Effects of 3-bromo-4,5-dihydroisoxazole derivatives on Nrf2 activation and heme oxygenase-1 expression
Articolo
Data di Pubblicazione:
2018
Citazione:
Effects of 3-bromo-4,5-dihydroisoxazole derivatives on Nrf2 activation and heme oxygenase-1 expression / A. Pinto, Z. El Ali, S. Moniot, L. Tamborini, C. Steegborn, R. Foresti, C. De Micheli. - In: CHEMISTRYOPEN. - ISSN 2191-1363. - 7:11(2018 Nov), pp. 858-864. [10.1002/open.201800185]
Abstract:
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.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
3-bromo-4,5-dihydroisoxazole; crystal structure; cycloaddition; Keap1; mass spectrometry
Elenco autori:
A. Pinto, Z. El Ali, S. Moniot, L. Tamborini, C. Steegborn, R. Foresti, C. De Micheli
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