Activation of mTOR signaling by novel fluoromethylene phosphonate analogues of phosphatidic acid.
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.
Department of Medicinal Chemistry, The University of Utah, 419 Wakara Way, Suite 205, Salt Lake City, UT 84108-1257, USA.
Yong
Y
Xu
Yimin
Y
Fang
Jie
J
Chen
Glenn D
GD
Prestwich
D002460:Cell Line; D006801:Humans; D010712:Phosphatidic Acids / Q000737:chemistry* / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases
D010712:Phosphatidic Acids; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases