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.

Fluorinated N,N'-Diarylureas As Novel Therapeutic Agents Against Cancer Stem Cells

“…We identified the anti-neoplastic effects of fluorinated N,N′-diarylureas (FNDs) in a high-throughput screening program (12) and found that several potent FNDs inhibited growth of CRC cell lines through inhibition of the mTOR pathway (12). Overexpression of mTORC1 and mTORC2 components, Raptor and Rictor, is important to tumorigenesis (13), and the activation of AMPK regulates cell growth by suppressing mTORC1 through direct phosphorylation of the tumor suppressor, TSC2, and Raptor (6).…”

Activators of AMPK: Not Just for Type II Diabetes

“…Proliferation of human colon adenocarcinoma cells was inhibited by another synthetic AMPK activator: 1-(4-(trifluoromethyl)phenyl)-3-(3,4,5-trifluorophenyl)urea (16) [64]. In this case, the active concentration of the compound was 3 μM and not 12 nM as in diaryl-2-azetidinones.…”

Biotinylated N,N'-diarylureas as probes for the activation of adenosine monophosphate-activated kinase (AMPK)

“…8 The total amount of AMPK was analyzed as a control. We found that 4'-trifluoromethylthiophenyl-3,4-dichlorophenylurea significantly increased phosphorylated AMPK at 1-3 µ M concentrations.…”

“…N,N'-Diarylureas were prepared as previously described. 8 Solvents were used from commercial vendors without further purification unless otherwise noted. Nuclear magnetic resonance spectra were determined in DMSO-d 6 using a Varian instrument ( 1 H, 400 MHz).…”

“…Recently, we reported that N,N'-diarylureas activated AMPK, 8 and we next sought to determine their binding target(s) using biotinylated derivatives.…”