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

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 alpha-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 Ca(2+) mobilization assays in RH7777 and CHO cells expressing the individual LPA GPCRs. In particular, the methylene phosphonate LPA analogue is a selective LPA(2) agonist, whereas the corresponding alpha-hydroxymethylene phosphonate is a selective LPA(3) agonist. Most importantly, the alpha-bromomethylene and alpha-chloromethylene phosphonates show pan-LPA receptor subtype antagonist activity. The alpha-bromomethylene phosphonates are the first reported antagonists for the LPA(4) GPCR. Each of the alpha-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 PPARgamma.

• Authors: Guowei Jiang, Yong Xu, Yuko Fujiwara, Tamotsu Tsukahara, Ryoko Tsukahara, Joanna Gajewiak, Gabor Tigyi, Glenn D Prestwich
• Journal: ChemMedChem (ChemMedChem) Vol. 2 Issue 5 Pg. 679-90 (May 2007) ISSN: 1860-7187 [Electronic] Germany
• PMID: 17443831 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Lysophospholipids
• Organophosphonates
• lysophosphatidic acid

Topics

• Animals
• CHO Cells
• Cricetinae
• Cricetulus
• Lysophospholipids (chemical synthesis, chemistry, metabolism)
• Organophosphonates (chemistry)