α-substituted phosphonate analogues of lysophosphatidic acid (LPA) selectively inhibit production and action of LPA

Guowei Jiang, Yong Xu, Yuko Fujiwara, Tamotsu Tsukahara, Ryoko Tsukahara, Joanna Gajewiak, Gabor Tigyi, Glenn D. Prestwich

Research output: Contribution to journalArticle

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Abstract

Isoform-selective agonists and antagonists of the lysophosphatidic acid (LPA) G-protein-coupled receptors (GPCRs) have important potential applications in cell biology and therapy. LPA GPCRs regulate cancer cell proliferation, invasion, angiogenesis, and biochemical resistance to chemotherapy- and radiotherapy-induced apoptosis. LPA and its analogues are also feedback inhibitors of the enzyme lysophospholipase D (lysoPLD, also known as autotaxin), a central regulator of invasion and metastasis. For cancer therapy, the ideal therapeutic profile would be a metabolically stabilized pan-LPA receptor antagonist that also inhibits lysoPLD. Herein we describe the synthesis of a series of novel α-substituted methylene phosphonate analogues of LPA. Each of these analogues contains a hydrolysis-resistant phosphonate mimic of the labile monophosphate of natural LPA. The pharmacological properties of these phosphono-LPA analogues were characterized in terms of LPA receptor subtype-specific agonist and antagonist activity using Ca2+ mobilization assays in RH7777 and CHO cells expressing the individual LPA GPCRs. In particular, the methylene phosphonate LPA analogue is a selective LPA2 agonist, whereas the corresponding α-hydroxymethylene phosphonate is a selective LPA3 agonist. Most importantly, the α-bromomethylene and a-chloromethylene phosphonates show pan-LPA receptor subtype antagonist activity. The α-bromomethylene phosphonates are the first reported antagonists for the LPA4 GPCR. Each of the α-substituted methylene phosphonates inhibits lysoPLD, with the unsubstituted methylene phosphonate showing the most potent inhibition. Finally, unlike many LPA analogues, none of these compounds activate the intracellular LPA receptor PPARγ.

Original languageEnglish (US)
Pages (from-to)679-690
Number of pages12
JournalChemMedChem
Volume2
Issue number5
DOIs
StatePublished - May 14 2007

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Organophosphonates
Lysophosphatidic Acid Receptors
G-Protein-Coupled Receptors
Cytology
lysophosphatidic acid
Peroxisome Proliferator-Activated Receptors
Chemotherapy
CHO Cells
Radiotherapy
Cell proliferation
Enzyme Inhibitors
Cell- and Tissue-Based Therapy
Cell Biology
Hydrolysis
Assays
Neoplasms
Protein Isoforms
Cell Proliferation
Pharmacology
Apoptosis

All Science Journal Classification (ASJC) codes

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

Cite this

Jiang, G., Xu, Y., Fujiwara, Y., Tsukahara, T., Tsukahara, R., Gajewiak, J., ... Prestwich, G. D. (2007). α-substituted phosphonate analogues of lysophosphatidic acid (LPA) selectively inhibit production and action of LPA. ChemMedChem, 2(5), 679-690. https://doi.org/10.1002/cmdc.200600280

α-substituted phosphonate analogues of lysophosphatidic acid (LPA) selectively inhibit production and action of LPA. / Jiang, Guowei; Xu, Yong; Fujiwara, Yuko; Tsukahara, Tamotsu; Tsukahara, Ryoko; Gajewiak, Joanna; Tigyi, Gabor; Prestwich, Glenn D.

In: ChemMedChem, Vol. 2, No. 5, 14.05.2007, p. 679-690.

Research output: Contribution to journalArticle

Jiang, G, Xu, Y, Fujiwara, Y, Tsukahara, T, Tsukahara, R, Gajewiak, J, Tigyi, G & Prestwich, GD 2007, 'α-substituted phosphonate analogues of lysophosphatidic acid (LPA) selectively inhibit production and action of LPA', ChemMedChem, vol. 2, no. 5, pp. 679-690. https://doi.org/10.1002/cmdc.200600280
Jiang, Guowei ; Xu, Yong ; Fujiwara, Yuko ; Tsukahara, Tamotsu ; Tsukahara, Ryoko ; Gajewiak, Joanna ; Tigyi, Gabor ; Prestwich, Glenn D. / α-substituted phosphonate analogues of lysophosphatidic acid (LPA) selectively inhibit production and action of LPA. In: ChemMedChem. 2007 ; Vol. 2, No. 5. pp. 679-690.
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