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Lars Gille - One of the best experts on this subject based on the ideXlab platform.

  • Synthetic Chromanol derivatives and their interaction with complex III in mitochondria from bovine, yeast, and Leishmania.
    Chemical research in toxicology, 2011
    Co-Authors: Lianet Monzote, Thomas Rosenau, Werner Stamberg, Anjan Patel, L. Maes, Paul Cos, Lars Gille
    Abstract:

    Synthetic Chromanol derivatives (TMC4O, 6-hydroxy-2,2,7,8-tetramethyl-chroman-4-one; TMC2O, 6-hydroxy-4,4,7,8-tetramethyl-chroman-2-one; and Twin, 1,3,4,8,9,11-hexamethyl-6,12-methano-12H-dibenzo[d,g][1,3]dioxocin-2,10-diol) share structural elements with the potent inhibitor of the mitochondrial cytochrome (cyt) bc1 complex stigmatellin. Studies with isolated bovine cyt bc1 complex demonstrated that these compounds partially inhibit the mammalian enzyme. The aim of this work was to comparatively investigate these toxicological aspects of synthetic vitamin E derivatives in mitochondria of different species. The Chromanols and atovaquone as reference compound were evaluated for their inhibition of the cyt bc1 activity in mitochondrial fractions from bovine hearts, yeast, and Leishmania. In addition, compounds were evaluated in vitro for their inhibitory activity against whole-cell Leishmania and mouse peritoneal macrophages. In these organisms, the Chromanols showed a species-selective inhibition of the cy...

  • The protection of bioenergetic functions in mitochondria by new synthetic Chromanols.
    Biochemical pharmacology, 2005
    Co-Authors: Katrin Staniek, Thomas Rosenau, Wolfgang Gregor, Hans Nohl, Lars Gille
    Abstract:

    Abstract α-Tocopherol is the most important lipophilic antioxidant of the Chromanol type protecting biomembranes from lipid peroxidation (LPO). Therefore, α-tocopherol and its derivatives are frequently used in the therapy or prevention of oxygen radical-derived diseases. In the present study, novel Chromanol-type antioxidants (twin-Chromanol, cis - and trans -oxaChromanol) as well as the well-known short-chain analogue of α-tocopherol, pentamethyl-Chromanol, were tested for their antioxidative potency in rat heart mitochondria (RHM). Our experiments revealed that the bioenergetic parameters of mitochondria were not deteriorated in the presence of Chromanols (up to 50 nmol/mg protein). Exposure of RHM to cumene hydroperoxide and Fe 2+ (final concentrations 50 μM each), inducing LPO, significantly affected their bioenergetic parameters which were determined in the presence of glutamate and malate (substrates of mitochondrial complex I). Alterations of the bioenergetic parameters were partially prevented in a concentration-dependent manner by preincubating RHM with antioxidants before adding the radical-generating system. In the lower concentration range, twin-Chromanol turned out to be more efficient than pentamethyl-Chromanol, both being far more protective than cis - and trans -oxaChromanol. Measurement of protein-bound SH groups and thiobarbituric acid-reactive substances revealed that this protective effect was due to their antioxidative action. Furthermore, HPLC measurements of α-tocopherol and α-tocopheryl quinone in rat liver mitochondria demonstrated an α-tocopherol-sparing effect of twin-Chromanol. In conclusion, new Chromanol-type antioxidants, especially twin-Chromanol, were able to improve bioenergetic and biochemical parameters of mitochondria exposed to oxidative stress.

  • Antioxidant properties of natural and synthetic Chromanol derivatives: study by fast kinetics and electron spin resonance spectroscopy.
    The Journal of organic chemistry, 2005
    Co-Authors: Wolfgang Gregor, Thomas Rosenau, Gottfried Grabner, Christian Adelwöhrer, Lars Gille
    Abstract:

    Chromanol-type compounds act as antioxidants in biological systems by reduction of oxygen-centered radicals. Their efficiency is determined by the reaction rate constants for the primary antioxidative reaction as well as for disproportionation and recycling reactions of the antioxidant-derived radicals. We studied the reaction kinetics of three novel Chromanols:  cis- and trans-oxaChromanol and the dimeric twin-Chromanol, as well as ubiChromanol and ubichromenol, in comparison to α-tocopherol and pentamethylChromanol. The antioxidant-derived radicals were identified by optical and electron spin resonance spectroscopy (ESR). The kinetics of the primary antioxidative reaction and the disproportionation of the chromanoxyl radicals were assessed by stopped-flow photometry in different organic solvents to simulate the different polarities associated with biomembranes. Furthermore, the reduction of the chromanoxyl radicals by ubiquinol and ascorbate was measured after laser-induced one-electron Chromanol oxidat...

Masataka Mochizuki - One of the best experts on this subject based on the ideXlab platform.

  • Substituent effect on the radical scavenging activity of 6-Chromanol derivatives
    RSC Adv., 2014
    Co-Authors: Keiko Inami, Miyuki Furukawa, Mariko Suzuki, Azusa Shimizu, Mine Morita, Masataka Mochizuki
    Abstract:

    Several 6-Chromanol derivatives with various substituents (one or two amino, acetylamino, chloro or nitro substituents at the 5-, 7-, 8- or 5,7-positions on the phenyl ring of 2,2-dimethyl-6-Chromanol) were synthesized, and their second order rate constants (k) for a reaction that demonstrates radical scavenging activity (reaction with the galvinoxyl radical) were determined. Three monoacetylamino compounds, 8-nitro compound, and 5,7-diamino, 5,7-diacetylamino, and 5,7-dinitro compounds were newly synthesized. log k was plotted against the Hammett sigma (σm) or Taft sigma (σ*) constants for the compounds containing each of the four substituents to obtain their reaction constants (ρ) from the slopes. The σ plots representing radical scavenging activity showed a linear correlation with negative ρ values for all compounds with substituted positions. The results indicate that the electron-donating effect of the amino and acetylamino groups on the chroman ring enhanced radical scavenging activity, whereas the electron-withdrawing effect of the chloro and nitro groups decreased this activity. Furthermore, the magnitude of ρ for the substituted compounds increased in the following order with respect to the substitution position: meta-substituted (−3.71 for 6a–d), ortho-monosubstituted (−0.86 for 4a–d, −0.87 for 5a–d), and ortho-disubstituted (−0.47 for 7a–d). The greater ρ magnitudes for the meta-substituted compound indicated that the radical scavenging reactions were more sensitive to inductive substituent effects than for the ortho-substituent compounds. The ρ values for ortho-mono- and ortho-disubstituted compounds were smaller than that for the meta-substituted compound, despite the fact that the k values for the ortho-substituted compounds were higher than those for the meta-substituted compounds. Thus, electron-donating groups in ortho-substituted 6-Chromanols accelerate the reaction rate through resonance stabilization in addition to the inductive substituent effect.

  • chlorine atom substitution influences radical scavenging activity of 6 Chromanol
    Bioorganic & Medicinal Chemistry, 2012
    Co-Authors: Keiko Inami, Yuko Iizuka, Miyuki Furukawa, Ikuo Nakanishi, Kei Ohkubo, Kiyoshi Fukuhara, Shunichi Fukuzumi, Masataka Mochizuki
    Abstract:

    Synthetic 6-Chromanol derivatives were prepared with several chlorine substitutions, which conferred both electron-withdrawing inductive effects and electron-donating resonance effects. A trichlorinated compound (2), a dichlorinated compound (3), and three monochlorinated compounds (4, 5, and 6) were synthesized; compounds 2, 3, and 6 were novel. The antioxidant activities of the compounds, evaluated in terms of their capacities to scavenge galvinoxyl radical, were associated with the number and positioning of chlorine atoms in the aromatic ring of 6-Chromanol. The activity of compound 1 (2,2-dimethyl-6-Chromanol) was slightly higher than the activities of compounds 2 (2,2-dimethyl-5,7-dichloro-6-Chromanol) or 3 (2,2-dimethyl-5,7,8-trichloro-6-Chromanol), in which the chlorine atoms were ortho to the phenolic hydroxyl group of 6-Chromanol. The scavenging activity of compound 3 was slightly higher than that of 2, which contained an additional chlorine substituted in the 8 position. The activities of polychlorinated compounds 2 and 3 were higher than the activities of any of the monochlorinated compounds (4–6). Compound 6, in which a chlorine was substituted in the 8 position, exhibited the lowest activity. Substitution of a chlorine atom meta to the hydroxyl group of 6-Chromanol (compounds 2 and 6) decreased galvinoxyl radical scavenging activity, owing to the electron-withdrawing inductive effect of chlorine. Positioning the chloro group ortho to the hydroxyl group (compounds 4 and 5) retained antioxidant activity because the intermediate radical was stabilized by the electron-donating resonance effect of chlorine in spite of the electron-withdrawing inductive effect of chlorine. Antioxidant activities of the synthesized compounds were evaluated for correlations with the O–H bond dissociation energies (BDEs) and the ionization potentials. The BDEs correlated with the second-order rate constants (k) in the reaction between galvinoxyl radical and the chlorinated 6-Chromanol derivatives in acetonitrile. This indicated that the antioxidant mechanism of the synthesized compounds consisted of a one-step hydrogen atom transfer from the phenolic OH group rather than an electron transfer followed by a proton transfer. The synthesized compounds also exhibited hydroxyl radical scavenging capacities in aqueous solution.

  • Reaction of 2,2,5,7,8-pentamethyl-6-Chromanol, an α-tocopherol analogue, with NO in the presence of oxygen
    Bioorganic & medicinal chemistry letters, 2000
    Co-Authors: Yoshiko Nagata, Masataka Mochizuki, Tamamo Nishio, Shigenobu Matsumoto, Hideko Kanazawa, Yoshikazu Matsushima
    Abstract:

    An alpha-tocopherol model compound, 2,2,5,7,8-pentamethyl-6-Chromanol, reacted with nitric oxide (NO) in the presence of various amounts of oxygen to afford four major products. Distribution of the products was varied depending on the ratio of NO and O2, and the preincubation time of NO and O2.

Peter T. Southwell-keely - One of the best experts on this subject based on the ideXlab platform.

  • Antioxidant activity of 5-alkoxymethyl-6-Chromanols
    Redox report : communications in free radical research, 2001
    Co-Authors: Min Chen, Indra Kohar, Peter T. Southwell-keely
    Abstract:

    AbstractThe 5-alkoxymethyl-2,2,7,8-tetramethyl-6-Chromanols (II) are excellent antioxidants against autoxidising safflower oil (ASO), although not as good as 2,2,5,7,8-pentamethyl-6-Chromanol (I), the model compound of -tocopherol. The aim of this work was to determine whether the rate of reaction of (II) with the radicals diphenylpicrylhydrazyl (DPP·) and galvinoxyl (ArO·) was directly proportional to their antioxidant activity against ASO. Compounds (II) reacted faster with DPP·. than with ArO·. but, in each case, slower than compound (I). The rates of reaction of I and II with both radicals followed the order I > II (R = H) > II (R = CH3) > II (R = other alkyls) and were directly proportional to their antioxidant activity against ASO.

  • Oxidations of the α‐tocopherol model compound 2,2,5,7,8‐pentamethyl‐6‐Chromanol. Formation of 2,2,7,8‐tetramethylchroman‐5,6‐dione
    Lipids, 1993
    Co-Authors: Indrajati Kohar, Cacang Suarna, Peter T. Southwell-keely
    Abstract:

    Overoxidation of α-tocopherol (1a) by silver nitrate produces tocored (9a) as a major product. The aim of the present work was to elucidate the pathway of formation of tocored using the α-tocopherol model compound, 2,2,5,7,8-pentamethyl-6-Chromanol (1b). Oxidation of 1b by silver nitrate in ethanol produces 2-(3-hydroxy-3-methylbutyl)-3,5,6-trimethyl-1,4-benzoquinone (6b) and 2,2,7,8-tetramethylchroman-5,6-dione (9b, the model compound of tocored) as major products. Formation of 6b is rapid and is accompanied by an equally rapid fall in pH. Formation of 9b only occurs after 6b has reached maximum concentration and has begun to decline. It appears that acid promotes the dehydration and recyclization of 6b into a quinone methide (2b), which is then rehydrated into 5-hydroxymethyl-2,2,7,8-tetramethyl-6-Chromanol (5b), the phenolic isomer of the quinone 6b. Oxidative deformylation of 5b leads to 9b. It is also demonstrated that 6b, heated in ethanol in the presence of acid and in the absence of any oxidizing agent, is converted into 9b, 1b, 5-ethoxymethyl-2,2,7,8-tetramethyl-6-Chromanol (4b) and 2-(3-hydroxy-3-methylbutyl)-3-ethoxymethyl-5,6-dimethyl-1,4-benzoquinone (7b). It seems that dehydration and recyclization of 6b into 5b occurs as above and that 6b then oxidizes 5b into 9b, while being reduced into the hydroquinone of 6b (6bH2). Compound 6bH2 then cyclizes in acid to 1b. A possible alternative pathway from 6b to 9b that does not involve 5b is also discussed. These results suggest that 6b and, by implication, α-tocopheryl quinone (6a), is not a stable compound and, in the presence of acid, is readily oxidized to 9b.

  • Oxidation of the α-tocopherol model compound 2,2,5,7,8-pentamethyl-6-Chromanol in the presence of alcohols
    Lipids, 1992
    Co-Authors: Cacang Suarna, Manuel Baca, Peter T. Southwell-keely
    Abstract:

    Oxidation of the vitamin E model compound, 2,2,5,7,8-pentamethyl-6-Chromanol (1b) byt-butyl hydroperoxide in chloroform has been studied in the presence of ethanol, heptanol and cholesterol. In the absence of an alcohol, the major products were the spirodimer (13b) and spirotrimer (14b) of 1b, together with 1H,2,3-dihydro-3,3,5,6,9,10,11a(R)-heptamethyl-7a(S)-(3-hydroxy-3-methylbutyl)-pyrano[2,3-a] xanthene 8(7aH), 11(11aH) dione (6b). In the presence of ethanol, heptanol and cholesterol, the major products were 5-ethoxymethyl-2,2,7,8-tetramethyl-6-Chromanol (16b), 5-heptoxymethyl-2,2,7,8-tetramethyl-6-Chromanol (17) and 5-cholesteroxymethyl-2,2,7,8-tetramethyl-6-Chromanol (18). However, when water was present in a homogeneous reaction, the most rapidly formed product was 2-(3-hydroxy-3-methylbutyl)-3,5,6-trimethyl-1,4-benzoquinone (5b). Compounds 13b, 14b, 16b, 17 and 18 are formedvia a quinone methide intermediate, and compound 5b is formedvia a phenoxylium ion. The phenoxylium species appears to be the preferred intermediate when water is present, whereas the quinone methide species is prefered in the absence of water.

  • Antioxidant activity of oxidation products of α-tocopherol and of its model compound 2,2,5,7,8-pentamethyl-6-Chromanol
    Lipids, 1991
    Co-Authors: Cacang Suarna, Peter T. Southwell-keely
    Abstract:

    A variety of oxidation products (4–29) of α-tocopherol, 1 and of its model compound, 2,2,5,7,8-pentamethyl-6-Chromanol (2) has been tested for antioxidant activity against autoxidizing safflower oil (ASO) and autoxidizing methyl linoleate (AML). The following compounds showed good antioxidant activity against both substrates: 5-hydroxymethyl-2,2,7,8-tetramethyl-6-Chromanol (4), 5-(2,2,5,7,8-pentamethyl-6-chromanoxy)methyl-2,2,7,8-tetramethyl-6-Chromanol (15), 1,2- bis (2,2,7,8-tetramethyl-6-Chromanol-5-)ethane (16), 5-ethoxymethyl-7,8-dimethyltocol (19), 5-mthoxymethyl-2,2,7,8-tetramethyl-6-Chromanol (21), 5-ethoxymethyl-2,2,7,8-tetramethyl-6-Chromanol (20), 5-propoxymethyl-2,2,7,8-tetramethyl-6-Chromanol (22), 5-butoxymethyl-2,2,7,8-tetramethyl-6-Chromanol (23), 5-(2-methyl-1-propoxy)methyl-2,2,7,8-tetramethyl-6-Chromanol (24), 5-(2-methyl-2-propoxy)methyl-2,2,7,8-tetramethyl-6-Chromanol (25), 5-heptoxymethyl-2,2,7,8-tetramethyl-6-Chromanol (26), 5-undecoxymethyl-2,2,7,8-tetramethyl-6-Chromanol (27), 5-phytoxymethyl-2,2,7,8-tetramethyl-6-Chromanol (28) and 5-cholesteroxymethyl-2,2,7,8-tetramethyl-6-Chromanol (29). 2,2,7,8-Tetramethylchroman-5,6-dione (17) and 1,2- bis (2,2,7-trimethylchroman-5,6-dione-8-)ethane (18) showed significant antioxidant activity against ASO but not against AML. If the corresponding oxidation products of 1 are formed in vivo it means that the antioxidant activity of 1 is not lost on oxidation. This may help to explain the outstanding capacity of 1 to protect cell membranes.

Yoshikazu Matsushima - One of the best experts on this subject based on the ideXlab platform.

Erhard Kemnitz - One of the best experts on this subject based on the ideXlab platform.

  • Synthesis of Vitamin K1 and K1‐Chromanol by Friedel–Crafts Alkylation in Heterogeneous Catalysis
    ChemCatChem, 2010
    Co-Authors: Simona M. Coman, Vasile I. Parvulescu, Stefan Wuttke, Erhard Kemnitz
    Abstract:

    The partly hydroxylated MgF 2 and AlF 3 materials are efficient and selective catalysts for the preparation of two important members of the vitamin K class: vitamin K 1 and vitamin K 1 -Chromanol. The high activity in combination with high selectivity in one of the target products is due to both the acidic strength and the synergistic effect of the presence of both, optimized Bronsted and Lewis sites. Therefore, the best catalyst for a target product can be obtained through a very simple tuning of the acidic properties of the material. Moreover, the results obtained in the present study (Y vitamin K1 =57.8% and Y vitamin K1-Chromanol = 71.4%) are also very encouraging from the environmental standpoint as green elements are introduced by using solid catalysts and a biphasic solvent system.

  • synthesis of vitamin k1 and k1 Chromanol by friedel crafts alkylation in heterogeneous catalysis
    Chemcatchem, 2010
    Co-Authors: Simona M. Coman, Vasile I. Parvulescu, Stefan Wuttke, Erhard Kemnitz
    Abstract:

    The partly hydroxylated MgF 2 and AlF 3 materials are efficient and selective catalysts for the preparation of two important members of the vitamin K class: vitamin K 1 and vitamin K 1 -Chromanol. The high activity in combination with high selectivity in one of the target products is due to both the acidic strength and the synergistic effect of the presence of both, optimized Bronsted and Lewis sites. Therefore, the best catalyst for a target product can be obtained through a very simple tuning of the acidic properties of the material. Moreover, the results obtained in the present study (Y vitamin K1 =57.8% and Y vitamin K1-Chromanol = 71.4%) are also very encouraging from the environmental standpoint as green elements are introduced by using solid catalysts and a biphasic solvent system.