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 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.