Synthesis of a 10,000-membered library of molecules resembling carpanone and discovery of vesicular traffic inhibitors.
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.
Goess
Brian C
BC
Department of Chemistry & Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
Hannoush
Rami N
RN
Chan
Lawrence K
LK
Kirchhausen
Tomas
T
Shair
Matthew D
MD
D001688:Biological Products / Q000737:chemistry* / Q000494:pharmacology; D005089:Exocytosis / Q000187:drug effects; D005453:Fluorescence; D006056:Golgi Apparatus / Q000187:drug effects; D013329:Structure-Activity Relationship
D001688:Biological Products