Design and synthesis of potent nonpeptidic farnesyltransferase inhibitors based on a terphenyl scaffold

被引:38
|
作者
Ohkanda, J
Lockman, JW
Kothare, MA
Qian, YM
Blaskovich, MA
Sebti, SM
Hamilton, AD
机构
[1] Yale Univ, Dept Chem, New Haven, CT 06520 USA
[2] Univ S Florida, Drug Discovery Program, H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA
[3] Univ S Florida, Dept Oncol & Biochem, Tampa, FL 33612 USA
[4] Univ S Florida, Dept Mol Biol, Tampa, FL 33612 USA
关键词
D O I
10.1021/jm0103099
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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.
引用
收藏
页码:177 / 188
页数:12
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