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

Bioorg Med Chem Lett. 2004 Mar 22;14(6):1461-4. doi: 10.1016/j.bmcl.2004.01.020.


Phosphonate analogues of phosphatidic acid (PA) were synthesized in which the bridging oxygen was replaced by an alpha-monofluoromethylene (-CHF-) or alpha-difluoromethylene (-CF(2)-) 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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Cell Line
  • Humans
  • Phosphatidic Acids / chemistry*
  • Phosphatidic Acids / pharmacology
  • Protein Kinases / metabolism
  • Protein Kinases / physiology*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • TOR Serine-Threonine Kinases


  • Phosphatidic Acids
  • Protein Kinases
  • MTOR protein, human
  • TOR Serine-Threonine Kinases