| Abstract
| - Lysophosphatidic acid (LPA, 1- or 2-acyl-sn-glycerol 3-phosphate) displays an intriguing cell biologythat is mediated via interactions both with G-protein coupled seven transmembrane receptors andwith the nuclear hormone receptor PPARγ. Synthesis and biological activities of fluorinatedanalogues of LPA are still relatively unknown. In an effort to identify receptor-selective LPAanalogues and to document in detail the structure−activity relationships of fluorinated LPAisosteres, we describe a series of monofluorinated LPA analogues in which either the sn-1 or thesn-2 hydroxy group was replaced by fluorine, or the bridging oxygen in the monophosphate wasreplaced by an α-monofluoromethylene (−CHF−) moiety. The sn-1 or sn-2 monofluorinated LPAanalogues were enantiospecifically prepared from chiral protected glycerol synthons, and theα-monofluoromethylene-substituted LPA analogues were prepared from a racemic epoxide withuse of a hydrolytic kinetic resolution. The sn-2 and sn-1 fluoro LPA analogues were unable to undergoacyl migration, effectively “freezing” them in the sn-1-O-acyl or sn-2-O-acyl forms, respectively.The α-monofluoromethylene LPA analogues were unique new nonhydrolyzable ligands withsurprising enantiospecific and receptor-specific biological readouts, with one compound showing a1000-fold higher activity than native LPA for one receptor subtype.
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