Synthesis of migration-resistant hydroxyethoxy analogues of lysophosphatidic acid.
[reaction: see text] The susceptibility of lysophosphatidic acid (LPA) to intramolecular acyl migration impedes the determination of specific receptor activation by the sn-1 and sn-2 LPA regioisomers. An efficient enantioselective synthesis of hydroxyethoxy (HE)-substituted analogues of sn-1-acyl and 2-acyl LPA derivatives that possess palmitoyl and oleoyl chains is described. While the palmitoyl derivatives fail to activate calcium release in cells transfected with LPA(2) or LPA(3) G-protein-coupled receptors, the LPA(3) receptor is activated by both 1-HE and 2-HE oleoyl LPA analogues with a potency 10-fold lower than that of the parent oleoyl LPA.
Qian
Lian
L
Department of Medicinal Chemistry, The University of Utah, 419 Wakara Way, Suite 205, Salt Lake City, Utah 84108-1257, USA.
Xu
Yong
Y
Arai
Hiroyuki
H
Aoki
Junken
J
McIntyre
Thomas M
TM
Prestwich
Glenn D
GD
D000215:Acylation; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D007536:Isomerism; D008246:Lysophospholipids / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D015394:Molecular Structure; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000819:agonists; D049368:Receptors, Lysophosphatidic Acid; D014157:Transcription Factors / Q000378:metabolism
D008246:Lysophospholipids; D018160:Receptors, Cytoplasmic and Nuclear; D043562:Receptors, G-Protein-Coupled; D049368:Receptors, Lysophosphatidic Acid; D014157:Transcription Factors; D002118:Calcium