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Transformations of chromanol and tocopherol and synthesis of ascorbate conjugates
Abstract
α-Tocopherol and as a model compound pentamethylchromanol could be transferred into simple and more complex 5a-ether derivatives including galactopyranose as well as ascorbic acid conjugates. Following elaboration of a glucopyranoside spacer element this could be used for tethering the vitamin E and the vitamin C components to give novel conjugates for subsequent biostudies concerning their proposed synergism of antioxidant properties in tissues.
... [45][46][47][48][49] Most of the synthetic chroman derivatives are conjugates with other antioxidant moieties or various pharmacophores. [50][51][52][53][54][55][56] Further, structural modifications to improve the antioxidant capacity of vitamin E include the introduction of heteroatoms such as sulfur, selenium and tellurium in various positions of the chroman scaffold. [57] Nanoparticle functionalization by trolox or other 2-subtituted chromans is a recent interesting strategy for the development of products with enhanced antioxidant activity and reduced toxicity. ...
... The invention [74] discloses analogues of tocopherol, tocotrienol and 1-azatocopherol in which the 6-OH group is alkylated. Synthetic procedures are described and analytical data are given, as well as determination of EC 50 Cell adhesion represents an important therapeutic target not only in oncology but also in acute and chronic inflammatory diseases and autoimmune inflammation. The development of agents targeting cell adhesion has focused on the blockade of integrin-ligand interactions by using monoclonal antibodies, antisense oligonucleotides or small interference RNAs, whereas very few small-molecule agents have been developed. ...
Introduction:
The vitamin E family consists of four tocopherols and four tocotrienols. α-Tocopherol is the most studied member of this family for its antioxidant and non-antioxidant properties, while tocotrienols have attracted recent research interest. The structural motifs of the vitamin E family and specifically the chroman moiety, are amenable to various modifications in order to improve their bioactivities towards numerous therapeutic targets. Areas covered: This review includes the patent literature from 2010 - 2015 related to vitamin E derivatives and it is focused on 2-, 5- or 6-substituted chroman analogues. The patent search was performed using Reaxys® and esp@cenet. Expert opinion: The chroman moiety of vitamin E is a privileged structure and an essential pharmacophore which inspired organic chemists to synthesize new analogues with improved bioactivities. Modifications at the 2- and 5- positions of the chroman ring resulted in very interesting active compounds in cellular and animal models of diseases related to oxidative stress. More recent publications and patents reported 6-substituted chromans as anticancer agents in vitro and in vivo. Additionally, an emerging interest is observed towards the use of vitamin E analogues incorporated in drug delivery systems and for medical imaging as contrast agents or fluorescent probes.
... Notably, 15m has been used in the glyco-or peptido-conjugation of interest in several biological studies [34][35][36] ; however, multistep synthetic sequences have been required 34 . To the best of our knowledge, these oxidative C-N coupling reactions have not been reported and provide a new entry to the synthesis of benzylic amine derivatives. ...
ortho-Quinone methides are useful transient synthetic intermediates in organic synthesis. These species are most often generated in situ by the acid- or base-mediated transformation of phenols that have been pre-functionalized at a benzylic position, or by biomimetic oxidation of the corresponding ortho-alkylphenols with metal oxidants or transition-metal complexes. Here we describe a method for the transition-metal-free oxidative generation of o-QMs from ortho-alkylarenols, using hypoiodite catalysis under nearly neutral conditions, which can then be applied in one-pot tandem reactions. This method for the chemoselective oxidative generation of ortho-quinone methides may prove superior to previous methods with respect to environmental issues and scope, and can be applied to various tandem reactions such as inter- or intramolecular [4 + 2] cycloaddition, oxa-6π-electrocyclization, conjugate addition and spiroepoxidation.
1,2,3-Triazoles with 1-position substituents, derived from α-tocopherol (vitamin E), were synthesized by 1,3-dipolar cycloaddition reactions of 5a-azido-α-tocopheryl acetate with alkynes, and were fully analytically characterized. NMR spectra of the compounds and crystal structures of derivatives with a truncated isoprenoid side chain are presented. The tocopheryl moiety is readily cleaved in basic media, as a prerequisite for the use in delivery systems showing pH-dependent drug release. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)
The synthesis of a new carbohydrate cholesterol substituted porphyrin is described. Due to its amphiphilic character this compound is easily built into model membranes. Furthermore, the vesicle forming properties of compound 4 were investigated by light scattering experiments and electron microscopy.
Efficient conversion of alkenes to acetals has been achieved by consecutive hydroformylation-acetalization reactions catalyzed by rhodium complexes and pyridinium p-toluenesulphonate or by a zwitterionic rhodium catalyst.
The antioxidant activities of 48 kinds of aminophenols, chromanols, indoles, carbazoles, aromatic amines, and related compounds were assessed in the oxidations of methyl linoleate in acetonitrile solution induced by azo radical initiator. Chromanols, aminochroman and p-phenylenediamines exhibited strong antioxidant activity. Indole and carbazole did not act as antioxidant per se, but those having either amino or hydroxy group as substituent at the para position acted as potent antioxidant. Amine-substituted compounds were in general more potent than hydroxy-substituted ones. These results were interpreted by both polar and resonance effect.
Protected β-oxy aldehydes react easily with 1,1-dimethoxypropene (1a) in the presence of ZnCl2 to give 2,2-dimethoxyoxetanes. Hydrolysis of these oxetanes and deprotection of the latent hydroxy function in a one-pot procedure gives 4-hydroxy-δ-lactones in moderate to good yields. Starting with β-oxy aldehydes having an α-branched side chain and defined stereochemistry, δ-lactones with completely defined stereochemistry can be synthesized. Dehydration of the hydroxy lactones with concentrated sulphuric acid gives easy access to 5,6-dihydro-2-pyrones. The usefulness of this route is demonstrated in the synthesis of a simple, optically active 5,6-dihydro-2-pyrone (37).
α-Tocopheryl alto-oligosaccharides were prepared as antioxidants water soluble.
2-(Per-O-acetyl-β-d-glycopyranosyl)-1,4-dimethoxybenzenes led to C-glycosyl-hydroquinones suitable for preparing C-glycosylated analogs of vitamin E, having the sugar moiety free or acetylated.
The reaction of α-tocopheryl acetate (vitamin E acetate, 3) with concentrated nitric acid proceeds according to a non-radical, two-step mechanism, producing 5-nitromethyl-γ-tocopheryl acetate (4) in good yields. In the first step, oxidation of 3 affords a benzylic cation intermediate (8), which in the second step adds nitrite to give 4. The acetyl group, which stabilizes intermediate 8 intramolecularly, remains bound to the tocopheryl moiety throughout the reaction.
Bromination of α-tocopherol is shown to proceed as a two-step process including the occurrence of an ortho-quinone methide, not as a radical-chain reaction, contrary to earlier reports. The ortho-quinone methide intermediate is also produced by oxidation of a-tocopherol with silver oxide and can be trapped in the presence of electron-rich dienophiles in a hetero-Diels-Alder reaction to form novel dichromanes in high yields.
Two series of C- and O-arylglycosides with potential antioxidant properties have been synthesized, characterized and structurally differentiated. Reinvestigation of a synthetic approach has provided better insight into the products obtained and their chemical structures. Regio- and stereochemical characterization and differentiation of each compound have been carried out in solution, in the crystal, and in the gas phase. A comparison between the data obtained in solution and the crystal structures suggests closely related features in the two states. Mass spectrometry proved very effective for characterization of and differentiation between C- and O-isomers, as well as positional isomers. Unimolecular reactions occurring in the gas phase are specific to the chemical structures, and ion abundances can be related to their stabilities. This study has allowed the evaluation of the influences of the different linkages between the two moieties and the positions of the substituents on the chemical properties of the compounds. The C-isomers show antioxidant capability, as peroxyl radical scavengers, and inhibit lipid peroxidation. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)
Thermally labile azo-initiators, dissolved in either the aqueous or lipid phase, have been used to generate peroxyl radicals at a known, steady rate in an aqueous dispersion of dilinoleoylphosphatidylcholine multilamellar liposomes at 37° C in order to study the antioxidant behaviour of ascorbate itself and ascorbate in combination with either α-tocopherol or a water-soluble α-tocopherol analogue (TROLOX(−)). It is found that ascorbate is an effective inhibitor of peroxidations initiated in the aqueous phase, with each ascorbate terminating 0.6 radical chains (i.e., n = 0.6), but it is a very poor inhibitor of peroxidations initiated in the lipid phase. Peroxidations initiated in the lipid-phase in the presence of either α-tocopherol or TROLOX(−) indicate that ascorbate is an excellent synergist with both phenolic antioxidants (n = 0.4). In peroxidations initiated in the aqueous phase ascorbate acts as a co-antioxidant with TROLOX(−) (n = 0.7), but the interpretation of the approximately additive effect obtained in the presence of α-tocopherol is complicated by the fact that under the experimental conditions employed α-tocopherol alone does not give a distinct, measurable inhibition period. The latter problem is shown to be due to a non-uniform distribution of the water-soluble initiator within the liposome. Other examples of the complicating effects of non-uniform distributions of reactants in kinetic studies of the autoxidation of organic substrates dispersed in water are described.
VITAMIN E (α-tocopherol) and vitamin C (ascorbic acid) react
rapidly with organic free radicals, and it is widely accepted that the
antioxidant properties of these compounds are responsible in part for
their biological activity1-5. Tissue vitamin C levels are
often considerably greater than those of vitamin E, for example in liver
the values are approximately 2 mM and 0.02 mM, respectively.
Nevertheless, vitamin E is considerably more lipophilic than vitamin C,
and in biomembranes has been found to be the more potent antioxidant,
particularly with respect to lipid peroxidation; penetration to a
precise site in the membrane may be an important feature of the
protection against highly reactive radicals6. Tappel has
suggested that the two vitamins act synergistically, vitamin E acting as
the primary antioxidant and the resulting vitamin E radical then
reacting with vitamin C to regenerate vitamin E7. We now
report direct observation of this interaction, which we feel may be an
important feature in the maintenance of vitamin E levels in tissues.
The effects of L-ascorbic acid 2-[3,4-dihydro-2,5,7,8-tetramethyl-2- (4,8,12-trimethyltridecyl)-2H-1-benzopyran-6yl-hydrogen phosphate] potassium salt (EPC-K1, CAS 127061-56-7), a new compound for ischemia-reperfusion injuries, on lipid peroxidation and phospholipase A2 activity were studied in vitro using rat brain homogenates and human plasma. EPC-K1 inhibited phospholipase A2 activity in human plasma in a concentration-dependent manner (IC50 = 7.3 x 10(-4) mol/l), whereas a mixture of alpha-tocopherol and ascorbic acid did not exhibit this effect. In rat brain homogenates, EPC-K1 also inhibited lipid peroxidation in a concentration-dependent manner (IC50 = 2.3 x 10(-6) mol/l). alpha-Tocopherol was less active than EPC-K1. These properties of EPC-K1 suggest that EPC-K1 may prove useful in the treatment of ischemia-reperfusion injuries.
Oxidation of the biological antioxidant alpha-tocopherol (vitamin E; TH) by peroxyl radicals yields 8a-(alkyldioxy)tocopherones, which either may hydrolyze to alpha-tocopheryl quinone (TQ) or may be reduced by ascorbic acid to regenerate TH. To define the chemistry of this putative two-electron TH redox cycle, we studied the hydrolysis and reduction of 8a-[(2,4-dimethyl-1-nitrilopent-2-yl)dioxy]tocopherone (1) in acetonitrile/buffer mixtures and in phospholipid liposomes. TQ formation in acetonitrile/buffer mixtures, which was monitored spectrophotometrically, declined with increasing pH and could not be detected above pH 4. The rate of TQ formation from 1 first increased with time and then decreased in a first-order terminal phase. Rearrangement of 8a-hydroxy-alpha-tocopherone (2) to TQ displayed first-order kinetics identical with the terminal phase for TQ formation from 1. Both rate constants increased with decreasing pH. Hydrolysis of 1 in acetonitrile/H2(18)O yielded [18O]TQ. These observations suggest that 1 loses the 8a-(alkyldioxy) moiety to produce the tocopherone cation (T+), which hydrolyzes to 2, the TQ-forming intermediate. Incubation of either 1 or 2 with ascorbic acid in acetonitrile/buffer yielded TH. Reduction of both 1 and 2 decreased with increasing pH. In phosphatidylcholine liposomes at pH 7, approximately 10% of the T+ generated from 1 was reduced to TH by 5 mM ascorbic acid. The results collectively demonstrate that T+ is the ascorbic acid reducible intermediate in a two-electron TH redox cycle, a process that probably would require biocatalysis to proceed in biological membranes.
Several derivatives of α-tocopherol substituted at the 5-methyl group were synthesized from the common intermediate, 5-chloromethyl-7,8-dimethyltocol acetate. These derivatives were evaluated for their activities in protecting rabbits against vitamin E deficiency induced muscular dystrophy and rats against dietary necrotic liver degeneration. It was found that the phytyl side chain of dl-α-tocopherol contributes to its biological activity in these animal systems, and that the presence of an intact 5-methyl group, although not essential for activity, greatly enhances it. Several of these derivatives were active in both test systems, while others were inactive. Some crossover of activities was seen in muscular dystrophy in the rabbit and dietary liver necrosis in the rat.
The events accompanying the inhibitory effect of alpha-tocopherol and/or ascorbate on the peroxidation of soybean L-alpha-phosphatidylcholine liposomes, which are an accepted model of biological membranes, were investigated by electron paramagnetic resonance, optical and polarographic methods. The presence of alpha-tocopherol radical in the concentration range 10(-8)-10(-7) M was detected from its EPR spectrum during the peroxidation of liposomes, catalysed by the Fe3+-triethylenetatramine complex. The alpha-tocopherol radical, generated in the phosphatidylcholine bilayer, is accessible to ascorbic acid, present in the aqueous phase at physiological concentrations. Ascorbic acid regenerates from it the alpha-tocopherol itself. A kinetic rate constant of about 2 X 10(5) M-1 X s-1 was estimated from the reaction as it occurs under the adopted experimental conditions. The scavenging effect of alpha-tocopherol on lipid peroxidation is maintained as long a ascorbic acid is present.
One useful method to monitor in vivo lipid peroxidation is the measurement of volatile hydrocarbons, mainly pentane and ethane, that derive from unsaturated fatty acid hydroperoxides. Vitamin E, the biological antioxidant, inhibits lipid peroxidation and the production of pentane and ethane. The rates of pentane production by male Sprague-Dawley rats fed a diet that contained 10% vitamin E-stripped corn oil and 0, 1, 3, 5 or 10 IU dl-alpha-tocopherol acetate/kg were monitored over a 12-wk period. During the eleventh and twelfth weeks, the rats were injected intraperitoneally with 3.3 and 13 mg of methyl ethyl ketone peroxide (MEKP)/kg body wt, respectively. Pentane production was then measured at intervals over a 50-min period, and the total amount of pentane produced over this time interval was estimated. An asymptotic function was found to describe the relationship between exhaled pentane and the low levels of dietary vitamin E that were fed to the rats. As measured by pentane production, rats had a higher minimal vitamin E requirement after they were treated with the potent peroxidation initiator MEKP than they did prior to treatment. The level of pentane exhaled by rats injected with 13 mg MEKP/kg body wt was significantly correlated with kidney and spleen tocopherol levels.
Free radicals vary widely in their thermodynamic properties, ranging from very oxidizing to very reducing. These thermodynamic properties can be used to predict a pecking order, or hierarchy, for free radical reactions. Using one-electron reduction potentials, the predicted pecking order is in agreement with experimentally observed free radical electron (hydrogen atom) transfer reactions. These potentials are also in agreement with experimental data that suggest that vitamin E, the primary lipid soluble small molecule antioxidant, and vitamin C, the terminal water soluble small molecule antioxidant, cooperate to protect lipids and lipid structures against peroxidation. Although vitamin E is located in membranes and vitamin C is located in aqueous phases, vitamin C is able to recycle vitamin E; i.e., vitamin C repairs the tocopheroxyl (chromanoxyl) radical of vitamin E, thereby permitting vitamin E to function again as a free radical chain-breaking antioxidant. This review discusses: (i) the thermodynamics of free radical reactions that are of interest to the health sciences; (ii) the fundamental thermodynamic and kinetic properties that are associated with chain-breaking antioxidants; (iii) the unique interfacial nature of the apparent reaction of the tocopherol free radical (vitamin E radical) and vitamin C; and (iv) presents a hierarchy, or pecking order, for free radical electron (hydrogen atom) transfer reactions.
Glucoconjugates of (+/-)-ibuprofen, (+/-)-alpha-tocopherol (vitamin E), gentisic acid, gallic acid, 2,6-bis(tert-butyl)-4-thiophenol, and N-acetyl-L-cysteine were prepared with the objective of increasing the bioavailability of such antioxidant and anti-inflammatory drugs. The O-glucosides were synthesized using benzylated alpha-D-glucopyranosyl trichloracetimidate as glycosyl donor. For the synthesis of the S-glucosides, the glycosyl donor 1,2,3,4,6-penta-O-acetyl-beta-D-glucopyranose provided higher yields than the corresponding O-acetylated imidate.
A procedure based on density functional theory is used for the calculation of the gas-phase bond dissociation enthalpy (BDE) and ionization potential for molecules belonging to the class of phenolic antioxidants. We show that use of locally dense basis sets (LDBS) vs full basis sets gives very similar results for monosubstituted phenols, and that the LDBS procedure gives good agreement with the change in experimental BDE values for highly substituted phenols in benzene solvent. Procedures for estimating the O--H BDE based on group additivity rules are given and tested. Several interesting classes of phenolic antioxidants are studied with these methods, including commercial antioxidants used as food additives, compounds related to Vitamin E, flavonoids in tea, aminophenols, stilbenes related to resveratrol, and sterically hindered phenols. On the basis of these results we are able to interpret relative rates for the reaction of antioxidants with free radicals, including a comparison of both H-atom-transfer and single-electron-transfer mechanisms, and conclude that in most cases H-atom transfer will be dominant.
We are attempting to develop novel synthetic antioxidants aimed at retarding the effects of free-radical induced cell damage. In this paper we discuss the design strategy and report the synthesis of seven novel antioxidants, including six catechols and a benzylic phenol. The bond dissociation enthalpy (BDE) for the most active (weakest) OH bond in each molecule was calculated by theoretical methods, as well as the BDE for the semiquinone radical. Reaction rates with the nitrogen-centered free radical DPPH(*) were measured in ethyl acetate. The log of k(DPPH) for bimolecular reaction correlated well with the primary BDE. The correlation between rate constants and calculated BDEs shows that the BDE is a good predictor of antioxidant activity with DPPH(*), suggesting that our design criteria are useful and that these compounds should undergo further testing in cell cultures and in animal models.
A study on the regeneration of alpha-tocopherol (vitamin E) by phenolic co-antioxidants in homogeneous hydrocarbon solution is reported. The behavior of some relevant phenols such as BHA, BHT, and trans-resveratrol appears to be nicely predicted by a model based on the knowledge of kinetic and thermochemical data concerning the various reactants. Despite its good reputation as an antioxidant, trans-resveratrol was found only moderately effective (k(inh) = 2.0 x 10(5) M(-1) s(-1) in chlorobenzene at 303 K) and unable to recycle vitamin E.
A series of novel lipophilic vitamin C derivatives, 6-O-acyl-2-O-alpha-D-glucopyranosyl-L-ascorbic acids possessing a branched-acyl chain of varying length from C(8) to C(16) (6-bAcyl-AA-2G), were evaluated as topical prodrugs of ascorbic acid (AA) with transdermal activity in a human living skin equivalent model. The permeability of 6-bAcyl-AA-2G was compared with those of the derivatives having a straight-acyl chain (6-sAcyl-AA-2G). Out of 10 derivatives of 6-sAcyl-AA-2G and 6-bAcyl-AA-2G, 6-sDode-AA-2G and 6-bDode-AA-2G exhibited most excellent permeability in this model. Measurement of the metabolites permeated from the skin model suggested that 6-bDode-AA-2G was mainly hydrolyzed via 6-O-acyl AA to AA by tissue enzymes, while 6-sDode-AA-2G was hydrolyzed via 2-O-alpha-D-glucopyranosyl-L-ascorbic acid to AA. The former metabolic pathway seems to be advantageous for a readily available source of AA, because 6-O-acyl AA, as well as AA, is able to show vitamin C activity.
Novel hybrids of lipoic acid and trolox connected through triamine spacers as well as analogues in which the lipoic acid was attached at different positions of the chroman moiety of vitamin E through an amide bond, were synthesized and exhibited strong inhibition of the microsomal lipid peroxidation. Moreover, the new molecules, at 1 microM concentration, reduced reperfusion arrhythmias and MDA content on isolated rat heart preparations, with the 2- and 5-subtituted chromans possessing the better cardioprotective activity.
Senju Pharmaceutical)
- K Ogata