Bergman Joel A, Hahne Kalub, Song Jiao, Hrycyna Christine A, Gibbs Richard A
Department of Medicinal Chemistry and Molecular Pharmacology and the Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA.
ACS Med Chem Lett. 2012 Jan 12;3(1):15-19. doi: 10.1021/ml200106d. Epub 2011 Nov 28.
We report the design and synthesis of novel FTPA-triazole compounds as potent inhibitors of isoprenylcysteine carboxyl methyltransferase (Icmt), through a focus on thioether and isoprenoid mimetics. These mimetics were coupled utilizing a copper-assisted cycloaddition to assemble the potential inhibitors. Using the resulting triazole from the coupling as an isoprenyl mimetic resulted in the biphenyl substituted FTPA triazole 10n. This lipid-modified analog is a potent inhibitor of Icmt (IC(50) = 0.8 ± 0.1 μM; calculated K(i) = 0.4 μM).
我们报告了新型FTFA-三唑化合物的设计与合成，该化合物是异戊烯基半胱氨酸羧基甲基转移酶（Icmt）的有效抑制剂，重点关注硫醚和类异戊二烯模拟物。利用铜辅助环加成反应将这些模拟物偶联，以组装潜在的抑制剂。将偶联反应生成的三唑用作异戊烯基模拟物，得到了联苯取代的FTFA三唑10n。这种脂质修饰的类似物是Icmt的有效抑制剂（IC(50) = 0.8 ± 0.1 μM；计算得出的K(i) = 0.4 μM）。
