29343-52-0Relevant articles and documents
Tandem IBX-Promoted Primary Alcohol Oxidation/Opening of Intermediate β,γ-Diolcarbonate Aldehydes to (E)-γ-Hydroxy-α,β-enals
Kumari, Anupama,Gholap, Sachin P.,Fernandes, Rodney A.
, p. 2278 - 2290 (2019/06/17)
A tandem IBX-promoted oxidation of primary alcohol to aldehyde and opening of intermediate β,γ-diolcarbonate aldehyde to (E)-γ-hydroxy-α,β-enal has been developed. Remarkably, the carbonate opening delivered exclusively (E)-olefin and no over-oxidation of γ-hydroxy was observed. The method developed has been extended to complete the stereoselective total synthesis of both (S)- and (R)-coriolides and d-xylo- and d-arabino-C-20 guggultetrols.
Characterization of Carbonyl-Phenol Adducts Produced by Food Phenolic Trapping of 4-Hydroxy-2-hexenal and 4-Hydroxy-2-nonenal
Hidalgo, Francisco J.,Zamora, Rosario
, p. 2043 - 2051 (2019/02/26)
4-Hydroxy-2-alkenals disappear in the presence of food phenolics (i.e., cathechin or quercetin), and the corresponding carbonyl-phenol adducts are produced. In an attempt to identify structure(s) of formed adducts, the reactions between model phenolics (resorcinol, 2-methylresorcinol, orcinol, and 2,5-dimethylresorcinol) and hydroxyalkenals (4-hydroxy-2-hexenal and 4-hydroxy-2-nonenal) were studied and the produced adducts were isolated by column chromatography and unambiguously characterized by one- A nd two-dimensional nuclear magnetic resonance and mass spectrometry as dihydrobenzofuranols (1), chromane-2,7-diols (2), and 2H-chromen-7-ols (3). These compounds were mainly produced at slightly basic pH values and moderate temperatures. Their activation energies (Ea) of formation were a25 kJ mol-1 for adducts 1, a32 kJ mol-1 for adducts 2, and a38 kJ mol-1 for adducts 3. A reaction pathway that explains their formation is proposed. All of these results confirm that, analogously to other lipid-derived carbonyl compounds, phenolics can trap 4-hydroxy-2-alkenals in an efficient way. Obtained results provide the basis for the potential detection of carbonyl-phenol adducts derived from hydroxyalkenals in food products.
Isotopic labelling for the characterisation of HNE-sequestering agents in plant-based extracts and its application for the identification of anthocyanidins in black rice with giant embryo
Colzani, Mara,Regazzoni, Luca,Criscuolo, Angela,Baron, Giovanna,Carini, Marina,Vistoli, Giulio,Lee, Yoon-Mi,Han, Sang-Ik,Aldini, Giancarlo,Yeum, Kyung-Jin
, p. 896 - 906 (2018/07/31)
Reactive carbonyl species (RCS) are cytotoxic molecules that originate from lipid peroxidation and sugar oxidation. Natural derivatives can be an attractive source of potential RCS scavenger. However, the lack of analytical methods to screen and identify bioactive compounds contained in complex matrices has hindered their identification. The sequestering actions of various rice extracts on RCS have been determined using ubiquitin and 4-hydroxy-2-nonenal (HNE) as a protein and RCS model, respectively. Black rice with giant embryo extract was found to be the most effective among various rice varieties. The identification of bioactive compounds was then carried out by an isotopic signature profile method using the characteristic isotopic ion cluster generated by the mixture of HNE: 2H5-HNE mixed at a 1:1 stoichiometric ratio. An in-house database was used to obtain the structures of the possible bioactive components. The identified compounds were further confirmed as HNE sequestering agents through HPLC-UV analysis.
A method to produce fully characterized ubiquitin covalently modified by 4-hydroxy-nonenal, glyoxal, methylglyoxal, and malondialdehyde
Colzani, Mara,Criscuolo, Angela,Casali, Gaia,Carini, Marina,Aldini, Giancarlo
, p. 328 - 336 (2016/02/03)
Reactive carbonyl species (RCS) and the corresponding protein adducts (advanced glycoxidation or lipoxidation end products, i.e. AGEs and ALEs) are now widely studied from different points of view, since they can be considered as biomarkers, pathogenic factors, toxic mediators and drug targets. One of the main limits of the research in this field is the lack of standardized and fully characterized AGEs and ALEs to be used for biological, toxicological, and analytical studies. In this work, we set up a procedure to prepare and fully characterize a set of AGEs and ALEs by incubating ubiquitin - a model protein selected as target for carbonylation - with four different RCS: 4-hydroxy-trans-2-nonenal (HNE), methylglyoxal (MGO), glyoxal (GO), and malondialdehyde (MDA). After 24 h of incubation, the extent of protein carbonylation was estimated using a recently developed quantitative strategy based on high-resolution mass spectrometry. The resulting AGEs and ALEs were fully characterized by both intact protein and bottom-up analyses in terms of: stoichiometry of the total amount of modified protein, elucidation of the structure of the RCS-deriving adducts, and localization of the RCS-modified amino acids. Each RCS exhibited different reactivity toward ubiquitin, as detected by quantifying the extent of protein modification. The order of reactivity was MGO > GO > HNE > MDA. A variety of reaction products was identified and mapped on lysine, arginine, and histidine residues of the protein. In summary, a highly standardized and reproducible method to prepare fully characterized AGEs/ALEs is here presented.
NADP+-dependent dehydrogenase activity of carbonyl reductase on glutathionylhydroxynonanal as a new pathway for hydroxynonenal detoxification
Moschini, Roberta,Peroni, Eleonora,Rotondo, Rossella,Renzone, Giovanni,Melck, Dominique,Cappiello, Mario,Srebot, Massimo,Napolitano, Elio,Motta, Andrea,Scaloni, Andrea,Mura, Umberto,Del-Corso, Antonella
, p. 66 - 76 (2015/04/14)
An NADP+-dependent dehydrogenase activity on 3-glutathionyl-4-hydroxynonanal (GSHNE) was purified to electrophoretic homogeneity from a line of human astrocytoma cells (ADF). Proteomic analysis identified this enzymatic activity as associated with carbonyl reductase 1 (EC 1.1.1.184). The enzyme is highly efficient at catalyzing the oxidation of GSHNE (KM 33 μM, kcat 405 min-1), as it is practically inactive toward trans-4-hydroxy-2-nonenal (HNE) and other HNE-adducted thiol-containing amino acid derivatives. Combined mass spectrometry and nuclear magnetic resonance spectroscopy analysis of the reaction products revealed that carbonyl reductase oxidizes the hydroxyl group of GSHNE in its hemiacetal form, with the formation of the corresponding 3-glutathionylnonanoic-δ-lactone. The relevance of this new reaction catalyzed by carbonyl reductase 1 is discussed in terms of HNE detoxification and the recovery of reducing power.
Reactivity of (E)-4-hydroxy-2-nonenal with fluorinated phenylhydrazines: Towards the efficient derivatization of an elusive key biomarker of lipid peroxidation
Matera, Riccardo,Gabbanini, Simone,Valvassori, Alice,Triquigneaux, Mathilde,Valgimigli, Luca
experimental part, p. 3841 - 3851 (2012/09/22)
4-Hydroxynonenal (4-HNE) is a major product of the oxidation of ε-6-polyunstaturated lipids and an effector of radical-mediated oxidative damage, whose analytical determination requires chemical derivatization. In this work, its reactivity with fluorinated phenylhydrazines was explored both under preparative and analytical settings. A five-step synthesis of 4-HNE on gram-scale with an overall yield of 30% is described. Reaction of 4-HNE with ortho-, meta-, or para-CF3-phenylhydrazine, as well as with the 3,5-di-CF3, 2,4-di-CF3, or pentafluoro analogues, in MeCN with 0.5 mM TFA yields the corresponding hydrazones with rate constants k f of 2.8±0.4, 1.7±0.1, 3.0±0.2, 0.6±0.1, 0.5±0.1, and 3.5±0.5 M-1s-1, respectively at 298 K. At higher temperatures, the hydrazones undergo intramolecular cyclization to form 1,6-dihydropyridazines that, depending on the solvent and temperature, may further react with the hydrazine to yield tetrahydropyridazine adducts and their oxidation products. Other reaction products were isolated, depending on the reaction conditions, and the complex reactivity of 4-HNE with the above nucleophiles is discussed. Due to the good yield and rate of formation of the hydrazone adducts, their stability and favorable UV absorbance, 2-(trifluoromethyl)phenylhydrazine and 2,3,4,5,6-pentafluorophenylhydrazine are the most interesting candidates for the development of rapid and efficient analytical derivatizations of 4-HNE. 4-Hydroxynonenal reacts rapidly at room temperature with 2-, 3-, or 4-CF3-phenylhydrazine, or with the 3,5-di-CF3, 2,4-di-CF3, or pentafluoro analogues, to form hydrazones, which may undergo cyclization to 1,6-dihydropyridazines and other addition/oxidation products. The product distribution can be controlled by solvent and temperature to develop rapid derivatization assays. Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
Liquid chromatography/electrospray ionisation mass spectrometric tracking of 4-hydroxy-2(E)-nonenal biotransformations by mouse colon epithelial cells using [1,2-13C2]-4-hydroxy-2(E)-nonenal as stable isotope tracer
Jouanin,Baradat,Gieules,Tache,Pierre,Gueraud,Debrauwer
, p. 2675 - 2681 (2012/03/10)
4-Hydroxy-2(E)-nonenal (HNE), a product of lipid peroxidation, has been extensively studied in several areas, including metabolism with radio-isotopes and quantification in various matrices with deuterium-labelled HNE as standard. The aim of this work was to evaluate the relevance of 13C-labelled HNE in biotransformation studies to discriminate metabolites from endogens by liquid chromatography/electrospray ionisation mass spectrometry (LC/ESI-MS). 13C-Labelled HNE was synthesised inimproved overall yield (20%), with the incorporation of two labels in the molecule. Immortalisedmouse colon epithelial cells were incubated with 2:3 molar amounts of HNE/13C-HNE in order to gain information on the detection of metabolites in complex media. Our results demonstrated that the stable isotope m/z values determined by mass spectrometry were relevant in distinguishing metabolites from endogens, and that metabolite structures could be deduced. Six conjugate metabolites and 4-hydroxy-2(E)-nonenoic acid were identified, together with an incompletely identified metabolite. Stable-isotope-labelled HNE has already been used for quantification purposes. However, this is the first report on the use of 13C-labelled HNE as a tracer for in vitro metabolism. 13C-Labelled HNE could also be of benefit for in vivo studies. Copyright
Design, Synthesis, ADME Properties, and Pharmacological Activities of β-Alanyl-D-histidine (D-Carnosine) Prodrugs with Improved Bioavailability
Orioli, Marica,Vistoli, Giulio,Regazzoni, Luca,Pedretti, Alessandro,Lapolla, Annunziata,Rossoni, Giuseppe,Canevotti, Renato,Gamberoni, Luca,Previtali, Massimo,Carini, Marina,Aldini, Giancarlo
body text, p. 1269 - 1282 (2012/05/20)
β-Alanyl-D-histidine (D-CAR, the enantiomer of the natural dipeptide carnosine) is a selective and potent sequestering agent of reactive carbonyl species (RCS) that is stable against carnosinase, but is poorly absorbed in the gastrointestinal tract. Herein we report a drug discovery approach aimed at increasing the oral bioavailability of D-CAR. In our study we designed, synthesized, and evaluated a series of novel lipophilic D-CAR prodrugs. The considered prodrugs can be divided into two categories: 1)derivatives with both terminal groups modified, in which the carboxyl terminus is always esterified while the amino terminus is protected by an amidic (N-acetyl derivatives) or a carbamate (ethyloxy or benzyloxy derivatives) function; 2)derivatives with only one terminus modified, which can be alkyl esters as well as amidic or carbamate derivatives. The prodrugs were designed considering their expected lipophilicity and their hydrolysis predicted by docking simulations on the most important human carboxylesterase (hCES1). The stability and metabolic profile of the prodrugs were studied by incubating them with rat and human serum and liver fractions. The octyl ester of D-CAR (compound 13) was chosen as a candidate for further pharmacological studies due to its rapid hydrolysis to the bioactive metabolite invitro. Pharmacokinetic studies in rats confirmed the invitro data and demonstrated that the oral bioavailability of D-CAR is increased 2.6-fold if given as an octyl ester relative to D-CAR. Compound 13 was then found to dose-dependently (at daily doses of 3 and 30mgkg-1 equivalent of D-CAR) decrease the development of hypertension and dyslipidemia, to restore renal functions of Zucker fa/fa obese rats, and to inhibit the carbonylation process (AGEs and pentosidine) as well as oxidative stress (urinary 8-epi-prostaglandin F2α and nitrotyrosine). A plausible mechanism underlying the protective effects of 13 is RCS sequestration, as evidenced by the significant increase in the level of adduct between CAR and 4-hydroxy-trans-2-nonenal (HNE, the main RCS generated by lipid oxidation) in the urine of treated animals. The modest oral absorption of D-carnosine (D-CAR), a bioactive compound able to detoxify reactive carbonyl species, prompted us to design, synthesize, and evaluate new lipophilic D-CAR prodrugs. Among these, D-CAR with an octyl ester has greater oral bioavailability than D-CAR, as demonstrated by pharmacokinetic studies. The new compound reduces the development of hypertension and dyslipidemia, and restores renal function in Zucker fa/fa obese rats.
Synthesis, physicochemical characterization, and biological activities of new carnosine derivatives stable in human serum as potential neuroprotective agents
Bertinaria, Massimo,Rolando, Barbara,Giorgis, Marta,Montanaro, Gabriele,Guglielmo, Stefano,Buonsanti, M. Federica,Carabelli, Valentina,Gavello, Daniela,Daniele, Pier Giuseppe,Fruttero, Roberta,Gasco, Alberto
body text, p. 611 - 621 (2011/03/20)
The synthesis and the physicochemical and biological characterization of a series of carnosine amides bearing on the amido group alkyl substituents endowed with different lipophilicity are described. All synthesized products display carnosine-like properties differentiating from the lead for their high serum stability. They are able to complex Cu2+ ions at physiological pH with the same stoichiometry as carnosine. The newly synthesized compounds display highly significant copper ion sequestering ability and are capable of protecting LDL from oxidation catalyzed by Cu2+ ions, the most active compounds being the most hydrophilic ones. All the synthesized amides show quite potent carnosine-like HNE quenching activity; in particular, 7d, the member of the series selected for this kind of study, is able to cross the blood-brain barrier (BBB) and to protect primary mouse hippocampal neurons against HNE-induced death. These products can be considered metabolically stable analogues of carnosine and are worthy of additional investigation as potential neuroprotective agents.
Formation of 4-hydroxynonenal from cardiolipin oxidation: Intramolecular peroxyl radical addition and decomposition
Liu, Wei,Porter, Ned A.,Schneider, Claus,Brash, Alan R.,Yin, Huiyong
experimental part, p. 166 - 178 (2011/12/15)
We report herein that oxidation of a mitochondria-specific phospholipid tetralinoleoyl cardiolipin (L4CL) by cytochrome c and H 2O2 leads to the formation of 4-hydroxy-2-nonenal (4-HNE) via a novel chemical mechanism that involves cross-chain peroxyl radical addition and decomposition. As one of the most bioactive lipid electrophiles, 4-HNE possesses diverse biological activities ranging from modulation of multiple signal transduction pathways to the induction of intrinsic apoptosis. However, where and how 4-HNE is formed in vivo are much less understood. Recently a novel chemical mechanism has been proposed that involves intermolecular dimerization of fatty acids by peroxyl bond formation; but the biological relevance of this mechanism is unknown because a majority of the fatty acids are esterified in phospholipids in the cellular membrane. We hypothesize that oxidation of cardiolipins, especially L4CL, may lead to the formation of 4-HNE via this novel mechanism. We employed L4CL and dilinoleoylphosphatidylcholine (DLPC) as model compounds to test this hypothesis. Indeed, in experiments designed to assess the intramolecular mechanism, more 4-HNE is formed from L4CL and DLPC oxidation than 1-palmitoyl-2-linoleoylphosphatydylcholine. The key products and intermediates that are consistent with this proposed mechanism of 4-HNE formation have been identified using liquid chromatography-mass spectrometry. Identical products from cardiolipin oxidation were identified in vivo in rat liver tissue after carbon tetrachloride treatment. Our studies provide the first evidence in vitro and in vivo for the formation 4-HNE from cardiolipin oxidation via cross-chain peroxyl radical addition and decomposition, which may have implications in apoptosis and other biological activities of 4-HNE.
