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

Producción científica: Article › revisión exhaustiva

15 Citas (Scopus)

Resumen

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.

Idioma original	English
Páginas (desde-hasta)	1600-1603
Número de páginas	4
Publicación	Bioorganic and Medicinal Chemistry Letters
Volumen	23
N.º	6
DOI	https://doi.org/10.1016/j.bmcl.2013.01.096
Estado	Published - mar 15 2013

Nota bibliográfica

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.

Financiación

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.

Financiadores	Número del financiador
National Institutes of Health (NIH)	2P20 RR020171
National Institute of General Medical Sciences
National Institute of Diabetes and Digestive and Kidney Diseases	R01DK071976
National Center for Research Resources	P20GM103486

ODS de las Naciones Unidas

Este resultado contribuye a los siguientes Objetivos de Desarrollo Sostenible

Good health and well being

ASJC Scopus subject areas

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

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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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Fluorinated N,N′-diarylureas as AMPK activators

Resumen

Nota bibliográfica

Financiación

ODS de las Naciones Unidas

ASJC Scopus subject areas

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