Fumaraldehyde monodimethyl acetal: An easily accessible and versatile intermediate.

Grée, René; Tourbah, H.; Carrié, R.

doi:10.1016/s0040-4039(00)85113-8

Cited by 75 publications

(37 citation statements)

References 23 publications

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“…Previously described methods (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38) mostly require anhydrous, inert, and/or cryogenic reaction conditions, use of organometallic reagent, and are used only for the preparation of either HNE or ONE. We required large amounts of both ONE and HNE for our studies so we visualized a convergent approach.…”

Section: Results and Dicussionmentioning

confidence: 99%

“…Previous procedures for HNE preparation employed variations in the Grignard reaction (25)(26)(27)(28)(29)(30), isomerization of 2-yne-1,4-diols with ruthenium catalyst (31), a method via 1,3-bis(methylthio)allyl-lithium (32), a sequence of addition/elimination/substitution reaction performed on the corresponding saturated aldehyde (33,34), epoxidation of 3(Z)-nonenol, oxidation, and isomerization (35). A method for chiral synthesis for HNE is also reported (36) which involves Sharpless epoxidation, reaction with an unstable Wittig reagent followed by isomerization (36).…”

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confidence: 99%

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Convenient and efficient syntheses of 4‐hydroxy‐2(E)‐nonenal and 4‐oxo‐2(E)‐nonenal

Kurangi

Tilve

Blair

2006

Lipids

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Lipid peroxidation products 4-hydroxy-2(E)-nonenal (HNE) and 4-oxo-2(E)-nonenal (ONE) were conveniently synthesized using Wittig and Horner-Wardsworth-Emmons (HWE) reaction. Wittig or HWE reaction between an easily prepared phosphorane or phosphonate with glyoxal dimethyl acetal gave a protected 4-oxo-2(E)-nonenal. Hydrolysis gave 4-oxo-2(E)-nonenal, whereas reduction followed by hydrolysis gave 4-hydroxy-2(E)-nonenal.

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Section: Results and Dicussionmentioning

confidence: 99%

mentioning

confidence: 99%

Convenient and efficient syntheses of 4‐hydroxy‐2(E)‐nonenal and 4‐oxo‐2(E)‐nonenal

Kurangi

Tilve

Blair

2006

Lipids

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“…4-HNE was synthesized according to Gree et al (1986) and Chandra and Srivastava (1997), and 4-HNE(Ac) 3 was prepared as described by Neely et al (2002). The identity of both compounds was confirmed by proton NMR (data not shown).…”

Section: Methodsmentioning

confidence: 99%

Mutagenic Effects of 4-Hydroxynonenal Triacetate, a Chemically Protected Form of the Lipid Peroxidation Product 4-Hydroxynonenal, as Assayed in L5178Y/Tk⁺/– Mouse Lymphoma Cells

Singh¹,

Chen²,

Chen³

et al. 2005

J Pharmacol Exp Ther

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The lipid peroxidation product 4-hydroxynon-2-enal (4-HNE) is cytotoxic and genotoxic at superphysiological concentrations. To characterize the mechanism of action of 4-HNE, we assessed genotoxic damage by 4-HNE and by 4-HNE triacetate [4-HNE(Ac) 3 ] using the mouse lymphoma assay that measures the mutant frequency in the Tk gene. As a strong electrophile, 4-HNE reacts readily with nucleophilic centers on cellular components. When added extracellularly, it may react preferentially with proteins in culture medium or on the cell surface and not reach deeper cellular targets such as nuclear DNA. Therefore, 4-HNE(Ac) 3 , a protected form of 4-HNE that is metabolically converted to 4-HNE in cells (Neely MD, Amarnath V, Weitlauf C, and Montine TJ, Chem Res Toxicol 15: 40 -47, 2002), was assayed in addition to 4-HNE. When added in serum-containing medium, 4-HNE was not mutagenic in the mouse lymphoma assay up to 38 M (cytotoxicity ϭ 13%). In contrast, exposure to 4-HNE(Ac) 3 , which mimics intracellular formation of 4-HNE, resulted in dose-dependent induction of mutations. At 17 M 4-HNE(Ac) 3 (cytotoxicity ϭ 33%), the mutant frequency was 719 ϫ 10 Ϫ6 (Ͼ7-fold higher than the spontaneous mutant frequency). Loss of heterozygosity analysis in the Tk mutants revealed that the majority of mutations induced by 4-HNE(Ac) 3 resulted from clastogenic events affecting a large segment of the chromosome. The results indicate that, in the presence of serum that approximates physiological conditions, 4-HNE generated intracellularly but not extracellularly is a strong mutagen via a clastogenic action at concentrations that may occur during oxidative stress.The production of partially reduced forms of dioxygen such as superoxide, hydrogen peroxide, or the hydroxyl radical (reactive oxygen species or ROS) is an inevitable consequence of aerobic life. Because of their high reactivity, ROS and/or their downstream products such as peroxynitrite (Crow, 2000) can attack all cellular constituents. It is often tacitly assumed that functionally relevant effects of ROS are due to damage to proteins and nucleic acids because such damage results in immediate functional consequences or mutations. However, ROS also target lipids. The hydroxyl radical can initiate a chain reaction that produces multiple lipid hydroperoxide molecules from a single initial event (Gutteridge and Halliwell, 1990). Since lipid hydroperoxides are oxidants capable of damaging cellular constituents, the chain reaction is in effect amplifying the initial oxidative insult. Peroxida-

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“…4-HNE was synthesized according to Gree et al (1986) and Chandra and Srivastava (1997). Worms were transferred two days after hatching onto plates containing E. coli expressing the appropriate double-stranded RNA (see section 2.1), and were maintained under these conditions (with daily transfers to fresh plates) for 3 days.…”

Section: Resistance Of C Elegans To Electrophilic Stress Caused By 4mentioning

confidence: 99%

Life span and stress resistance of Caenorhabditis elegans are differentially affected by glutathione transferases metabolizing 4-hydroxynon-2-enal

Ayyadevara

Dandapat

Singh

et al. 2007

Mechanisms of Ageing and Development

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The lipid peroxidation product 4-hydroxynon-2-enal (4-HNE) forms as a consequence of oxidative stress, and acts as a signaling molecule or, at superphysiological levels, as a toxicant. The steadystate concentration of the compound reflects the balance between its generation and its metabolism, primarily through glutathione conjugation. Using an RNAi-based screen, we identified in Caenorhabditis elegans five glutathione transferases (GSTs) capable of catalyzing 4-HNE conjugation. RNAi knock-down of these GSTs (products of the gst-5, gst-6, gst-8, gst-10, and gst-24 genes) sensitized the nematode to electrophilic stress elicited by exposure to 4-HNE. However, interference with the expression of only two of these genes (gst-5 and gst-10) significantly shortened the life span of the organism. RNAi knock-down of the other GSTs resulted in at least as much 4-HNE adducts, suggesting tissue-specificity of effects on longevity. Our results are consistent with the oxidative stress theory of organismal aging, broadened by considering electrophilic stress as a contributing factor. According to this extended hypothesis, peroxidation of lipids leads to the formation of 4-HNE in a chain reaction which amplifies the original damage. 4-HNE then acts as an "aging effector" via the formation of 4-HNE-protein adducts, and a resulting change in protein function.

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Fumaraldehyde monodimethyl acetal: An easily accessible and versatile intermediate.

Cited by 75 publications

References 23 publications

Convenient and efficient syntheses of 4‐hydroxy‐2(E)‐nonenal and 4‐oxo‐2(E)‐nonenal

Convenient and efficient syntheses of 4‐hydroxy‐2(E)‐nonenal and 4‐oxo‐2(E)‐nonenal

Mutagenic Effects of 4-Hydroxynonenal Triacetate, a Chemically Protected Form of the Lipid Peroxidation Product 4-Hydroxynonenal, as Assayed in L5178Y/Tk⁺/– Mouse Lymphoma Cells

Life span and stress resistance of Caenorhabditis elegans are differentially affected by glutathione transferases metabolizing 4-hydroxynon-2-enal

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Fumaraldehyde monodimethyl acetal: An easily accessible and versatile intermediate.

Cited by 75 publications

References 23 publications

Convenient and efficient syntheses of 4‐hydroxy‐2(E)‐nonenal and 4‐oxo‐2(E)‐nonenal

Convenient and efficient syntheses of 4‐hydroxy‐2(E)‐nonenal and 4‐oxo‐2(E)‐nonenal

Mutagenic Effects of 4-Hydroxynonenal Triacetate, a Chemically Protected Form of the Lipid Peroxidation Product 4-Hydroxynonenal, as Assayed in L5178Y/Tk+/– Mouse Lymphoma Cells

Life span and stress resistance of Caenorhabditis elegans are differentially affected by glutathione transferases metabolizing 4-hydroxynon-2-enal

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Mutagenic Effects of 4-Hydroxynonenal Triacetate, a Chemically Protected Form of the Lipid Peroxidation Product 4-Hydroxynonenal, as Assayed in L5178Y/Tk⁺/– Mouse Lymphoma Cells