by Western blot analysis and P-gp activity via the efflux of the fluorescent substrate rhodamine 123 in the presence or absence of the P-gp specific inhibitor elacridar. αT, γT and αT3 neither influenced the protein expression nor the activity of P-gp. γT3 induced P-glycoprotein activity and protein expression which is in accordance with the literature. To induce P-glycoprotein, both methylation at position 7’ but not 5’ of the chromanol ring as well as an isoprenoid side chain are required as none of the two structural features individually showed an effect.

Anticancer and antiangiogenic activity of surfactant-free nanoparticles based on self-assembled polymeric derivatives of vitamin E: structure-activity relationship.

α-Tocopheryl succinate (α-TOS) is a well-known mitochondrially targeted anticancer compound, however, it is highly hydrophobic and toxic. In order to improve its activity and reduce its toxicity, new surfactant-free biologically active nanoparticles (NP) were synthesized. A methacrylic derivative of α-TOS (MTOS) was prepared and incorporated in amphiphilic pseudoblock copolymers when copolymerized with N-vinylpyrrolidone (VP) by free radical polymerization (poly(VP-co-MTOS)). The selected poly(VP-co-MTOS) copolymers formed surfactant-free NP by nanoprecipitation with sizes between 96 and 220 nm and narrow size distribution, and the in vitro biological activity was tested. In order to understand the structure-activity relationship three other methacrylic monomers were synthesized and characterized: MVE did not have the succinate group, SPHY did not have the chromanol ring, and MPHY did not have both the succinate group and the chromanol ring. The corresponding families of copolymers (poly(VP-co-MVE), poly(VP-co-SPHY), and poly(VP-co-MPHY)) were synthesized and characterized, and their biological activity was compared to poly(VP-co-MTOS). Both poly(VP-co-MTOS) and poly(VP-co-MVE) presented triple action: reduced cell viability of cancer cells with little or no harm to normal cells (anticancer), reduced viability of proliferating endothelial cells with little or no harm to quiescent endothelial cells (antiangiogenic), and efficiently encapsulated hydrophobic molecules (nanocarrier). The anticancer and antiangiogenic activity of the synthesized copolymers is demonstrated as the active compound (vitamin E or α-tocopheryl succinate) do not need to be cleaved to trigger the biological action targeting ubiquinone binding sites of complex II. Poly(VP-co-SPHY) and poly(VP-co-MPHY) also formed surfactant-free NP that were also endocyted by the assayed cells; however, these NP did not selectively reduce cell viability of cancer cells. Therefore, the chromanol ring of the vitamin E analogues has an important role in the biological activity of the copolymers. Moreover, when succinate moiety is substituted and vitamin E is directly linked to the macromolecular chain through an ester bond, the biological activity is maintained.

The DFT local reactivity descriptors of α-tocopherol.

The calculations of local reactivity descriptors, the electron donor Fukui function f(-)(r), the average local ionization energy Ī(r), the Fukui function dual descriptor f((2))(r), and the electron acceptor Fukui function f(+)(r) for α-tocopherol, the main biologically active form of vitamin E for antioxidant reactions in phospholipid membranes, is presented. The calculations are performed at B3LYP/6-311++G** level of theory in the gas-phase. The obtained results indicate that the most preferred sites for donating electron in a reaction with radical or oxidizing molecule are associated mostly with π electrons above and below the aromatic part of the α-tocopherol chromanol ring. The most reactive sites for accepting electrons are associated with the leaving H(9) atom in the extension of the phenolic OH bond on the α-tocopherol chromanol ring plane, in the place where the formation of H-bond of the precursor complex between approaching reactive oxygen radical and phenolic OH group of α-tocopherol could be expected. The separated reactive sites in α-tocopherol suggest that the proton and electron, along with the hydrogen atom transfer (HAT) process, could also be transferred to different proton and electron acceptors as in bidirectional proton coupled electron transfer (PCET) reactions. The results presented in this paper suggest that large charge redistribution and significant π-π interactions may be expected in antioxidant reactions of α-tocopherol.