Phosphorothioate analogues of alkyl lysophosphatidic acid as LPA 3 receptor-selective agonists

Lian Qian, Yong Xu, Ted Simper, Guowei Jiang, Junken Aoki, Makiko Umezu-Goto, Hiroyuki Arai, Shuangxing Yu, Gordon B. Mills, Ryoko Tsukahara, Natalia Makarova, Yuko Fujiwara, Gabor Tigyi, Glenn D. Prestwich

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Abstract

The metabolically stabilized LPA analogue 1-oleoyl-2-O-methyl-rac- glycerophosphorothioate (OMPT) was recently shown to be a potent subtype-selective agonist for LPA3, a G-protein-coupled receptor (GPCR) in the endothelial differentiation gene (EDG) family. Further stabilization was achieved by replacing the sn-1 O-acyl group with an O-alkyl ether. A new synthetic route for the enantiospecific synthesis of the resulting alkyl LPA phosphorothioate analogues is described. The pharmacological properties of the alkyl OMPT analogues were characterized for subtype-specific agonist activity using Ca2+-mobilization assays in RH7777 cells expressing the individual EDG family LPA receptors. Alkyl OMPT analogues induced cell migration in cancer cells mediated through LPA1. Alkyl OMPT analogues also activated Ca2+ release through LPA2 activation but with less potency than sn-1-oleoyl LPA. In contrast, alkyl OMPT analogues were potent LPA3 agonists. The alkyl OMPTs 1 and 3 induced cell proliferation at submicromolar concentrations in 10T1/2 fibroblasts. Interestingly, the absolute configuration of the sn-2 methoxy group of the alkyl OMPT analogues was not recognized by any of the LPA receptors in the EDG family. By using a reporter gene assay for the LPA-activated nuclear transcription factor PPARγ, we demonstrated that phosphorothioate diesters have agonist activity that is independent of their ligand properties at the LPA-activated GPCRs. The availability of new alkyl LPA analogues expands the scope of structure-activity studies and will further refine the molecular nature of ligand-receptor interactions for this class of GPCRs.

Original languageEnglish (US)
Pages (from-to)376-383
Number of pages8
JournalChemMedChem
Volume1
Issue number3
DOIs
StatePublished - Mar 1 2006

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Lysophosphatidic Acid Receptors
Genes
Ligands
Assays
Peroxisome Proliferator-Activated Receptors
Cells
G-Protein-Coupled Receptors
Reporter Genes
Ether
Cell Movement
Cell proliferation
Transcription Factors
Fibroblasts
Cell Proliferation
Pharmacology
Stabilization
Chemical activation
Availability
lysophosphatidic acid
Neoplasms

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry

Cite this

Qian, L., Xu, Y., Simper, T., Jiang, G., Aoki, J., Umezu-Goto, M., ... Prestwich, G. D. (2006). Phosphorothioate analogues of alkyl lysophosphatidic acid as LPA 3 receptor-selective agonists. ChemMedChem, 1(3), 376-383. https://doi.org/10.1002/cmdc.200500042

Phosphorothioate analogues of alkyl lysophosphatidic acid as LPA 3 receptor-selective agonists. / Qian, Lian; Xu, Yong; Simper, Ted; Jiang, Guowei; Aoki, Junken; Umezu-Goto, Makiko; Arai, Hiroyuki; Yu, Shuangxing; Mills, Gordon B.; Tsukahara, Ryoko; Makarova, Natalia; Fujiwara, Yuko; Tigyi, Gabor; Prestwich, Glenn D.

In: ChemMedChem, Vol. 1, No. 3, 01.03.2006, p. 376-383.

Research output: Contribution to journalArticle

Qian, L, Xu, Y, Simper, T, Jiang, G, Aoki, J, Umezu-Goto, M, Arai, H, Yu, S, Mills, GB, Tsukahara, R, Makarova, N, Fujiwara, Y, Tigyi, G & Prestwich, GD 2006, 'Phosphorothioate analogues of alkyl lysophosphatidic acid as LPA 3 receptor-selective agonists', ChemMedChem, vol. 1, no. 3, pp. 376-383. https://doi.org/10.1002/cmdc.200500042
Qian, Lian ; Xu, Yong ; Simper, Ted ; Jiang, Guowei ; Aoki, Junken ; Umezu-Goto, Makiko ; Arai, Hiroyuki ; Yu, Shuangxing ; Mills, Gordon B. ; Tsukahara, Ryoko ; Makarova, Natalia ; Fujiwara, Yuko ; Tigyi, Gabor ; Prestwich, Glenn D. / Phosphorothioate analogues of alkyl lysophosphatidic acid as LPA 3 receptor-selective agonists. In: ChemMedChem. 2006 ; Vol. 1, No. 3. pp. 376-383.
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abstract = "The metabolically stabilized LPA analogue 1-oleoyl-2-O-methyl-rac- glycerophosphorothioate (OMPT) was recently shown to be a potent subtype-selective agonist for LPA3, a G-protein-coupled receptor (GPCR) in the endothelial differentiation gene (EDG) family. Further stabilization was achieved by replacing the sn-1 O-acyl group with an O-alkyl ether. A new synthetic route for the enantiospecific synthesis of the resulting alkyl LPA phosphorothioate analogues is described. The pharmacological properties of the alkyl OMPT analogues were characterized for subtype-specific agonist activity using Ca2+-mobilization assays in RH7777 cells expressing the individual EDG family LPA receptors. Alkyl OMPT analogues induced cell migration in cancer cells mediated through LPA1. Alkyl OMPT analogues also activated Ca2+ release through LPA2 activation but with less potency than sn-1-oleoyl LPA. In contrast, alkyl OMPT analogues were potent LPA3 agonists. The alkyl OMPTs 1 and 3 induced cell proliferation at submicromolar concentrations in 10T1/2 fibroblasts. Interestingly, the absolute configuration of the sn-2 methoxy group of the alkyl OMPT analogues was not recognized by any of the LPA receptors in the EDG family. By using a reporter gene assay for the LPA-activated nuclear transcription factor PPARγ, we demonstrated that phosphorothioate diesters have agonist activity that is independent of their ligand properties at the LPA-activated GPCRs. The availability of new alkyl LPA analogues expands the scope of structure-activity studies and will further refine the molecular nature of ligand-receptor interactions for this class of GPCRs.",
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