Cyclic phosphatidic acid (CPA) is a naturally occurring analog of lysophosphatidic

Cyclic phosphatidic acid (CPA) is a naturally occurring analog of lysophosphatidic acid (LPA) in which the sn-2 hydroxy group forms a 5-membered ring with the sn-3 phosphate. no stereoselective differences were found between the two isomers toward the inhibition of autotaxin or lung metastasis of B16-F10 melanoma cells in vivo. These results extend the potential utility of these compounds as potential lead compounds warranting evaluation as cancer therapeutics. and B16-F10 melanoma metastasis without significant stereochemical preference. The lack of stereoselectivity is underlined by the equal efficacy of the racemic mixture. Interestingly at the LPA5 GPCR the S-stereoisomer (S-3-CCPA) showed significantly higher efficacy. This is the first indication that the LPA5 receptor unlike the LPA1 2 3 receptors shows stereo-selective activation by CCPA ligands. ? Figure 1 Dose response relationship of ATX inhibition by LPA R-3-CCPA URB754 S-3-CCPA and Racemic-3-CCPA analogs. Acknowledgements This research was supported by NIH grant CA92160 (G.T.) Van Vleet Professorship (D.M.) Breast Cancer Research Foundation (N.P.) and Lpath Inc. (G.M.). Abbreviations ATXAutotaxinBSABovine serum albuminCCPACarbacyclic phosphatidic acidCPACyclic phosphatidic acidDICDi-isopropyl carbodiimideDMAPDimethyl amino pyridineGPCRG-protein coupled receptorsHRMSHigh resolution mass spectrometryLPALysophosphatidic acidNMRNuclear magnetic resonancePPTSPyridinium –p-toluene sulfonateTMSBrTrimethyl silyl bromide Footnotes Publisher’s Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting typesetting and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content and all legal disclaimers that apply to the journal pertain. References and notes 1 Liu S Umezu-Goto M Murph M Lu Y Liu W Zhang F Yu S Stephens LC Cui X Murrow G Coombes K Muller W Hung MC Perou CM Lee URB754 AV Fang X Mills GB. Cancer Cell. 2009;15:539. [PMC free article] [PubMed] 2 Parrill AL. Biochim.Biophys.Acta. 2008;1781:540. [PMC free article] [PubMed] 3 Murakami-Murofushi K Uchiyama A Fujiwara Y Kobayashi T Kobayashi S Mukai M Murofushi H Tigyi G. Biochim.Biophys.Acta. 2002;1582:1. [PubMed] 4 Fujiwara Y. Biochim.Biophys.Acta. 2008;1781:519. [PMC free article] [PubMed] 5 Baker DL Fujiwara Y Pigg KR Tsukahara R Kobayashi S Murofushi H Uchiyama A Murakami-Murofushi K Koh E Bandle RW Byun HS Bittman R Fan D URB754 Murph M Mills GB Tigyi G. J.Biol.Chem. 2006;281:22786. [PMC free article] [PubMed] 6 Uchiyama A Mukai M Fujiwara Y Kobayashi S Kawai N Murofushi H Inoue M Enoki S Tanaka Y Niki T Kobayashi T Tigyi G Murakami-Murofushi K. Biochim.Biophys.Acta. CTSL1 2007;1771:103. [PMC free article] [PubMed] 7 Williams JR Khandoga AL Goyal P Fells JI Perygin DH Siess W Parrill AL Tigyi G Fujiwara Y. J.Biol.Chem. 2009;284:17304. [PMC free article] [PubMed] 8 Stracke ML Arestad A Levine M Krutzsch HC Liotta LA. Melanoma Res. 1995;5:203. [PubMed] 9 Umezu-Goto M Kishi Y Taira A Hama K Dohmae N Takio K Yamori T Mills GB Inoue K Aoki J Arai H. J.Cell Biol. 2002;158:227. [PMC free article] [PubMed] 10 Tokumura A Majima E Kariya Y Tominaga K Kogure K Yasuda K Fukuzawa K. J.Biol.Chem. 2002;277:39436. [PubMed] 11 Tsuda S Okudaira S Moriya-Ito K Shimamoto C Tanaka M Aoki J Arai H Murakami-Murofushi K Kobayashi T. J.Biol.Chem. 2006;281:26081. [PubMed] 12 Yang Y Mou L Liu N Tsao MS. Am.J.Respir.Cell Mol.Biol. 1999;21:216. [PubMed] 13 Wu JM Xu Y Skill NJ Sheng H Zhao Z Yu M Saxena R Maluccio MA. Mol.Cancer. 2010;9:71. [PMC free article] [PubMed] 14 Vidot S Witham J Agarwal R Greenhough S Bamrah HS Tigyi GJ Kaye SB Richardson A. Cell Signal. 2010;22:926. [PubMed] 15 Kehlen A Englert N Seifert A Klonisch T Dralle H Langner J Hoang-Vu C. Int.J.Cancer. 2004;109:833. [PubMed] 16 Nouh MA Wu XX Okazoe H Tsunemori H Haba R Abou-Zeid AM Saleem MD Inui M Sugimoto M Aoki J Kakehi Y. Cancer Sci. 2009;100:1631. [PubMed] 17 Masuda A Nakamura K Izutsu K Igarashi K Ohkawa R Jona M Higashi K Yokota URB754 H Okudaira S Kishimoto T Watanabe T Koike Y Ikeda H Kozai Y Kurokawa M.