1120215-02-2Relevant academic research and scientific papers
Selectivity of 3-bromo-isoxazoline inhibitors between human and Plasmodium falciparum glyceraldehyde-3-phosphate dehydrogenases
Bruno, Stefano,Margiotta, Marilena,Pinto, Andrea,Cullia, Gregorio,Conti, Paola,De Micheli, Carlo,Mozzarelli, Andrea
, p. 2654 - 2659 (2016)
Compounds based on the 3-Br-isoxazoline scaffold fully inhibit glyceraldehyde 3-phosphate dehydrogenase from Plasmodium falciparum by selectively alkylating all four catalytic cysteines of the tetramer. Here, we show that, under the same experimental conditions that led to a fast and complete inhibition of the protozoan enzyme, the human ortholog was only 25% inhibited, with the alkylation of a single catalytic cysteine within the tetramer. The partial alkylation seems to produce a slow conformational rearrangement that severely limits the accessibility of the remaining active sites to bulky 3-Br-isoxazoline derivatives, but not to the substrate or smaller alkylating agents.
Effects of 3-Bromo-4,5-dihydroisoxazole Derivatives on Nrf2 Activation and Heme Oxygenase-1 Expression
Pinto, Andrea,El Ali, Zeina,Moniot, Sébastien,Tamborini, Lucia,Steegborn, Clemens,Foresti, Roberta,De Micheli, Carlo
, p. 858 - 864 (2018)
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.
Continuous Preparation and Use of Dibromoformaldoxime as a Reactive Intermediate for the Synthesis of 3-Bromoisoxazolines
Battilocchio, Claudio,Bosica, Francesco,Rowe, Sam M.,Abreu, Bruna L.,Godineau, Edouard,Lehmann, Matthias,Ley, Steven V.
, p. 1588 - 1594 (2017)
We report the multistep continuous process for the preparation of dibromoformaldoxime (DBFO) as a precursor to generate 3-bromoisoxazolines. We also report process improvements that afford a productivity of over 620 mmol h-1 of DBFO.
Synthesis of 3-aminoisoxazoles via the addition-elimination of amines on 3-bromoisoxazolines
Girardin, Melina,Alsabeh, Pamela G.,Lauzon, Sophie,Dolman, Sarah J.,Ouellet, Stephane G.,Hughes, Greg
supporting information; experimental part, p. 1159 - 1162 (2009/08/07)
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.
