title: Synthesis, Chiral Separation, Absolute Configuration Assignment, and Biological Activity of Enantiomers of Retro-1 as Potent Inhibitors of Shiga Toxin.
abstract: The Shiga toxin (Stx) family is composed of related protein toxins produced by the bacteria Shigella dysenteriae and certain pathogenic strains of E. coli. No effective therapies for Stx intoxication have been developed yet. However, inhibitors that act on the intracellular trafficking of these toxins may provide new options for the development of therapeutic strategies. This study reports the synthesis, chromatographic separation, and pharmacological evaluation of the two enantiomers of Retro-1, a compound active against Stx and other such protein toxins. Retro-1 works by inhibiting retrograde transport of these toxins inside cells. In vitro experiments proved that the configuration of the stereocenter at position 5 is not crucial for the activity of this compound. X-ray diffraction data revealed (S)-Retro-1 to be slightly more active than (R)-Retro-1.
authors.affiliation: CEA, iBiTec-S/SCBM, CEA-Saclay, LabEx LERMIT, 91191 Gif-sur-Yvette (France).
authors.forename: Hajer
authors.initials: H
authors.lastname: Abdelkafi
authors.affiliation: CEA, iBiTec-S/SIMOPRO, CEA-Saclay, LabEx LERMIT, 91191 Gif-sur-Yvette (France).
authors.forename: Aurélien
authors.initials: A
authors.lastname: Michau
authors.affiliation: CEA, iBiTec-S/SIMOPRO, CEA-Saclay, LabEx LERMIT, 91191 Gif-sur-Yvette (France).
authors.forename: Alexandra
authors.initials: A
authors.lastname: Clerget
authors.affiliation: CEA, iBiTec-S/SCBM, CEA-Saclay, LabEx LERMIT, 91191 Gif-sur-Yvette (France).
authors.forename: David-Alexandre
authors.initials: DA
authors.lastname: Buisson
authors.affiliation: Institut Curie, PSL Research University, Chemical Biology of Membranes and Therapeutic Delivery unit 26 rue d'Ulm, 75248 Paris Cedex 05 (France).|CNRS UMR3666, 75005 Paris (France).|INSERM U1143, 75005 Paris (France).
authors.forename: Ludger
authors.initials: L
authors.lastname: Johannes
authors.affiliation: CEA, iBiTec-S/SIMOPRO, CEA-Saclay, LabEx LERMIT, 91191 Gif-sur-Yvette (France). daniel.gillet@cea.fr.
authors.forename: Daniel
authors.initials: D
authors.lastname: Gillet
authors.affiliation: CEA, iBiTec-S/SIMOPRO, CEA-Saclay, LabEx LERMIT, 91191 Gif-sur-Yvette (France).
authors.forename: Julien
authors.initials: J
authors.lastname: Barbier
authors.affiliation: CEA, iBiTec-S/SCBM, CEA-Saclay, LabEx LERMIT, 91191 Gif-sur-Yvette (France). jean-christophe.cintrat@cea.fr.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Cintrat
mesh_terms: D001570:Benzodiazepinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D004926:Escherichia coli / Q000737:chemistry; D008958:Models, Molecular; D015394:Molecular Structure; D022621:Shiga Toxin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012762:Shigella dysenteriae / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C549072:7-bromo-5-phenyl-4-propionyl-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one; D001570:Benzodiazepinones; D022621:Shiga Toxin
keywords: Retro-1; Shiga toxin; benzodiazepines; retrograde transport