Design and synthesis of potent nonpeptidic farnesyltransferase inhibitors based on a terphenyl scaffold
Design and synthesis of potent nonpeptidic farnesyltransferase inhibitors based on a terphenyl scaffold
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DOI：
10.1021/jm0103099
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发表时间：
2002-01-03
影响因子：
7.3
通讯作者：
Hamilton, AD
中科院分区：
文献类型：
--
作者：
Ohkanda, J;Lockman, JW;Hamilton, AD
通过对三苯基支架上的羧酸基、疏水基和锌结合基进行修饰，设计并合成了一系列简单的、非肽的蛋白质法尼基转移酶（FTase）的Cys-Val-Ile-Met四肽底物的模拟物。4-硝基-2-苯基-3'-甲氧基羰基联苯的晶体结构表明，三苯基片段提供了一个大的疏水表面，可能模仿四肽中三个末端残基的疏水侧链。2-苯基-3-（N-（1-（4-苯基）- 1h -咪唑-5-基）甲基）氨基-3'羧基联苯，其中游离巯基被1-（4-氰基）咪唑基取代，在体外对FTase具有亚微摩尔抑制活性，并在全细胞中抑制H-Ras加工。
By modification of key carboxylate, hydrophobic, and zinc-binding groups projected from a sterically restricted terphenyl scaffold, a series of simple and nonpeptide mimetics of the Cys-Val-Ile-Met tetrapeptide substrate of protein farnesyltransferase (FTase) have been designed and synthesized. A crystal structure of 4-nitro-2-phenyl-3'-methoxycarbonylbiphenyl shows that the triphenyl fragment provides a large hydrophobic surface that potentially mimics the hydrophobic side chains of the three terminal residues in the tetrapeptide. 2-Phenyl-3-(N-(1-(4-eyanobenzyl)-1H-imidazol-5-yl)methyl)amino-3'carboxylbiphenyl, in which the free thiol group was replaced with a 1-(4-cyanobenzyl)imidazole group, shows submicromolar inhibition activity against FTase in vitro and inhibits H-Ras processing in whole cells.