Peng Hairuo, Carrico Dora, Thai Van, Blaskovich Michelle, Bucher Cynthia, Pusateri Erin E, Sebti Said M, Hamilton Andrew D
Department of Chemistry, Yale University, New Haven, CT 06520, USA.
Org Biomol Chem. 2006 May 7;4(9):1768-84. doi: 10.1039/b517572k. Epub 2006 Mar 21.
A series of compounds based on the carboxyl-terminal CAAL sequence of PGGTase-I substrates was designed and synthesized. Using piperazin-2-one as a semi-rigid scaffold, we have introduced critical pharmacophores in a well-defined arrangement to mimic the CAAL sequence. High potency and exceptional selectivity were obtained for inhibition of PGGTase-I with structures such as 45 and 70. Potency of this series of GGTIs was dependent on the presence of an L-leucine residue with a free carboxyl terminus, as well as an S configuration of the 3-aryl group. The selectivity was significantly enhanced by 5-methyl substitution on the imidazole ring and fluorine substitution on the 3-aryl group. Modification of the 6-position of the piperazinone scaffold was found to be unfavorable. Compounds 44 and 69, the corresponding methyl esters of 45 and 70, were found to selectively block processing of Rap1A by PGGTase-I in whole cells with IC(50) values of 0.4 microM and 0.7 microM respectively.
设计并合成了一系列基于PGGTase-I底物羧基末端CAAL序列的化合物。以哌嗪-2-酮作为半刚性骨架，我们以明确的排列方式引入了关键药效基团以模拟CAAL序列。对于结构如45和70的化合物，在抑制PGGTase-I方面获得了高效能和优异的选择性。该系列GGTIs的效能取决于具有游离羧基末端的L-亮氨酸残基的存在，以及3-芳基的S构型。咪唑环上的5-甲基取代和3-芳基上的氟取代显著增强了选择性。发现对哌嗪酮骨架的6-位进行修饰是不利的。发现化合物44和69（分别为45和70的相应甲酯）在全细胞中以IC(50)值分别为0.4 microM和0.7 microM的浓度选择性阻断PGGTase-I对Rap1A的加工。
