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Effects of 3-Bromo-4,5-dihydroisoxazole Derivatives on Nrf2 Activation and Heme Oxygenase-1 Expression

Title data

Pinto, Andrea ; El Ali, Zeina ; Moniot, Sébastien ; Tamborini, Lucia ; Steegborn, Clemens ; Foresti, Roberta ; de Micheli, Carlo:
Effects of 3-Bromo-4,5-dihydroisoxazole Derivatives on Nrf2 Activation and Heme Oxygenase-1 Expression.
In: ChemistryOpen. Vol. 7 (November 2018) Issue 11 . - pp. 858-864.
ISSN 2191-1363
DOI: https://doi.org/10.1002/open.201800185

Abstract in another language

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 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.

Further data

Item Type: Article in a journal
Refereed: Yes
Keywords: 3-bromo-4,5-dihydroisoxazole; Keap1; crystal structure; cycloaddition; mass spectrometry
Institutions of the University: Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Chemistry > Chair Biochemistry > Chair Biochemistry - Univ.-Prof. Dr. Clemens Steegborn
Faculties
Faculties > Faculty of Biology, Chemistry and Earth Sciences
Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Chemistry
Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Chemistry > Chair Biochemistry
Result of work at the UBT: No
DDC Subjects: 500 Science > 540 Chemistry
Date Deposited: 22 Nov 2018 08:12
Last Modified: 27 Nov 2019 07:53
URI: https://eref.uni-bayreuth.de/id/eprint/46369