title: Cyclopamine analogs bearing exocyclic methylenes are highly potent and acid-stable inhibitors of hedgehog signaling.
abstract: The chemical synthesis and biological evaluation of new cyclopamine analogs bearing exocyclic methylenes in different positions is described. Bis-exo-cyclopamine 6 was identified as a potent inhibitor of the Gli1-dependent luciferase expression in Shh-LIGHTII cells. An extension of this study to F-ring-modified structures shows the necessity of a rigidly positioned nitrogen atom for bioactivity as well as the presence of the C21 methyl group for acid stability and bioactivity.
authors.affiliation: Universität Leipzig, Institut für Organische Chemie, Johannisallee 29, D-04103 Leipzig, Germany.
authors.forename: Johann
authors.initials: J
authors.lastname: Moschner
authors.affiliation: Universität Leipzig, Institut für Organische Chemie, Johannisallee 29, D-04103 Leipzig, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Chentsova
authors.affiliation: Universität Leipzig, Institut für Organische Chemie, Johannisallee 29, D-04103 Leipzig, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Eilert
authors.affiliation: Universität Leipzig, Institut für Organische Chemie, Johannisallee 29, D-04103 Leipzig, Germany.
authors.forename: Irene
authors.initials: I
authors.lastname: Rovardi
authors.affiliation: Rice University, Department of Chemistry, BioScience Research Collaborative, 6500 Main St., Houston, Texas 77030, USA.
authors.forename: Philipp
authors.initials: P
authors.lastname: Heretsch
authors.affiliation: Universität Leipzig, Institut für Organische Chemie, Johannisallee 29, D-04103 Leipzig, Germany.
authors.forename: Athanassios
authors.initials: A
authors.lastname: Giannis
keywords: cyclopamine; hedgehog signaling pathway; natural products; steroidal alkaloids; structure–activity relationship