Journal
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Volume 128, Issue 16, Pages 5391-5403Publisher
AMER CHEMICAL SOC
DOI: 10.1021/ja056338g
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Funding
- NIGMS NIH HHS [P01 GM062566, P01 GM62566-05] Funding Source: Medline
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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 pm) 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 IC50 of 14 mu M. 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.
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