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) |
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Pages (from-to) | 1461-1464 |
Number of pages | 4 |
Journal | Bioorganic and Medicinal Chemistry Letters |
Volume | 14 |
Issue number | 6 |
DOIs | |
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