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 journalArticle

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 languageEnglish (US)
Pages (from-to)1461-1464
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume14
Issue number6
DOIs
StatePublished - Mar 22 2004

    Fingerprint

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

Cite this