α-Substituted Phosphonate Analogues of Lysophosphatidic Acid (LPA) Selectively Inhibit Production and Action of LPA
Guowei Jiang
Department of Medicinal Chemistry, The University of Utah, 419 Wakara Way, Suite 205, Salt Lake City, UT 84108-1257, USA, Fax: (+1) 801-585-9053
Search for more papers by this authorYong Xu Dr.
Department of Medicinal Chemistry, The University of Utah, 419 Wakara Way, Suite 205, Salt Lake City, UT 84108-1257, USA, Fax: (+1) 801-585-9053
Search for more papers by this authorYuko Fujiwara Dr.
Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA
Search for more papers by this authorTamotsu Tsukahara Dr.
Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA
Search for more papers by this authorRyoko Tsukahara Dr.
Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA
Search for more papers by this authorJoanna Gajewiak Dr.
Department of Medicinal Chemistry, The University of Utah, 419 Wakara Way, Suite 205, Salt Lake City, UT 84108-1257, USA, Fax: (+1) 801-585-9053
Search for more papers by this authorGabor Tigyi Dr.
Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA
Search for more papers by this authorGlenn D. Prestwich Dr.
Department of Medicinal Chemistry, The University of Utah, 419 Wakara Way, Suite 205, Salt Lake City, UT 84108-1257, USA, Fax: (+1) 801-585-9053
Search for more papers by this authorGuowei Jiang
Department of Medicinal Chemistry, The University of Utah, 419 Wakara Way, Suite 205, Salt Lake City, UT 84108-1257, USA, Fax: (+1) 801-585-9053
Search for more papers by this authorYong Xu Dr.
Department of Medicinal Chemistry, The University of Utah, 419 Wakara Way, Suite 205, Salt Lake City, UT 84108-1257, USA, Fax: (+1) 801-585-9053
Search for more papers by this authorYuko Fujiwara Dr.
Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA
Search for more papers by this authorTamotsu Tsukahara Dr.
Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA
Search for more papers by this authorRyoko Tsukahara Dr.
Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA
Search for more papers by this authorJoanna Gajewiak Dr.
Department of Medicinal Chemistry, The University of Utah, 419 Wakara Way, Suite 205, Salt Lake City, UT 84108-1257, USA, Fax: (+1) 801-585-9053
Search for more papers by this authorGabor Tigyi Dr.
Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA
Search for more papers by this authorGlenn D. Prestwich Dr.
Department of Medicinal Chemistry, The University of Utah, 419 Wakara Way, Suite 205, Salt Lake City, UT 84108-1257, USA, Fax: (+1) 801-585-9053
Search for more papers by this authorGraphical Abstract
Metabolically stabilized: We present the total synthesis and pharmacological characterization of α-substituted phosphonate analogues of LPA. The compounds include isoform-selective agonists and antagonists for the LPA GPCRs, and also include potent inhibitors of lysophospholipase D, a key enzyme involved in LPA biosynthesis.
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 α-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.
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