title: Fluorinated N,N'-diarylureas as AMPK activators.
abstract: 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.
authors: Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY 40536-0509, United States.
authors: Vitaliy
authors: V
authors: Sviripa
authors: Wen
authors: W
authors: Zhang
authors: Michael D
authors: MD
authors: Conroy
authors: Eric S
authors: ES
authors: Schmidt
authors: Alice X
authors: AX
authors: Liu
authors: Johnny
authors: J
authors: Truong
authors: Chunming
authors: C
authors: Liu
authors: David S
authors: DS
authors: Watt
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000737:chemistry* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D054879:Halogenation; D006801:Humans; D009536:Niacinamide / Q000031:analogs & derivatives / Q000737:chemistry / Q000633:toxicity; D010671:Phenylurea Compounds / Q000737:chemistry / Q000633:toxicity; D000077157:Sorafenib; D013329:Structure-Activity Relationship; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D014508:Urea / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity
chemical_list: D010671:Phenylurea Compounds; D009536:Niacinamide; D014508:Urea; D000077157:Sorafenib; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases