Enantioselective responses to a phosphorothioate analogue of lysophosphatidic acid with LPA3 receptor-selective agonist activity.
The metabolically stabilized LPA analogue, 1-oleoyl-2-O-methyl-rac-glycerophosphothioate (OMPT), is a potent agonist for the LPA(3) G-protein-coupled receptor. A new enantiospecific synthesis of both (2R)-OMPT and (2S)-OMPT is described. Calcium release assays in both LPA(3)-transfected insect Sf9 and rat hepatoma Rh7777 cells showed that (2S)-OMPT was 5- to 20-fold more active than (2R)-OMPT. Similar results were found for calcium release, MAPK and Akt activation, and IL-6 release in human OVCAR3 ovarian cancer cells.
Qian
Lian
L
Department of Medicinal Chemistry, The University of Utah, 419 Wakara Way, Suite 205, Salt Lake City, UT 84108, USA.
Xu
Yong
Y
Hasegawa
Yutaka
Y
Aoki
Junken
J
Mills
Gordon B
GB
Prestwich
Glenn D
GD
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis; D008246:Lysophospholipids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009946:Organothiophosphorus Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010712:Phosphatidic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D049368:Receptors, Lysophosphatidic Acid; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C480604:1-oleoyl-2-O-methylglycerophosphothioate; D015850:Interleukin-6; D008246:Lysophospholipids; D009946:Organothiophosphorus Compounds; D010712:Phosphatidic Acids; D011518:Proto-Oncogene Proteins; D043562:Receptors, G-Protein-Coupled; D049368:Receptors, Lysophosphatidic Acid; C494918:AKT1 protein, human; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020929:Mitogen-Activated Protein Kinase Kinases; D002118:Calcium