Synthesis of Monofluorinated Analogues of Lysophosphatidic Acid

Abstract

Lysophosphatidic acid (LPA, 1- or 2-acyl-sn-glycerol 3-phosphate) displays an intriguing cell biology that is mediated via interactions both with G-protein coupled seven transmembrane receptors and with the nuclear hormone receptor PPARgamma. Synthesis and biological activities of fluorinated analogues of LPA are still relatively unknown. In an effort to identify receptor-selective LPA analogues and to document in detail the structure-activity relationships of fluorinated LPA isosteres, we describe a series of monofluorinated LPA analogues in which either the sn-1 or the sn-2 hydroxy group was replaced by fluorine, or the bridging oxygen in the monophosphate was replaced by an alpha-monofluoromethylene (-CHF-) moiety. The sn-1 or sn-2 monofluorinated LPA analogues were enantiospecifically prepared from chiral protected glycerol synthons, and the alpha-monofluoromethylene-substituted LPA analogues were prepared from a racemic epoxide with use of a hydrolytic kinetic resolution. The sn-2 and sn-1 fluoro LPA analogues were unable to undergo acyl migration, effectively "freezing" them in the sn-1-O-acyl or sn-2-O-acyl forms, respectively. The alpha-monofluoromethylene LPA analogues were unique new nonhydrolyzable ligands with surprising enantiospecific and receptor-specific biological readouts, with one compound showing a 1000-fold higher activity than native LPA for one receptor subtype.

Fluorophosphonate-functionalised titanium via a pre-adsorbed alkane phosphonic acid: a novel dual action surface finish for bone regenerative applications

“…Herein, we report the facile functionalisation of Ti using octadecylphosphonic acid (ODPA) for the subsequent attachment of (3S)1-fluoro-3-hydroxy-4-(oleoyloxy)butyl-1-phosphonate (FHBP), a phosphatase-resistant LPA analogue [15][16][17], which we have found to be a potent pairing with 1,25D in promoting hOB maturation [5,18]. The alignment/configuration of Ti-tethered ODPA to FHBP is most likely akin to the self-assembly of phospholipids.…”

24,25-Dihydroxyvitamin D3 cooperates with a stable, fluoromethylene LPA receptor agonist to secure human (MG63) osteoblast maturation

“…1). Our focus for using FHBP stems from its development as a phosphataseresistant, -fluoromethylene LPA analog with selective agonistic activity for the LPA3 receptor [26,27]. Of relevance to hOB fate, we recently reported that much lower concentrations of this compound, relative to LPA, co-operate with 1,25D in driving hOB maturation [17].…”

Chiral Pool Synthesis of N-Cbz-cis-(3R,4R)-3-methylamino-4-methylpiperidine from L-Malic acid

“…Chemoselective deprotection of nitro compound 8 with HF-pyridine at rt furnished alcohol 9 in high yield, 40,41 substitution of which with MsCl at rt provided compound 10. Cbz protected piperidine 11 was obtained from the subsequent reduction of the nitro group with H 2 /Raney Ni, intramolecular cyclization and substitution reaction with benzyl chloroformate.…”