Fluorinated N,N¡ä-diarylureas as AMPK activators

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• 作者：Vitaliy Sviripa^a ; ^b ; ^&dagger ; ; Wen Zhang^a ; ^c ; ^&dagger ; ; Michael D. Conroy^a ; Eric S. Schmidt^a ; Alice X. Liu^a ; ^d ; Johnny Truong^a ; Chunming Liu^a ; ^c ; ^{cli229@uky.edu} ; David S. Watt^a ; ^b ; ^c ; ^{dwatt@uky.edu}
• 关键词：N ; N&prime ; -Diarylureas ; AMPK activation
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2013
• 出版时间：15 March, 2013
• 年：2013
• 卷：23
• 期：6
• 页码：1600-1603
• 全文大小：304 K

文摘

Adenosine monophosphate-activated kinase (AMPK) plays a central role in regulating energy homeostasis in eukaryotic cells. AMPK also regulates lipid synthesis by inhibiting acetyl-CoA carboxylase (ACC) and regulates mTOR signaling by activating TSC2. Due to its important roles in cell metabolism, AMPK is an attractive target for metabolic diseases, such as type II diabetes and obesity. AMPK activators, such as metformin, that are used for diabetes treatment are also effective anticancer agents. However, the efficacies of many known AMPK activators are relatively low. For example, metformin activates AMPK at millimolar levels. In this study, we identified a novel family of AMPK activators, namely fluorinated N,N¡ä-diarylureas, that activate AMPK at 1-3 ¦ÌM concentrations. These novel agents strongly inhibit the proliferation of colon cancer cells. We studied the potential mechanisms of these agents, performed a structure-activity relationship (SAR) study and identified several fluorinated N,N¡ä-diarylureas as potent AMPK activators.