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

doi:10.1016/j.bmcl.2013.01.096

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

Molecular and Cellular Biochemistry

Research output: Contribution to journal › Article › peer-review

13 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 language	English
Pages (from-to)	1600-1603
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	23
Issue number	6
DOIs	https://doi.org/10.1016/j.bmcl.2013.01.096
State	Published - 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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.bmcl.2013.01.096

Cite this

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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 1-3 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.",

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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. ",

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AU - Truong, Johnny

AU - Liu, Chunming

AU - Watt, David S.

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N2 - 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.

AB - 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.

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Fluorinated N,N′-diarylureas as AMPK activators

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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