title: Design and synthesis of new hybrid molecules that activate the transcription factor Nrf2 and simultaneously release carbon monoxide.
abstract: The transcription factor Nrf2 and its downstream target heme oxygenase-1 (HO-1) are essential protective systems against oxidative stress and inflammation. The products of HO-1 enzymatic activity, biliverdin and carbon monoxide (CO), actively contribute to this protection, suggesting that exploitation of these cellular systems may offer new therapeutic avenues in a variety of diseases. Starting from a CO-releasing compound and a chemical scaffold exhibiting electrophilic characteristics (esters of fumaric acid), we report the synthesis of hybrid molecules that simultaneously activate Nrf2 and liberate CO. These hybrid compounds, which we termed "HYCOs", release CO to myoglobin and activate the CO-sensitive fluorescent probe COP-1, while also potently inducing nuclear accumulation of Nrf2 and HO-1 expression and activity in different cell types. Thus, we provide here the first example of a new class of pharmacologically active molecules that target the HO-1 pathway by combining an Nrf2 activator coordinated to a CO-releasing group.
authors.affiliation: Inserm, Unité 955, Equipe 3 and Faculté de Médicine, Université Paris-Est Créteil, 8 Rue du General Sarrail, 94000 Créteil (France).
authors.forename: Jayne Louise
authors.initials: JL
authors.lastname: Wilson
authors.forename: Sarah
authors.initials: S
authors.lastname: Fayad Kobeissi
authors.forename: Souhila
authors.initials: S
authors.lastname: Oudir
authors.forename: Benjamin
authors.initials: B
authors.lastname: Haas
authors.forename: Brian
authors.initials: B
authors.lastname: Michel
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Dubois Randé
authors.forename: Anthony
authors.initials: A
authors.lastname: Ollivier
authors.forename: Thierry
authors.initials: T
authors.lastname: Martens
authors.forename: Michael
authors.initials: M
authors.lastname: Rivard
authors.forename: Roberto
authors.initials: R
authors.lastname: Motterlini
authors.forename: Roberta
authors.initials: R
authors.lastname: Foresti
mesh_terms: D000480:Alkynes / Q000737:chemistry; D000818:Animals; D002248:Carbon Monoxide / Q000737:chemistry* / Q000494:pharmacology*; D003035:Cobalt / Q000737:chemistry; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D004952:Esters / Q000737:chemistry; D051547:Heme Oxygenase-1 / Q000737:chemistry* / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects
chemical_list: D000480:Alkynes; D056831:Coordination Complexes; D004952:Esters; D051267:NF-E2-Related Factor 2; D003035:Cobalt; D002248:Carbon Monoxide; D051547:Heme Oxygenase-1
keywords: biological activity; drug design; enzymes; fluorescent probes; heme proteins