Fluorinated N,N′-diarylureas as AMPK activators

• Published in: Bioorganic & medicinal chemistry letters 2013-03, Vol.23 (6), p.1600-1603
• Main Authors: Sviripa, Vitaliy, Zhang, Wen, Conroy, Michael D., Schmidt, Eric S., Liu, Alice X., Truong, Johnny, Liu, Chunming, Watt, David S.
• Format: Article
• Language: English
• Subjects: AMP-Activated Protein Kinases - chemistry; AMP-Activated Protein Kinases - metabolism; AMPK activation; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Halogenation; Humans; N,N′-Diarylureas; Niacinamide - analogs & derivatives; Niacinamide - chemistry; Niacinamide - toxicity; Phenylurea Compounds - chemistry; Phenylurea Compounds - toxicity; Structure-Activity Relationship; TOR Serine-Threonine Kinases - antagonists & inhibitors; TOR Serine-Threonine Kinases - metabolism; Urea - chemical synthesis; Urea - chemistry; Urea - toxicity
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2013.01.096

Halogenated N,N′-diarylureas inhibit mechanistic-target-of-rapamycin (mTOR) signaling by activating AMP-activated protein kinase (AMPK) at 1–3μM concentrations. 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′-diarylureas, that activate AMPK at 1–3μM 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′-diarylureas as potent AMPK activators.