- Effects of 3-Bromo-4,5-dihydroisoxazole Derivatives on Nrf2 Activation and Heme Oxygenase-1 Expression
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Natural and synthetic electrophilic compounds have been shown to activate the antioxidant protective Nrf2 (nuclear factor erythroid 2-related factor 2)/heme oxygenase-1 (HO-1) axis in cells and tissues. Here, we tested the ability of different isoxazoline-based electrophiles to up-regulate Nrf2/HO-1. The potency of activation is dependent on the leaving group at the 3-position of the isoxazoline nucleus, and an additional ring on the molecule limits the Nrf2/HO-1 activating properties. Among the synthetized compounds, we identified 3-bromo-5-phenyl-4,5-dihydroisoxazole 1 as the derivative with best activating properties in THP-1 human monocytic cells. We have confirmed that the target of our compounds is the Cys151 of the BTB domain of Keap1 by using mass spectrometry analyses and X-ray crystallography. Our findings demonstrate that these compounds affect the Nrf2/HO-1 axis and highlight a positive activity that can be of relevance from a therapeutic perspective in inflammation and infection.
- Pinto, Andrea,El Ali, Zeina,Moniot, Sébastien,Tamborini, Lucia,Steegborn, Clemens,Foresti, Roberta,De Micheli, Carlo
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p. 858 - 864
(2018/10/24)
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- Palladium-free Sonogashira-type cross-coupling reaction of bromoisoxazolines or N-alkoxyimidoyl bromides and alkynes
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A Cu(I)-catalysed Sonogashira-type cross coupling reaction with aliphatic or aromatic bromoisoxazolines or N-alkoxyimidoyl bromides and alkynes is reported. The protocol we developed employs catalytic amount of copper(I), non-toxic ligand bathophenanthroline and is tolerant to a wide range of functional groups and is therefore particulary adapted in the context of drug discovery.
- Probst,Deprez,Willand
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supporting information
p. 1066 - 1070
(2018/03/26)
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- Discovery of covalent inhibitors of glyceraldehyde-3-phosphate dehydrogenase, a target for the treatment of malaria
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We developed a new class of covalent inhibitors of Plasmodium falciparum glyceraldehyde-3-phosphate dehydrogenase, a validated target for the treatment of malaria, by screening a small library of 3-bromo-isoxazoline derivatives that inactivate the enzyme through a covalent, selective bond to the catalytic cysteine, as demonstrated by mass spectrometry. Substituents on the isoxazolinic ring modulated the potency up to 20-fold, predominantly due to an electrostatic effect, as assessed by computational analysis.
- Bruno, Stefano,Pinto, Andrea,Paredi, Gianluca,Tamborini, Lucia,De Micheli, Carlo,La Pietra, Valeria,Marinelli, Luciana,Novellino, Ettore,Conti, Paola,Mozzarelli, Andrea
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p. 7465 - 7471
(2015/01/16)
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- Promiscuity and selectivity in covalent enzyme inhibition: A systematic study of electrophilic fragments
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Covalent ligand-target interactions offer significant pharmacological advantages. However, off-target reactivity of the reactive groups, which usually have electrophilic properties, must be minimized, and the selectivity of irreversible inhibitors is a crucial requirement. We therefore performed a systematic study to determine the selectivity of several electrophilic groups that can be used as building blocks for covalently binding ligands. Six reactive groups with modulated electrophilicity were combined with 11 nonreactive moieties, resulting in a small combinatorial library of 72 fragment-like compounds. These compounds were screened against a group of 11 enzyme targets to assess their selectivity and their potential for promiscuous binding to proteins. The assay results showed a considerably lower degree of promiscuity than initially expected, even for those members of the screening collection that contain supposedly highly reactive electrophiles.
- J?st, Christian,Nitsche, Christoph,Scholz, Therese,Roux, Lionel,Klein, Christian D.
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supporting information
p. 7590 - 7599
(2014/12/11)
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- Δ2-isoxazolines from arylcyclopropanes: III. Phenylcyclopropanes substituted in three-membered ring in reaction with nitrosyl chloride activated with oxides of sulfur(IV, VI)
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The reaction of phenylcyclopropanes substituted in the three-membered ring with nitrosyl chloride activated with sulfur(IV, VI) oxides provided in good yield substituted 5-phenylisoxazolines as a mixture of structural isomers.
- Bondarenko,Gavrilova,Saginova,Zyk,Zefirov
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experimental part
p. 218 - 225
(2009/09/25)
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- Synthesis of 3-aminoisoxazoles via the addition-elimination of amines on 3-bromoisoxazolines
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A novel two-step procedure for the synthesis of 3-amino-5-substituted- isoxazoles is described. In the presence of a base, readily available 3-bromoisoxazolines react with amines to afford 3-aminoisoxazolines. An oxidation protocol was developed for these heterocycles to provide 3-aminoisoxazoles in consistently high yield.
- Girardin, Melina,Alsabeh, Pamela G.,Lauzon, Sophie,Dolman, Sarah J.,Ouellet, Stephane G.,Hughes, Greg
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supporting information; experimental part
p. 1159 - 1162
(2009/08/07)
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- NITRILE OXIDES IN MEDICINAL CHEMISTRY-- 2. SYNTHESIS OF THE TWO ENANTIOMERS OF DIHYDROMUSCIMOL
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The cycloaddition of bromonitrile oxide to monosubstituted olefins has a high regioselectivity yielding 3-bomo-5-substituted isoxazolines contaminated by minor amounts (4-9percent) of the 4-substituted isomer.The adducts of bromonitrile oxide to allyl alcohol and N-protected allylamine were employed as key intermediates in the preparation of racemic dihydromuscimol (DHM).The synthesis of (R)-(-)- and (S)-(+)-DHM was accomplished by using the two diastereomers obtained by the cycloaddition of bromonitrile oxide to (S)-(+)-isopropylidene-3-buten-1,2-diol.The enantiomeric excess of R)-(-)- and (S)-(+)-DHM, determined by capillary GLC on the appropriate precursors, were 98.8 and >99.0 percent.A spectroscopic survey of the tautomerism of 3-hydroxyisoxazolines indicates the predominant or exclusive occurence of the NH form.
- Amici, Marco De,Micheli, Carlo De,Misani, Valeria
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p. 1975 - 1986
(2007/10/02)
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- Carboxy- and Cyano-Hydroxylation of Alkenes. - Synthesis of 3-Hydroxy-4-amino Acids and Butyrolactones via the Isoxazoline Route
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Dichloro- and dibromoformaldoximes are useful 1,3-dipolar cycloaddition reagents.They are conveniently preparated in situ, in high yields by dihalogenation of glyoxalic acid aldoxime with N-bromo- and N-chlorosuccinimide or tert-butyl hypochlorite.Dehydrohalogenation with potassium hydrogen carbonate in the presence of alkenes gives 3-halo-isoxazolines in a one-pot reaction.Reduction with iron pentacarbonyl gives β-hydroxynitriles.Methoxylation and catalytic reduction give β-hydroxy esters.Allyl alcohols and allylamines are transformed with halonitrile oxides into butyrolactones (DL-angelica lactone) and DL-3-hydroxy-4-amino acids (carnitine, 4-amino-3-hydroxybutyric acid), respectively.The lactonization is best effected by heating the γ-silyloxy ester in acetic acid with potassium hydrogen sulfate as catalyst.A synthesis of N-Boc-dihydromuscimol is described.
- Halling, Karen,Thomsen, Ib,Torssell, Kurt B. G.
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p. 985 - 990
(2007/10/02)
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- CONVERSION OF ISOXAZOLINES TO β-HYDROXY ESTERS. SYNTHESIS OF 2-DEOXY-D-RIBOSE
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A simple and efficient preparation of β-hydroxy esters with a well-defined stereochemistry has been developed using 3-bromoisoxazolines as key-intermediates.A synthesis of 2-deoxy-D-ribose is also reported.
- Caldilora, P.,Ciancaglione, M.,De Amici, M.,De Micheli, C.
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p. 4647 - 4650
(2007/10/02)
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- SUBSTITUTED PHENYLCYCLOPROPANES IN THE SYNTHESIS OF 2-ISOXAZOLINES
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Diverse 2-isoxazolines with substituents in both the aromatic ring and isoxazoline ring were obtained in the process of nitrosation of various substituted phenylcyclopropanes with sodium nitrite in mixture of chloroform and trifluoroacetic acid.
- Gazzaeva, R. A.,Shabarov, Yu. S.,Saginova, L. G.
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p. 246 - 250
(2007/10/02)
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- SYNTHESIS OF ANALOGUES OF THE ANTITUMOR ANTIBIOTIC AT-125 (ACIVICIN)
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Several haloisoxazoline analogues of α-amino-3-chloro-4,5-dihydro-5-isoxazole acetic acid (1, AT-125) were prepared by means of 1,3-dipolar cycloaddition methodology.The chemistry of these compounds is discussed, and a possible biological mode of action of AT-125 presented.
- Stevens, Robert V.,Polniaszek, Richard P.
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p. 743 - 748
(2007/10/02)
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