Goess Brian C, Hannoush Rami N, Chan Lawrence K, Kirchhausen Tomas, Shair Matthew D
Department of Chemistry & Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
J Am Chem Soc. 2006 Apr 26;128(16):5391-403. doi: 10.1021/ja056338g.
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.
已实现了类似于天然产物卡帕酮的一万种分子库的拆分-混合合成。该合成的特点是开发了氮亲核试剂、烯酮和羟胺之间的固相多组分反应，以及惠斯根环加成反应在固相中应用以提供取代三唑。合成在高容量（500微米）聚苯乙烯珠粒中进行，采用单珠单储备溶液策略，这使得能够对所得文库进行表型筛选。使用全细胞荧光成像，我们从基于卡帕酮的文库中发现了一系列抑制高尔基体胞吐作用的分子。该系列中最有效的成员的IC(50)为14微摩尔。我们还报告了表现出这种有趣表型的分子的构效关系。这些胞吐作用抑制剂可能是研究囊泡运输的有用试剂。
