title: 3,6-dibromocarbazole piperazine derivatives of 2-propanol as first inhibitors of cytochrome c release via Bax channel modulation.
abstract: There is compelling evidence that Bax channel activity stimulates cytochrome c release leading ultimately to cell death, which is a key event in ischemic injuries and neurodegenerative diseases. Here 3,6-dibromocarbazole piperazine derivatives of 2-propanol are described as the first small and potent modulators of the cytochrome c release triggered by Bid-induced Bax activation in a mitochondrial assay. Furthermore, a mechanism of action is proposed, and fluorescent derivatives allowing the localization of such inhibitors are reported.
authors.affiliation: Serono Pharmaceutical Research Institute, 14 Chemin des Aulx, 1228 Plan-les-Ouates, Geneva, Switzerland. agnes.bombrun@serono.com
authors.forename: Agnes
authors.initials: A
authors.lastname: Bombrun
authors.forename: Patrick
authors.initials: P
authors.lastname: Gerber
authors.forename: Giulio
authors.initials: G
authors.lastname: Casi
authors.forename: Olivier
authors.initials: O
authors.lastname: Terradillos
authors.forename: Bruno
authors.initials: B
authors.lastname: Antonsson
authors.forename: Serge
authors.initials: S
authors.lastname: Halazy
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002227:Carbazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D003574:Cytochrome c Group / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D005456:Fluorescent Dyes; D006367:HeLa Cells; D006801:Humans; D007202:Indicators and Reagents; D008081:Liposomes; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D010879:Piperazines / Q000138:chemical synthesis* / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2; D013329:Structure-Activity Relationship; D051028:bcl-2-Associated X Protein
chemical_list: C494826:BAX protein, human; D002227:Carbazoles; D003574:Cytochrome c Group; D004791:Enzyme Inhibitors; D005456:Fluorescent Dyes; D007202:Indicators and Reagents; D008081:Liposomes; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein