ORGN 508 |
| Yong Xu and Glenn D. Prestwich. Department of Medicinal Chemistry, University of Utah, 419 Wakara Way, STE 205, Salt Lake City, UT 84108 |
| Lysophosphatidic acid (LPA) is a naturally occurring phospholipid that exhibits pleiotrophic biological activities, ranging from rapid morphological changes to long-term cellular effects such as induction of gene expression and stimulation of cell proliferation and survival on a wide spectrum of cell types. The preparation of receptor-specific agonists and antagonists for LPA receptors is an active area of ligand design. Recently experimental and theoretic reports indicate that α-monofluoromethylenephosphonate is an excellent phosphate mimic. Therefore, we have developed three methods for the synthesis of α-monofluoromethylenephosphonates as metabolically stabilized LPA analogues: Hydrolytic kinetic resolution (HKR) of a racemic monofluorinated epoxides; Lewis acid catalyzed ring opening of monofluorinated epoxides by alcohol; Hydrogenation of α-fluorovinylphosphonates. The α-monofluoromethylenephosphonate analogues, unique new nonhydrolyzable LPA ligands, showed surprising enantiospecific and receptor-specific biological readouts. One analogue was a long-lived hyperagonist, showing a 1000-fold higher activity than 18:1 LPA for LPA3 receptor and one was a selective LPA1 receptor agonist. |
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Total Synthesis, Asymmetric Reactions and Syntheses, Bioorganic
9:00 AM-11:00 AM, Wednesday, March 31, 2004 Anaheim Convention Center -- Hall C, Poster
Division of Organic Chemistry |