Synthesis of Rigidified eIF4E/eIF4G Inhibitor-1 (4EGI-1) Mimetic and Their in Vitro Characterization as Inhibitors of Protein鈥揚rotein Interaction

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• 作者：Poornachandran Mahalingam ; Khuloud Takrouri ; Ting Chen ; Rupam Sahoo ; Evangelos Papadopoulos ; Limo Chen ; Gerhard Wagner ; Bertal H. Aktas ; Jose A. Halperin ; Michael Chorev
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：June 26, 2014
• 年：2014
• 卷：57
• 期：12
• 页码：5094-5111
• 全文大小：644K
• ISSN：1520-4804

文摘

The 4EGI-1 is the prototypic inhibitor of eIF4E/eIF4G interaction, a potent inhibitor of translation initiation in vitro and in vivo and an efficacious anticancer agent in animal models of human cancers. We report on the design, synthesis, and in vitro characterization of a series of rigidified mimetic of this prototypic inhibitor in which the phenyl in the 2-(4-(3,4-dichlorophenyl)thiazol-2-yl) moiety was bridged into a tricyclic system. The bridge consisted one of the following: ethylene, methylene oxide, methylenesulfide, methylenesulfoxide, and methylenesulfone. Numerous analogues in this series were found to be markedly more potent than the parent prototypic inhibitor in the inhibition of eIF4E/eIF4G interaction, thus preventing the eIF4F complex formation, a rate limiting step in the translation initiation cascade in eukaryotes, and in inhibition of human cancer cell proliferation.