title: Evaluation of the antiprion activity of 6-aminophenanthridines and related heterocycles.
abstract: Series of 6-aminophenanthridines and related heterocyclic compounds such as benzonaphtyridines were prepared. Reduction of one of the three aromatic rings was also performed. The compounds were first tested for their antiprion activity in a previously described yeast-based colourimetric prion assay. The most potent derivatives were then assayed ex vivo against the mammalian prion PrP(Sc) in a cell-based assay. Several of the new compounds were found more potent than the parent lead 6-aminophenanthridine. The most promising compounds against yeast and mammalian prions were 8-azido-6-aminophenanthridine (3m), and 7,10-dihydrophenanthridin-6-amine (14). In the mammalian cell-based assay, the IC50 of these two compounds were around 5 μM and 1.8 μM, respectively.
authors.affiliation: Inserm UMR 1078, Université de Bretagne Occidentale, Faculté de Médecine et des Sciences de la Santé, Etablissement Français du Sang (EFS) Bretagne, CHRU Brest, Hôpital Morvan, Laboratoire de Génétique Moléculaire, Brest, France.
authors.forename: Phuhai
authors.initials: P
authors.lastname: Nguyen
authors.affiliation: Laboratoire de Chimie Organique 2, Inserm U1022, Université Paris Descartes, Paris, France. Electronic address: oumata@manros-therapeutics.com.
authors.forename: Nassima
authors.initials: N
authors.lastname: Oumata
authors.affiliation: Inserm UMR 1078, Université de Bretagne Occidentale, Faculté de Médecine et des Sciences de la Santé, Etablissement Français du Sang (EFS) Bretagne, CHRU Brest, Hôpital Morvan, Laboratoire de Génétique Moléculaire, Brest, France.
authors.forename: Flavie
authors.initials: F
authors.lastname: Soubigou
authors.affiliation: Inserm UMR 1078, Université de Bretagne Occidentale, Faculté de Médecine et des Sciences de la Santé, Etablissement Français du Sang (EFS) Bretagne, CHRU Brest, Hôpital Morvan, Laboratoire de Génétique Moléculaire, Brest, France.
authors.forename: Justine
authors.initials: J
authors.lastname: Evrard
authors.affiliation: Protein Phosphorylation & Disease Laboratory, CNRS UPS2682, Roscoff, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Desban
authors.affiliation: UMR 8015 CNRS, Laboratoire de Cristallographie et RMN Biologiques, Université Paris Descartes, Paris, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Lemoine
authors.affiliation: UMR 8015 CNRS, Laboratoire de Cristallographie et RMN Biologiques, Université Paris Descartes, Paris, France.
authors.forename: Serge
authors.initials: S
authors.lastname: Bouaziz
authors.affiliation: Inserm UMR 1078, Université de Bretagne Occidentale, Faculté de Médecine et des Sciences de la Santé, Etablissement Français du Sang (EFS) Bretagne, CHRU Brest, Hôpital Morvan, Laboratoire de Génétique Moléculaire, Brest, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Blondel
authors.affiliation: Inserm UMR 1078, Université de Bretagne Occidentale, Faculté de Médecine et des Sciences de la Santé, Etablissement Français du Sang (EFS) Bretagne, CHRU Brest, Hôpital Morvan, Laboratoire de Génétique Moléculaire, Brest, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Voisset
mesh_terms: D000818:Animals; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D008958:Models, Molecular; D015394:Molecular Structure; D010617:Phenanthridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011328:Prions / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C549408:6-aminophenanthridine; D006571:Heterocyclic Compounds; D010617:Phenanthridines; D011328:Prions
keywords: Neurodegenerative diseases; Phenanthridine; Prions; Protein misfolding