Fluorinated N,N′-diarylureas as AMPK activators

Vitaliy Sviripa, Wen Zhang, Michael D. Conroy, Eric S. Schmidt, Alice X. Liu, Johnny Truong, Chunming Liu, David S. Watt

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

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 1-3 μM 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.

Original languageEnglish
Pages (from-to)1600-1603
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume23
Issue number6
DOIs
StatePublished - Mar 15 2013

Bibliographical note

Funding Information:
We thank Center for Clinical and Translational Science at University of Kentucky for CCTS Pilot Award. C.L. was supported by R01 DK071976 from the NIH . D.S.W. was supported by NIH Grant Number 2P20 RR020171 from the National Center for Research Resources. J.T. was a summer research student supported the REU program under NSF DBI-1004931 (to Trevor Creamer, PI). This study was supported in part by NIH Grant Number P20GM103486 from the National Institute of General Medical Sciences, its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH or the NIGMS.

Keywords

  • AMPK activation
  • N,N′-Diarylureas

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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