title: Synthesis of a 10,000-membered library of molecules resembling carpanone and discovery of vesicular traffic inhibitors.
abstract: Split-and-pool synthesis of a 10,000-membered library of molecules resembling the natural product carpanone has been achieved. The synthesis features development of solid-phase multicomponent reactions between nitrogen nucleophiles, enones, and hydroxylamines, and a solid-phase application of the Huisgen cycloaddition affording substituted triazoles. The synthesis was performed in high-capacity (500 microm) polystyrene beads using a one bead-one stock solution strategy that enabled phenotypic screens of the resulting library. Using whole-cell fluorescence imaging, we discovered a series of molecules from the carpanone-based library that inhibit exocytosis from the Golgi apparatus. The most potent member of this series has an IC(50) of 14 microM. We also report structure-activity relationships for the molecules exhibiting this interesting phenotype. These inhibitors of exocytosis may be useful reagents for the study of vesicular traffic.
authors.affiliation: Department of Chemistry & Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
authors.forename: Brian C
authors.initials: BC
authors.lastname: Goess
authors.forename: Rami N
authors.initials: RN
authors.lastname: Hannoush
authors.forename: Lawrence K
authors.initials: LK
authors.lastname: Chan
authors.forename: Tomas
authors.initials: T
authors.lastname: Kirchhausen
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Shair
mesh_terms: D001688:Biological Products / Q000737:chemistry* / Q000494:pharmacology; D005089:Exocytosis / Q000187:drug effects; D005453:Fluorescence; D006056:Golgi Apparatus / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D001688:Biological Products