Tocopherol Analogues Research Articles

Potential nonhormonal therapeutics for medical treatment of leiomyomas.

Uterine leiomyomas are a common disorder resulting in significant morbidity for women and substantial economic impact on the health care system. Current therapies include conservative surgery, hysterectomy, and hormonal therapy. Conservative surgical therapy often fails because of recurrence, and hysterectomy dramatically limits reproductive options. Radiologic therapies are associated with considerable risk of morbidity and mortality and are not likely to be compatible with reproduction. Hormonal therapies such as gonadotropin-releasing hormone (GnRH) analogues or progestins with or without estrogen are utilized by many patients, but long-term use of either is often responsible for unacceptable morbidity and hormonal therapies are not compatible with reproduction. Newer hormonal alternatives such as progesterone antagonists and selective agonists as well as "add-back" estrogen therapy in addition to GnRH analogues have been developed and show promise. However, no hormonal therapy that significantly alters estrogen and progesterone production or function is likely to be compatible with reproduction. Thus, it is important to develop novel nonhormonal therapies for medical treatment of leiomyomas. Other laboratories have evaluated pirfenidone, halofuginone, heparin, and interferon-alpha (IFN-alpha). Recent work in our laboratory suggests potential use of two additional classes of compounds, thiazolidinediones and tocopherol analogs. The rationale, evidence, and potential for the use of each of these compounds in the treatment of leiomyomas are discussed.

Kinetics of Oxy-chemiluminescence and Its Use in the Analysis of Antioxidants

The influence of the antioxidant (chroman C1, a synthetic analog of tocopherol) on the chemiluminescence kinetics during diphenylmethane and cumene oxidation is studied. Principles are considered for choosing a standard oxidized mixture in which the concentration and reactivity of an antioxidant are determined most reliably. The results of exact computer simulations and analytical calculations assuming quasi-stationarity with respect to different types of radicals are compared. A strategy is proposed to interpret the results and choose the experimental conditions (model oxidation system, type of hydrocarbon, interval of initiation rates) under which the antioxidant concentration and reactivity can be determined most reliably. The chemiluminescence method is used to study natural antioxidants in sunflower and corn oil.

Anti-angiogenic potential of tocotrienol in vitro.

Modulation of angiogenesis is now a recognized strategy for the prevention of various angiogenesis-mediated disorders. We investigated, using well-characterized in vitro systems, the anti-angiogenic property of vitamin E compounds, with particular emphasis on tocotrienol, a natural analog of tocopherol. Tocotrienol, but not tocopherol, inhibited the proliferation of bovine aortic endothelial cells in dose dependent manner at half-maximal concentrations in the low micromolar range. Tocotrienol also significantly inhibited the formation of networks of elongated endothelial cells within 3D collagen gels. From these results, we suggest that tocotrienol is a potential candidate for the development of useful therapeutic agents or preventive food factors for tumor angiogenesis.

Study of phenolic compounds as natural antioxidants by a fluorescence method

Much work has been carried out in recent years on the beneficial effect of phenolic compounds as natural antioxidants which help to neutralize free radicals. In fact, researchers have focused their attention on the pathological role of free radicals in a variety of diseases, among which the most important are atherosclerosis and cancer. Thus, among the components of the so-called ‘Mediterranean Diet’, phenolic compounds have received increased attention as epidemiological studies have shown that consumption of foods and beverages rich in phenolics is correlated with reduced incidence of heart disease. In this study, four phenolic compounds: (1) 3,4,5-trihydroxybenzoic acid (gallic acid); (2) trans 3,4′,5-trihydroxystilbene ( trans-resveratrol); (3) 3,3′,4′,5,7-pentahydroxyflavone (quercetin) and its glycoside (4) 3,3′,4′,5,7-pentahydroxyflavone–3-rutinoside (Rutin) have been subjected to antioxidant study by a fluorimetric assay. In this method, the rate of peroxidation induced by 2,2′-azobis (2-methylpropionamidine) dihydrochloride was monitored through the loss of fluorescence of the protein B-phycoerythrin (B-PE). Under appropriate conditions, the loss of B-PE fluorescence in the presence of reactive species is an index of oxidative damage of the protein. The inhibition of the action of reactive species by phenolic compounds, reflected in the protection against the loss of B-PE fluorescence in the fluorimetric assay, is a measure of its antioxidant capacity against the reactive species. The antioxidant effects of phenolic compounds have been investigated at different concentrations to relate activity to structural effects. It has been observed that the fluorescence decay due to peroxyl radical attack on B-PE decreases exponentially with time. As a reference compound for antioxidant capacity we used 6-hydroxy-2,5,7,8-tetramethyl-chroman-2-carboxylicacid (trolox), a water soluble tocopherol analogue. This compound reacts rapidly with peroxyl radicals, and, until the trolox is consumed, no loss in phycoerythrin fluorescence is observed. A linear correlation of the net protection value with the concentration of trolox was demonstrated. The phenolic compounds studied react with peroxyl radicals in a similar way to trolox. Quercetin and rutin were shown to have strong antioxidant activities. The results obtained here are in agreement with previous studies confirming that quercetin is the most antioxidant of the four polyphenolics.

Differential effects of vitamin E and three hydrophilic antioxidants on the actinomycin D-induced and colcemid-accelerated apoptosis in human leukemia CMK-7 cell line.

The actinomycin D (AD)-induced apoptosis in human leukemia CMK-7 cell line is greatly accelerated by microtubule disruption with colcemid (CL). We studied the effect of antioxidants on this apoptosis in order to learn how the universal signal mediators, reactive oxygen species (ROS), are involved. Caspase-3 activation and DNA fragmentation were both suppressed by vitamin E (VE), t-butylhydroxyanisole, and luteolin. The ROS formation in the AD treatment was evidenced by flow cytometry, and further supported by suppression of caspase-3 activation by superoxide radical-forming enzyme inhibitors (TTFA, rotenone, and DPI). The inhibition of apoptosis by VE was completed during the initial 1-h treatment with AD, but it did not appear when VE was added with CL to washed cells after AD treatment. Luteolin, an iron chelator PDTC, and a water-soluble VE analogue, trolox, inhibited the apoptosis when added with CL after the AD treatment. Western blot analysis showed that the proteolytic cleavage of procaspase-9 and procaspase-3 were both inhibited when VE was added with AD or when luteolin was added with CL, and that the cytochrome c liberation was suppressed by both antioxidants. This result implies that the ROS are initially formed in lipophilic environments (e.g. mitochondrial membrane) and then they diffuse into an aqueous environment (i.e. cytoplasm) where they promote the apoptotic process in combination with the cytoskeletal disruption. Thus, the different antioxidants are effective to scavenge ROS for preventing the apoptosis in its different phases.

Serum proteins modified by neutrophil-derived oxidants as mediators of neutrophil stimulation.

Reactive oxygen intermediates (ROI) released during inflammation may act as important mediators of neutrophil effector functions. The objective of this investigation was to evaluate the influence of ROI generation on neutrophil adhesion molecule regulation and degranulation. Induction of the neutrophil oxidative burst via Fcgamma receptor cross-linking was accompanied by up-regulation of neutrophil surface CD11b, CD35, and CD66b only in the presence of selected serum proteins, such as purified human C4, C5, or human serum albumin (HSA). Scavenging of ROI attenuated protein-dependent receptor regulations. Moreover, exogenous hydrogen peroxide was effective to increase neutrophil CD11b expression in a protein-dependent way. HSA exposed to neutrophil-derived ROI displayed signs of oxidative modification in terms of carbonyl formation. Such modified HSA transferred to resting neutrophils bound readily to the cell surface and effected receptor modulation as well as cellular spreading. In contrast, neither native HSA nor HSA protected against oxidation by the tocopherol analog Trolox exhibited agonistic properties. In conclusion, we demonstrate that neutrophil-derived ROI modify selected serum proteins, which, in turn, act as proinflammatory mediators of neutrophil stimulation.

Carotenoids, Flavonoids, Total Phenolic Compounds and Antioxidant Activity of Two Creeping Cotoneaster Species Fruits Extracts

Cotoneaster horizontalis Decne. and Cotoneaster microphyllus Wall. ex Lindl. species are two creeping bushes, commonly used as ornamental plants in gardens and parks. The aim of this paper was to assess the concentrations of some classes of bioactive compounds classes, carotenoids, flavonoids and total phenolic compounds, in fresh fruits of these species. Carotenoids and flavonoids were determined through acetone and methanol extraction followed by spectrophotometry. For total phenolics, methanol extraction and a spectrophotometric Folin-Ciocalteu method was used. The total antioxidant capacity was quantified through photochemiluminescence method by comparison with the standard substance used for calibration, Trolox� as tocopherol analogue (ACL procedure) using Photochem apparatus, Analytik Jena AG, Germany. Average values found in Cotoneaster horizontalis and Cotoneaster microphyllus fruit tissue were 380.63 mg/kg, respectively 179.63 mg/kg, carotenoids; 8036.07 mg/kg, respectively 6888.06 mg/kg flavonoids; and 16342.06 mg/kg GAE, respectively 18631.35 mg/kg GAE total phenolic compounds. These values are comparable to those found in other wild and cultivated related Rosaceae, including domestic rowans. Cotoneaster microphyllus fruits emphasized an increased antioxidant activity (up to 39.69 μmol Trolox equivalent/g dry weight).

Effects of gamma-tocotrienol on ApoB synthesis, degradation, and secretion in HepG2 cells.

gamma-Tocotrienol (gamma-T3), a naturally occurring analog of tocopherol (vitamin E), has been shown to have a hypocholesterolemic effect in animals and humans. Unlike tocopherol, it has also been shown to reduce plasma apoB levels in hypercholesterolemic subjects. The aim of this study was to define the mechanism of action of gamma-T3 on hepatic modulation of apoB production using cultured HepG2 cells as the model system. HepG2 cells preincubated with gamma-T3 were initially shown to inhibit the rate of incorporation of [14C]acetate into cholesterol in a concentration- and time-dependent manner, with a maximum 86+/-3% inhibition at 50 micromol/L observed within 6 hours. gamma-T3, on the other hand, had no significant effect on the uptake of [14C]glycerol into pools of cellular triacylglycerol and phospholipid relative to untreated control. The rate of apoB synthesis and secretion was then studied by an [35S]methionine pulse-labeling experiment and quantified by immunoprecipitating apoB on chasing up to 3 hours. An average reduction of 24+/-3% in labeled apoB in the media was apparent with gamma-T3 despite a 60+/-2% increase in apoB synthesis. Fractionation of secreted apoB revealed a relatively denser lipoprotein particle, suggesting a less stable particle. Using a digitonin-permeabilized HepG2 cell system, the effects of gamma-T3 on apoB translocation and degradation in the endoplasmic reticulum were further investigated. The generation of a specific N-terminal 70-kDa proteolytic fragment proved to be a sensitive measure of the rate of apoB translocation and degradation. The abundance of this fragment increased significantly in gamma-T3-treated cells relative to untreated control cells (50+/-21%) after 2 hours of chase. In addition, the presence of gamma-T3 resulted in an average decrease of 64+/-8% in intact apoB. Taken together, the data suggest that gamma-T3 stimulates apoB degradation possibly as the result of decreased apoB translocation into the endoplasmic reticulum lumen. It is speculated that the lack of cholesterol availability reduces the number of secreted apoB-containing lipoprotein particles by limiting translocation of apoB into the endoplasmic reticulum lumen.

Theoretical Parameters to Characterize Antioxidants. Part 1. The case of vitamin E and analogs

AbstractThe objectives of ibis work were (a) to evaluate parameters obtained by quantum‐mechanical calculations as predictors of antioxidant activities, and (b) to obtain information on the molecular mechanism(s) underlying the antioxidant effects of vitamin E and analogs. To this effect, we selected a large series of tocopherol analogs for which some experimental antioxidant activities were available in the literature (i. e., peak of oxidation potential, Ep, and rate constant of the reaction with a free radical log ks). AM1 Semi‐empirical calculations were performed, the results of which were validated by ab initio calculations on a subset of compounds. The quantum chemical descriptors considered here (HOMO, ΔHox and ΔHabs) were fairly well correlated with the experimental antioxidant activities (Ep and ks). Moreover, these theoretical parameters were intercorrelated, suggesting that vitamin E analogs may act by a dual mechanism of single‐electron transfer (SET) and direct H‐atom abstraction.

α-Tocopheryl hemisuccinate administration increases rat liver subcellular α-tocopherol levels and protects against carbon tetrachloride-induced hepatotoxicity

Rats were administered a series of tocopherol analogs 18 h prior to a hepatotoxic dose of carbon tetrachloride (CCl 4). Of the compounds tested, only d- α-tocopheryl hemisuccinate (TS) provided significant protection against CCl 4-induced hepatotoxicity. No protection was observed with either d- α-tocopherol ( α-T) or a tocopherol succinate ether derivative, d- α-tocopheryloxybutyric acid (TSE). None of the tocopherol analogs significantly inhibited CYP2E1 activity as measured by oxidation of p-nitrophenol. Liver homogenates and subcellular fractions (cytosol, nuclei, plasma membranes, mitochondria and microsomes) were collected 18 h after tocopherol analog administration in the absence of CCl 4. Homogenate and subcellular α-T levels were not significantly increased following TSE administration but were increased 2–3 fold following TS and α-T administration. Total tocopherol levels ( α-T+TS+TSE) in liver homogenates and subcellular fractions were highest in rats supplemented with TS. In these animals, TS was detected in all subcellular fractions and total tocopherol levels were increased from 6–23 fold over those seen in controls and 2–9 fold over α-T treated rats. In vitro studies in which liver homogenates and subcellular fractions were peroxidized with ascorbate and ADP/Fe suggest that increasing levels of α-T but not TS correlates with increased protection against lipid peroxidation. These results suggest that the ability of TS to protect against CCl 4-induced hepatotoxicity relates to its enhanced hepatic accumulation and subsequent hydrolysis to α-T.

Reaction of Ascorbate with the α-Tocopheroxyl Radical in Micellar and Bilayer Membrane Systems

The reaction by which the antioxidant capacity of α-tocopherol is sustained by recycling of the α-tocopheroxyl radical in membranes or lipoproteins by aqueous ascorbate has been studied by laser flash photolysis in model micellar and membrane systems. In bilayers of dimyristoylphosphatidylcholine at 35°C the measured second-order rate constant was 3 × 10 5 M −1 s −1, or about five times slower than previously reported in a solvent system. The rate of reaction was decreased on addition of negatively charged lipid (dipalmitoylphosphatidic acid) and increased by addition of positively charged lipid (didodecyldimethylammonium bromide). These effects of bilayer charge were suppressed by increasing the ionic strength of the aqueous medium. Micellar charge also had an effect on the pH dependence of the reaction rate. Arrhenius data showed that the enthalpy of activation was effectively zero for the reaction in solution between ascorbate and radicals of water-soluble tocopherol analogues, but was positive in membrane and micellar systems. In all cases the entropy of activation was strongly negative. The kinetic deuterium isotope ratio varied between 3 and 8. The data strongly support a concerted electron and proton transfer mechanism for the reaction between α-tocopheroxyl radical and ascorbate.

Synthesis and Antioxidant Activity of 4H-1,3-Benzodioxin-6-ol Derivatives: New Vitamin E Analogs

Abstract 4H-1,3-Benzodioxin-6-ol (HBD) derivatives 1—5, new tocopherol (Vitamin E) analogs, have been synthesized by condensation of acetaldehyde with the corresponding hydroquinone. For each HBD derivative except for 4, two diastereomeric isomers were produced. These stereoisomers were separated by column chromatography and the configuration of each isomer was identified by two dimensional NMR techniques and ESR measurements of the HBD radicals. The second-order rate constants, ks, for the reaction of 9 kinds of HBD derivatives with substituted phenoxyl radical (PhO·) in ethanol have been measured with a stopped-flow spectrophotometer. These HBD derivatives reacted at rates that were only about 5—20% of those observed with the corresponding tocopherols. The logs of the second-order rate constants, ks, obtained for HBD derivatives were found to correlate with their peak oxidation potentials, Ep. Electron spin resonance measurements were done for HBD radicals in toluene, and the proton hyperfine coupling constants, aiH, and giso-values were determined. The log of the rate constants, ks, was also found to correlate with the sum of the hyperfine coupling constants (a5H + a7H) at 5- and 7-positions of both HBD radicals and tocopheryloxyl radicals, that is, the unpaired π-spin densities (ρ5 + ρ7) at the two ortho carbon atoms.

Beneficial effects of MDL 74,405, a cardioselective water soluble tocopherol analogue, on the recovery of function of stunned myocardium in intact dogs

Postischaemic myocardial dysfunction ("stunning") is caused in part by the generation of reactive oxygen species resulting in oxidant stress. The aim of this study was to test the hypothesis that the systemic administration of MDL 74,405, a hydrophilic cardioselective alpha tocopherol analogue, is beneficial in attenuating myocardial stunning. Open chest dogs undergoing a 15 min coronary artery occlusion and 4 h of reperfusion received an intravenous infusion of either saline (controls, n = 9) or MDL 74,405 (n = 8) at a dose of 0.3 mg.kg-1 x h-1 starting 30 min before coronary occlusion and ending 60 min after reflow. Regional myocardial function (assessed as systolic wall thickening) was similar in control and treated groups at baseline and during ischaemia. Following reperfusion, however, the dogs treated with MDL 74,405 had significant improvement in the recovery of function, which was evident 2 h after restoration of flow and was sustained throughout the rest of the reperfusion phase. Analysis of covariance showed that the differences in wall thickening after reperfusion between the two groups were independent of collateral flow during occlusion. Furthermore, the enhanced recovery effected by MDL 74,405 could not be attributed to non-specific factors such as coronary flow after reperfusion, arterial pressure, heart rate, or other haemodynamic variables. Measurements of MDL 74,405 showed that the myocardial content of the antioxidant at 4 h of reperfusion was approximately 30 times greater than the plasma concentration at 1 h of reperfusion, suggesting preferential cardiac accumulation of this drug. This study shows (1) that systemic administration of the alpha tocopherol analogue MDL 74,405 in the setting of myocardial ischaemia and reperfusion does not result in adverse cardiovascular effects, at least in the first few hours after injection; (2) that the drug accumulates in myocardial tissue at concentrations much higher than in the plasma; (3) that intravenous infusion of MDL 74,405 produces an attenuation of myocardial stunning comparable to that previously observed with intracoronary administration of other antioxidants; and (4) that this beneficial effect is independent of non-specific actions on haemodynamic variables or coronary flow. The results suggest that the systemic administration of hydrophilic, cardioselective alpha tocopherol analogues represents an effective therapeutic approach to the alleviation of postischaemic dysfunction.

Antioxidant Inhibition of Skin Inflammation Induced by Reactive Oxidants: Evaluation of the Redox Couple Dihydrolipoate/Lipoate

Reactive oxygen species play an important role in mediating skin inflammation, and antioxidants may provide protection. We investigated the anti-inflammatory activity of natural antioxidants, such as superoxide dismutase, catalase, trolox (a water-soluble tocopherol analog) and the redox couple dihydrolipoate/lipoate in skin. Furthermore we compared the anti-inflammatory potency of natural R and racemic dihydrolipoate, as well as R and S lipoate. Skin inflammation in hairless mice was induced by intradermal injection of the hydrogen peroxide producing enzyme glucose oxidase (GOD) or by topical application of the prooxidant drug anthralin. Intradermal injection of the antioxidants inhibited skin inflammation caused by GOD (catalase, dihydrolipoate) and anthralin (trolox, superoxide dismutase, dihydrolipoate). There was no statistically significant difference between the anti-inflammatory activity of the natural R and racemic dihydrolipoate. R or S lipoate did not inhibit skin inflammation when injected intradermally. In feeding experiments, however, R lipoate significantly inhibited GOD-mediated skin inflammation, while S lipoate was only marginally protective. We conclude that (1) several natural antioxidants such as catalase, superoxide dismutase and dihydrolipoate have anti-inflammatory properties in dermatitis induced by reactive oxidants, (2) lipoate (oxidized dihydrolipoate) has skin anti-inflammatory activity when administered orally and (3) naturally occurring R lipoate is a more potent anti-inflammatory agent than the non-physiological S lipoate.

Chain-breaking phenolic antioxidants: steric and electronic effects in polyalkylchromanols, tocopherol analogs, hydroquinones, and superior antioxidants of the polyalkylbenzochromanol and naphthofuran class

Antioxidant activities of four classes of phenols were measured by the inhibition of thermally initiated autoxidation of styrene at 30 o C. Clans I, 6-hydroxypolyalkylchromans (model compounds) showed the same inhibition rate constants (k inh ) an their α-tocopherol analogs, in the range 1.5×10 6 M -1 s -1 to 3.8×10 6 M -1 s -1 for two methyl or ethyl groups ortho to the phenolic hydroxyl group

Inhibition of lipid peroxidation promoted by iron(III) and ascorbate

Peroxidation of rat liver microsomes and of phospholipid isolated from them was studied using iron(III) and ascorbate initiation. One-half equivalent of citrate per iron equivalent maintained solubility of the metal ion at neutral pH. Several metal chelators, including additional citrate, blocked peroxidation, but catalase did not. These characteristics are consistent with those reported by others ( D. M. Miller and S. D. Aust (1989) Arch. Biochem. Biophys. 271, 113–119 ). Several antioxidants, principally tocopherol analogues and nitroxides, and, as well, a nonenzymatic component of “thymol-free” catalase, potently blocked lipid peroxidation, or, equivalently, dioxygen depletion from suspensions of peroxidizing microsomes. Chromanols were the most active antioxidants. No thiol studied had significant antioxidant activity in the test system.

Tocopherol analogs suppress arachidonic acid metabolism via phospholipase inhibition.

alpha-Tocopherol and three derivatives in which the phytol chain is modified or deleted were examined for their effect on cultured keratinocyte arachidonic acid metabolism. 2,2,5,7,8-Pentamethyl-6-hydroxychromane (PMC), in which the phytol chain is replaced by a methyl group, inhibited basal, bradykinin (BK)- and A23187-stimulated prostaglandin E2 (PGE2) synthesis with an apparent Ki of 1.3 microM. The Ki of the analogue with six carbon atoms in the side chain (C6) was 5 microM while that of the C11 analogue was 10 microM. No effect of alpha-tocopherol was observed. The mechanism of inhibition was studied using PMC. The effect of PMC on phospholipase and cyclooxygenase activity was assayed using stable isotope mass measurements of PGE2 formation, which assesses arachidonate release and cyclooxygenase metabolism simultaneously. BK-stimulated formation of PGE2, derived from endogenous phospholipid, was decreased 60% by 5 microM PMC and eliminated by 50 microM PMC, compared with controls. No difference in PGE2 formed from exogenous arachidonic acid was observed, indicating no effect of PMC on cyclooxygenase activity. In contrast, no effect of 5 microM PMC was observed on BK-stimulated [3H]arachidonic acid release from prelabeled cultures. The capacity of PMC to inhibit phospholipase activity in vitro was also assessed. PMC inhibited hydrolysis of phospholipid substrate by up to 60%. These results suggest that alpha-tocopherol analogues with alterations in the phytol chain inhibit eicosanoid synthesis by preferential inhibition of phospholipase.

Oxidation and reaction of trolox c, a tocopherol analog, in aqueous solution. A pulse-radiolysis study [Erratum to document cited in CA110(21):193140s

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTOxidation and reaction of trolox c, a tocopherol analog, in aqueous solution. A pulse-radiolysis study [Erratum to document cited in CA110(21):193140s]Michael J. Thomas and Benon H. J. BielskiCite this: J. Am. Chem. Soc. 1989, 111, 21, 8326Publication Date (Print):October 1, 1989Publication History Published online1 May 2002Published inissue 1 October 1989https://doi.org/10.1021/ja00203a072RIGHTS & PERMISSIONSArticle Views70Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (147 KB) Get e-Alerts Get e-Alerts

Oxidation and reaction of trolox c, a tocopherol analog, in aqueous solution. A pulse-radiolysis study

Trolox c, 3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylic acid, 1, a water-soluble {alpha}-tocopherol analogue, was oxidized with Br{sub 2}{sup {minus}} to give the phenoxyl radical 2. These radicals disproportionate by a second-order, pH-dependent process to give 1 and an unstable intermediate 3, identified as 4,5-dihydro-3,6,8,9-tetramethyl-2H-3,9a-epoxy-1-benzoxepin-2,7(3H)-dione, which has a strong UV absorption at 235 nm. The disproportionation rate constant decreases with increasing pH, the greatest change occurring between pH 2 and 9, where it decreased by 10{sup 4}. The rate constant versus pH plot is consistent with a scheme that involves three reactions of the protonated and the unprotonated forms of 2. Intermediate 3 undergoes slow pH-dependent decomposition to 2-hydroxy-2-methyl-4-(2,5,6-trimethyl-2,4-dioxo-2,5-cyclohexadienyl)butanoic acid, 4. The same first-order rate constant was found for the decay of 3 and the appearance of 4. Simultaneous intramolecular cyclization during disproportionation is unique to 2 and similar derivatives, but would not occur in analogues that have hydrocarbon chains instead of a carboxyl moiety.

Synthesis of fluorine analogues of vitamin E. II. Synthesis of 2-(3-chloropropyl)-2,5,7,8-tetramethyl-6-chromanol and its application for stereocontrolled Wittig reaction with trifluoromethyl ketones.

As the extension of our research to find a biologically active analogue of vitamin E, a more convenient method for the synthesis of fluorine derivatives of 6-chromanol than our previous method was developed. Thus, 2-(3-chloropropyl)-2, 5, 7, 8-tetramethyl-6-chromanol (3) was synthesized by the reaction of 6-chloro-3-methyl-2-hexen-1-ol (2) and trimethylhydroquinone, and the phosphonium ylides (5 and 6) derived from 3 were condensed with trifluoromethylated ketones to give 2-(trifluoroprenyl)-6-chromanol compounds (1a, 1b and 1c) by means of the Wittig reaction as modified by Schlosser. By the use of this revised procedure, the total yields of the chromanols were much improved. Further, the modified Wittig reaction showed higher stereoselectivity than the previous syntheses of these compounds. The double bonds of the side-chain of the products were reduced to give fluorine derivatives of tocopherol analogues. Compound 3 was found to be a useful intermediate for the facile synthesis of vitamin E derivatives.