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J Am Chem Soc. 2006 Apr 26;128(16):5391-403.

Synthesis of a 10,000-membered library of molecules resembling carpanone and discovery of vesicular traffic inhibitors.

Author information

1
Department of Chemistry & Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA.

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.

PMID:
16620111
PMCID:
PMC2785548
DOI:
10.1021/ja056338g
[Indexed for MEDLINE]
Free PMC Article

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