- Modulation of the mitochondrial cytochrome bc1 complex activity by chromanols and related compounds
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Tocopherols (α-, β-, γ-, and δ-Toc) and tocopheryl quinones (α-, β-, γ-, and δ-TQ) were recently suggested to modulate mitochondrial electron transfer in mammals. Intriguingly, Tocs and stigmatellin, a potent inhibitor of the mitochondrial cytochrome (cyt) bc 1 complex, possess a common structural feature: the chroman core. Therefore, we studied the interference of Tocs as well as synthetic model compounds (low molecular weight TQ analogues and tetramethyl chromanones) at the mitochondrial cyt bc1 complex. Enzymatic experiments revealed that besides the inhibitor stigmatellin, among natural vitamin E-related derivatives, γ-TQ/δ-TQ and, among synthetic compounds, TMC2O (6-hydroxy-4,4,7,8-tetramethylchroman-2-one) were most effective in decreasing the cyt bc1 activities. Stopped-flow photometric and low-temperature electron paramagnetic resonance spectroscopic experiments showed for TMC2O an inhibition of electron transfer to cyt c1 and a modulation of the environment of the Rieske iron - sulfur protein (ISP). Docking experiments suggest a binding interaction of the 6-OH group and 1-O atom/2-C( = O) group of TMC2O with Glu-271 (cyt b) and His-161 (ISP) in the cyt bc1 complex, respectively. This binding pose is similar but not identical to the potent inhibitor stigmatellin. The data suggest that chroman-2-ones are possible templates for modulatory molecules for the cyt bc1 target.
- Muellebner, Andrea,Patel, Anjan,Stamberg, Werner,Staniek, Katrin,Rosenau, Thomas,Netscher, Thomas,Gille, Lars
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Read Online
- QUINONES AND PROCESS OF OBTAINING SAME
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Disclosed is a process for the oxidation of at least one chroman (C1) in a solvent mixture comprising at least two solvents or in a C-bearing solvent, with a gaseous compound comprising, essentially consisting of, or consisting of oxygen in the presence of a copper catalyst, said copper catalyst exhibiting the oxidation state (+1) or (+2). A further part of the disclosure is a composition comprising at least one chroman (C1) and/or at least one quinone (C30), a solvent mixture comprising at least two solvents or a C-bearing solvent, a copper catalyst, said copper catalyst exhibiting the oxidation state (+1) or (+2) and a gaseous compound comprising, essentially consisting or consisting of oxygen. A quinone preparation and a process of making same is also part of the invention.
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Page/Page column 73; 74; 75; 77-80; 84-92; 94-96; 102-104
(2019/09/04)
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- Vitamin E hydroquinone is an endogenous regulator of ferroptosis via redox control of 15-lipoxygenase
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Ferroptosis is a form of programmed cell death associated with inflammation, neurodegeneration, and ischemia. Vitamin E (alpha-tocopherol) has been reported to prevent ferroptosis, but the mechanism by which this occurs is controversial. To elucidate the biochemical mechanism of vitamin E activity, we systematically investigated the effects of its major vitamers and metabolites on lipid oxidation and ferroptosis in a striatal cell model. We found that a specific endogenous metabolite of vitamin E, alpha-tocopherol hydroquinone, was a dramatically more potent inhibitor of ferroptosis than its parent compound, and inhibits 15-lipoxygenase via reduction of the enzyme's non-heme iron from its active Fe3+ state to an inactive Fe2+ state. Furthermore, a non-metabolizable isosteric analog of vitamin E which retains antioxidant activity neither inhibited 15-lipoxygenase nor prevented ferroptosis. These results call into question the prevailing model that vitamin E acts predominantly as a non-specific lipophilic antioxidant. We propose that, similar to the other lipophilic vitamins A, D and K, vitamin E is instead a pro-vitamin, with its quinone/hydroquinone metabolites responsible for its anti-ferroptotic cytoprotective activity.
- Hinman, Andrew,Holst, Charles R.,Latham, Joey C.,Bruegger, Joel J.,Ulas, G?zde,McCusker, Kevin P.,Amagata, Akiko,Davis, Dana,Hoff, Kevin G.,Kahn-Kirby, Amanda H.,Kim, Virna,Kosaka, Yuko,Lee, Edgar,Malone, Stephanie A.,Mei, Janet J.,Richards, Steve James,Rivera, Veronica,Miller, Guy,Trimmer, Jeffrey K.,Shrader, William D.
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- Highly stereoselective construction of the C2 stereocentre of α-tocopherol (Vitamin E) by asymmetric addition of Grignard reagents to ketones
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Tertiary alcohol precursors of both C2 diastereoisomers of α-tocopherol were prepared in three ways by our recently reported asymmetric Grignard synthesis. The versatility of Grignard chemistry inherent in its three-way disconnection was exploited to allow the synthesis of three product grades: 77:23 dr (5 steps), 81:19 dr (5 steps) and 96:4 dr (7 steps, one gram scale) from readily available and abundant starting materials. The products were converted to their respective α-tocopherols in 3 steps, which allowed a definitive re-assignment of their absolute configurations.
- Bieszczad, Bartosz,Gilheany, Declan G.
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p. 6483 - 6492
(2017/08/16)
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- Effect of α-tocopherol on the hemin-catalyzed decomposition of 1-palmitoyl-2-linoleoyl-3-sn-phosphatodylcholine 13-hydroperoxide in micelles and liposomes
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The secondary process of lipid peroxidation produces some toxic aldehydes. Since this process takes place via free radical reaction in lipophilic circumstances, α-tocopherol would suppress the formation of such aldehydes by trapping free-radical intermedi
- Yamauchi, Ryo,Watanabe, Siori,Martín, Ana S,Iwamoto, Satoshi
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- Towards a modern definition of vitamin e - Evidence for a quinone hypothesis
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We report on the synthesis, biological and pharmacological activity of the tocoquinone natural product, α-tocopherol quinone (ATQ); an oxidative metabolite of α-tocopherol. ATQ is a potent cellular protectant against oxidative stress, whose biological activity is dependent upon its ability to undergo reversible two-electron redox cycling. ATQ is orally bioavailable, with a favorable pharmacokinetic profile and has demonstrated a beneficial clinical response in patients with Friedreich's ataxia. ATQ is a member of a broader class of vitamin E derived quinone metabolites which may be ascribable in whole or in part to the activity of vitamin E.
- Shrader, William D.,Amagata, Akiko,Barnes, Adam,Hinman, Andrew,Jankowski, Orion,Lee, Edgar,Kheifets, Viktoria,Komatsuzaki, Ryo,Mollard, Paul,Murase, Katsuyuki,Rioux, Patrice,Wesson, Kieron,Miller, Guy
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scheme or table
p. 391 - 395
(2012/03/11)
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- Bromination of tocopherols: Oxidative halogenations and rearrangements
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The bromination behaviour of all four tocopherols and the corresponding model compounds in acidic and basic aqueous media was studied. Acidic conditions resulted in quinones and brominated quinones, with the bromination of the tocopherol preceeding the oxidation to the quinone. Buffer type and concentration did not influence the reaction results, whereas pH and the ratio of buffer and ethanol used as a co-solvent strongly affected the reaction rates. In alkaline media, two or three major products and a multitude of minor byproducts were obtained, because the combination of oxidizing hypobromite and alkaline conditions allowed for more complex reaction pathways (oxidation, substitution, condensation, elimination than the acidic conditions did. The para-quinones were major reaction products observed for all four tocopherols. Interestingly, if the quinone was substituted at C-5, it rearranged in a Michael-type addition process followed by substitution with a bromonium ion. The absence of a substituent at C-5, the presence of a bromine atom at C-7, or the absence of bromine in the reaction medium were all able to prevent this reaction. The rearrangement products could react further by substitution of the newly acquired bromine group for a hydroxy group. In the cases of γ- and δ-tocopherol, further rearrangement led to the formation of trioxo compounds. Bromination of all four tocopherols under alkaline conditions was compared, and the products were characterized to provide standard compounds for study of the interplay of tocopherols with halogenativeenzymes. Brominated para-quinones and rearrangement products were the major products. A "reactivity pairing" between α- and β-tocopherol on one hand and γ- and δ-tocopherol on the other was observed.
- Boehmdorfer, Stefan,Patel, Anjan,Hofinger, Andreas,Netscher, Thomas,Gille, Lars,Rosenau, Thomas
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experimental part
p. 3036 - 3049
(2011/06/28)
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- SYNTHESIS OF ALPHA-TOCOPHEROLQUINONE DERIVATIVES, AND METHODS OF USING THE SAME
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The present invention is directed to a method of synthesizing a compound of Formula I: the method comprising oxidizing alpha-tocopherol with a metal salt oxidizing agent to form the compound of Formula I, wherein the stoichiometric ratio (mol/mol) of metal salt oxidizing agent/alpha-tocopherol is 1.6 to 4. The invention is also directed to a method of synthesizing a compound of Formula I, the method comprising (a) hydrolyzing alpha-tocopheryl acetate in the presence of a base; (b) neutralizing the hydrolyzing of (a), thereby forming alpha-tocopherol; and (c) oxidizing the alpha-tocopherol of I (b) with a metal salt oxidizing agent to form the compound of Formula I, wherein the stoichiometric ratio (mol/mol) of metal salt oxidizing agent/aipha-tocopherol is 1.6 to 4.
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Page/Page column 23-25
(2011/10/05)
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- Tocotrienamines and tocopheramines: Reactions with radicals and metal ions
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The antioxidant activity of vitamin E (VE) homologs a, c and d-tocotrienamines (4b-6b), never studied before, and a, c and d-tocopheramines (4a-7a) was investigated by means of different total antioxidant capacity (TAC) tests. In all the test model systems, compounds 4a-7a and 4b-6b showed similar or higher TAC values than the parental vitamin E forms and their physiological metabolites. α-Homologs of VE amines showed markedly higher activity than the VE congeners in the TEAC test, which is tailored for liposoluble antioxidants, while c-homologs of the amine analogs showed higher activity in the FRAP tests. Kinetics analysis of the reaction with DPPH showed higher second order rate k for 4a than for α-tocopherol (1a). α-Tocopherolquinone 1f was the common main oxidation product for both 1a and α-tocopheramine (4a) exposed to ferric ions or DPPH, and the implied oxidative deamination of 4a was accompanied by a nitration reaction of phenolic substrates that were added to the reaction medium. Possible mechanisms of these reactions were studied.
- Galli, Francesco,Mazzini, Francesco,Bamonti, Luca,Gille, Lars,B?hmdorfer, Stefan,Piroddi, Marta,Netscher, Thomas,Kelly, Frank J.,Rosenau, Thomas
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experimental part
p. 6483 - 6491
(2011/12/04)
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- REDUCTION OF ALPHA-TOCOPHEROL QUINONE
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α-tocopherol quinone is chemically reduced by combination with a reducing agent, such as tin (II) ion in the form of stannous chloride (SnCl2-2H20), or by chromium (III) ion, such as chromium (III) in the form of chromium chloride (CrCl3- 6H20). Purified α-tocopherol is obtained from α-tocopherol formed by reduction of an oxidized α-tocopherol, such as α-tocopherol quinone, by tin (II) ion or chromium (III) ion. Purified a-tocopherol of the invention can be administered to patients in need thereof, α-tocopherol is preserved by combination with a reducing agent.
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Page/Page column 12
(2011/11/30)
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- A novel and efficient synthesis of tocopheryl quinones by homogeneous and heterogeneous methyltrioxorhenium/hydrogen peroxide catalytic systems
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A convenient and efficient application of heterogeneous poly(4-vinylpyridine), poly(4-vinyl-pyridine N-oxide), and polystyrene/ methylrhenium trioxide systems for the selective oxidation of tocopherols and tocopherol derivatives to the corresponding ortho- and para-tocopherylquinones is described. Environment friendly, easily available, and low-cost hydrogen peroxide (H2O2) was used as the oxygen atom donor. The antiviral activity of the newly synthesized tocopherylquinones and their parent tocopherols against influenza A virus is also reported. On the basis of the biological assay, the activity of tocopherols against influenza virus is higher than that showed by the corresponding tocopherylquinones, thus suggesting, for the first time, a drawback effect of the oxidative metabolism on the antiviral activity of these compounds.
- Saladino, Raffaele,Neri, Veronica,Farina, Angela,Crestini, Claudia,Nencioni, Lucia,Palamara, Anna Teresa
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experimental part
p. 321 - 331
(2009/04/10)
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- Photolysis of α-Tocopherol in Olive Oils and Model Systems
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The photolysis of α-tocopherol (I) in olive oil (O) and in some model systems (n-hexane = H; anhydrous n-hexane = HA, and triolein = T) was studied under sunlight and under artificial light (λ > 290 nm) by HPLC and GC/MS. In O and T, I disappeared linearly to 50% of the starting concentration, reached a constant value, and finally disappeared rapidly from the medium. In the model system, photolysis followed a pseudo-first-order kinetics. Although no peaks attributable to photoproducts were found in O, a main product identified by 1H and 13C NMR and GC/MS as 5-formyltocopherol (II) was found in the model systems. Irradiation of compound II led to species undetectable by HPLC in agreement with a slower consecutive kinetic process than that of I. In the HA and T systems, the formation of II occurred at lower levels than in H. The possible behavior of photodegradation is discussed.
- Pirisi, Filippo M.,Angioni, Alberto,Bandino, Giovanni,Cabras, Paolo,Guillou, Claude,Maccioni, Elisabetta,Reniero, Fabiano
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p. 4529 - 4533
(2007/10/03)
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- Oxidation of alpha-tocopherol during the peroxidation of dilinoleoylphosphatidylcholine in liposomes.
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Liposomal suspensions of dilinoleoylphosphatidylcholine (DLPC) containing alpha-tocopherol (0.1 mol%, based on DLPC were oxidized at 37 degrees C. The oxidation was initiated by a lipid-soluble or water-soluble free radical initiator, or by the addition of CuSO4 and fructose. In all the oxidation systems, alpha-tocopherol suppressed the formation of DLPC hydroperoxides until all the alpha-tocopherol had been depleted. The oxidation products of alpha-tocopherol were 8a-alkyldioxy-alpha-tocopherones, 5,6-epoxy-alpha-tocopherylquinone, 2,3-epoxy-alpha-tocopherylquinone, and alpha-tocopherylquinone. The 8a-alkyldioxy-alpha-tocopherones were decomposed in the liposomes primarily by being hydrolyzed to produce alpha-tocopherylquinone. The results indicate that alpha-tocopherol can trap peroxyl radical to form 8a-alkyldioxy-alpha-tocopherones which are hydrolyzed to alpha-tocopherylquinone in phospholipid bilayers. In another oxidation pathway, alpha-tocopherol may be oxidized by peroxyl radicals to form isomeric epoxy-alpha-tocopherylquinones.
- Yamauchi,Yagi,Kato
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p. 616 - 620
(2007/10/03)
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- Nitric oxide-induced oxidation of α-tocopherol
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Exposure of α-tocopherol (α-T) to nitric oxide under aerobic conditions resulted in a complex oxidation process whose final outcome was dictated by the nature of the reaction medium. In a cyclohexane solution, a prevailing route led to a mixture of relatively unstable polar products positive to Griess reagent. On standing at room temperature these were partially converted to the novel 2,3-dimethyl-4-acetyl-4-hydroxy-5-nitroso-2-cyclopentenone derivative. Reaction of α-T via a secondary oxidation path led to the formation of α-tocopherylquinone (α-TQ) as well as of little amounts of the corresponding nitrite ester. A quite different product pattern was observed when the reaction was carried out on a suspension of α-T in 0.1 M phosphate buffer, pH 7.4. Besides a significant formation of α-TQ and its nitrite ester, product analysis revealed a characteristic pattern of apolar compounds consisting of a yellow dimer and a series of related oligomers. These results provide an improved chemical background to inquire into the role of α-T in nitric oxide-induced tissue injury.
- D'Ischia, Marco,Novellino, Luisa
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p. 1747 - 1753
(2007/10/03)
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- Total synthesis of naturally occurring α-tocopherol. Assymetric alkylation and asymmetric epoxidation as means to introduce (R)-configuration at C(2) of the chroman moiety
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Based on the reductive, stereospecific ring closure of (2R,4'R,8'R)-α-'Tocopherylquinone' or corresponding analogues with a short, functionalized side chain (B, Scheme 1) to 1 resp. the chroman system of 1 (C), two different approaches for the introduction of the required tertiary methyl-substituted alcohol structure in the side chain of the aromatic precursors (A, Scheme 1) were developed. The first approach uses asymmetric alkylation in three different versions featuring a) diastereoselective steering with chiral auxiliaries I-IV (Scheme 2) attached as esters to α-keto acids, b) intermediate transfer of chirality in an ester enolate (from 18, Scheme 4) derived from an optically active α-hydroxyacid, c) enantioselective alkylation of phytenal (20) and subsequent ring closure with chirality transfer (Schemes 5-7). The second approach is based on the asymmetric epoxidation of β-metallylalcohol (Sharpless epoxidation), the corresponding epoxyalcohol being converted in situ to the (S)- or (R)-chlorodiol (S)- and (R)-29, respectively, for isolation (Schemes 8 and 9). Nucleophilic epoxide opening with a (3R,7R)-3,7,11-trimethyldodecyl (C15**) and an ArCH2 unit in appropriate sequence is used to assemble the C-framework of the target molecule via corresponding epoxide intermediates from either chlorodiol. Combined with the use of the methoxymethyl-ether function for protection of the hydroquinone system, the epoxide approach provides a short route to 1 (Scheme 10).
- Hubscher,Barner
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p. 1068 - 1086
(2007/10/02)
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- Products and Stoichiometry of Reaction of Vitamin E with Alkylperoxy Radicals
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Oxidation of vitamin E (α-tocopherol, E) at 50 deg C in acetonitrile and hexane by alkylperoxy radicals gives up to 50percent yield of the 4-(alkylperoxy)cyclohexadienone derived from combination of RO2* and E radicals; this product rapidly hydrolyzes to tocopherylquinone.E consumes two RO2* radicals, and kinetic studies indicate that the rate constant for RO2 + E -> RO2H + E is greater than 2*1E5 M-1 s-1.
- Winterle, John,Dulin, David,Mill, Theodore
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p. 491 - 495
(2007/10/02)
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