Activation of mTOR signaling by novel fluoromethylene phosphonate analogues of phosphatidic acid

Yong Xu; Yimin Fang; Jie Chen; Glenn D. Prestwich

doi:10.1016/j.bmcl.2004.01.020

Activation of mTOR signaling by novel fluoromethylene phosphonate analogues of phosphatidic acid

Yong Xu, Yimin Fang, Jie Chen, Glenn D. Prestwich

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

Abstract

Phosphonate analogues of phosphatidic acid (PA) were synthesized in which the bridging oxygen was replaced by an α-monofluoromethylene (-CHF-) or α-difluoromethylene (-CF₂-) moiety using hydrolytic kinetic resolution (HKR) of a racemic epoxide as the key step. Since PA activates signaling in the mTOR (mammalian target of rapamycin) pathway, these metabolically stabilized PA analogues were evaluated in quiescent HEK 293 cells. Most of these analogues surpassed PA in activating S6 kinase, a downstream target of mTOR signaling. The unnatural (2R) analogues were more slightly active than the natural (2S) enantiomers for both the mono- and difluoromethylene phosphonates.

Original language	English (US)
Pages (from-to)	1461-1464
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	14
Issue number	6
DOIs	https://doi.org/10.1016/j.bmcl.2004.01.020
State	Published - Mar 22 2004

Keywords

Fluoromethylene phosphonate
HEK 293 cells
Hydrolytic kinetic resolution
Phosphatidic acid
S6 Kinase
Target of rapamycin

ASJC Scopus subject areas

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

Online availability

10.1016/j.bmcl.2004.01.020

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title = "Activation of mTOR signaling by novel fluoromethylene phosphonate analogues of phosphatidic acid",

abstract = "Phosphonate analogues of phosphatidic acid (PA) were synthesized in which the bridging oxygen was replaced by an α-monofluoromethylene (-CHF-) or α-difluoromethylene (-CF2-) moiety using hydrolytic kinetic resolution (HKR) of a racemic epoxide as the key step. Since PA activates signaling in the mTOR (mammalian target of rapamycin) pathway, these metabolically stabilized PA analogues were evaluated in quiescent HEK 293 cells. Most of these analogues surpassed PA in activating S6 kinase, a downstream target of mTOR signaling. The unnatural (2R) analogues were more slightly active than the natural (2S) enantiomers for both the mono- and difluoromethylene phosphonates.",

keywords = "Fluoromethylene phosphonate, HEK 293 cells, Hydrolytic kinetic resolution, Phosphatidic acid, S6 Kinase, Target of rapamycin",

author = "Yong Xu and Yimin Fang and Jie Chen and Prestwich, {Glenn D.}",

note = "Funding Information: We thank the Human Frontier Science Program (RG0073-2000B) and the NIH (HL070231) for support at Uutah, the NIH (GM58064) to Dr. J. Chen at UIUC and the American Cancer Society.",

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doi = "10.1016/j.bmcl.2004.01.020",

language = "English (US)",

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T1 - Activation of mTOR signaling by novel fluoromethylene phosphonate analogues of phosphatidic acid

AU - Xu, Yong

AU - Fang, Yimin

AU - Chen, Jie

AU - Prestwich, Glenn D.

N1 - Funding Information: We thank the Human Frontier Science Program (RG0073-2000B) and the NIH (HL070231) for support at Uutah, the NIH (GM58064) to Dr. J. Chen at UIUC and the American Cancer Society.

PY - 2004/3/22

Y1 - 2004/3/22

N2 - Phosphonate analogues of phosphatidic acid (PA) were synthesized in which the bridging oxygen was replaced by an α-monofluoromethylene (-CHF-) or α-difluoromethylene (-CF2-) moiety using hydrolytic kinetic resolution (HKR) of a racemic epoxide as the key step. Since PA activates signaling in the mTOR (mammalian target of rapamycin) pathway, these metabolically stabilized PA analogues were evaluated in quiescent HEK 293 cells. Most of these analogues surpassed PA in activating S6 kinase, a downstream target of mTOR signaling. The unnatural (2R) analogues were more slightly active than the natural (2S) enantiomers for both the mono- and difluoromethylene phosphonates.

AB - Phosphonate analogues of phosphatidic acid (PA) were synthesized in which the bridging oxygen was replaced by an α-monofluoromethylene (-CHF-) or α-difluoromethylene (-CF2-) moiety using hydrolytic kinetic resolution (HKR) of a racemic epoxide as the key step. Since PA activates signaling in the mTOR (mammalian target of rapamycin) pathway, these metabolically stabilized PA analogues were evaluated in quiescent HEK 293 cells. Most of these analogues surpassed PA in activating S6 kinase, a downstream target of mTOR signaling. The unnatural (2R) analogues were more slightly active than the natural (2S) enantiomers for both the mono- and difluoromethylene phosphonates.

KW - Fluoromethylene phosphonate

KW - HEK 293 cells

KW - Hydrolytic kinetic resolution

KW - Phosphatidic acid

KW - S6 Kinase

KW - Target of rapamycin

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DO - 10.1016/j.bmcl.2004.01.020

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JO - Bioorganic and Medicinal Chemistry Letters

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ER -

Activation of mTOR signaling by novel fluoromethylene phosphonate analogues of phosphatidic acid

Abstract

Keywords

ASJC Scopus subject areas

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