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首页> 外文期刊>Journal of Medicinal Chemistry >Design and synthesis of potent nonpeptidic farnesyltransferase inhibitors based on a terphenyl scaffold.
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Design and synthesis of potent nonpeptidic farnesyltransferase inhibitors based on a terphenyl scaffold.

机译：基于三联苯骨架的有效非肽法呢基转移酶抑制剂的设计和合成。

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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-cyanobenzyl)-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.
机译：通过修饰从空间受限的三联苯醚骨架中伸出的关键的羧酸根，疏水基和锌结合基团，设计并合成了一系列蛋白质法呢基转移酶（FTase）的Cys-Val-Ile-Met四肽底物的一系列简单和非肽模拟物。 4-硝基-2-苯基-3'-甲氧基羰基联苯的晶体结构表明，三苯基片段提供了较大的疏水表面，该表面潜在地模仿了四肽中三个末端残基的疏水侧链。 2-苯基-3-（N-（1-（4-（氰基苄基）-1H-咪唑-5-基）甲基）氨基-3'羧基联苯，其中游离硫醇基团被1-（4-氰基苄基）取代咪唑基团，在体外对FTase表现出亚微摩尔抑制活性，并在全细胞中抑制H-Ras加工。

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