Abstract
Cyclic phosphatidic acid (CPA) is a naturally occurring analog of lysophosphatidic acid (LPA) in which the sn-2 hydroxy group forms a five-membered ring with the sn-3 phosphate. Here, we describe the synthesis of R-3-CCPA and S-3-CCPA along with their pharmacological properties as inhibitors of lysophospholipase D/autotaxin, agonists of the LPA(5) GPCR, and blockers of lung metastasis of B16-F10 melanoma cells in a C57BL/6 mouse model. S-3CCPA was significantly more efficacious in the activation of LPA(5) compared to the R-stereoisomer. In contrast, 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.
Copyright © 2010 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Disease Models, Animal
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Lung Neoplasms / drug therapy
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Lung Neoplasms / secondary
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Lysophospholipase / antagonists & inhibitors
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Lysophospholipase / metabolism
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Melanoma, Experimental / pathology
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Mice
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Mice, Inbred C57BL
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Multienzyme Complexes / antagonists & inhibitors
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Multienzyme Complexes / metabolism
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Phosphatidic Acids / chemical synthesis
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Phosphatidic Acids / chemistry*
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Phosphatidic Acids / pharmacology
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Phosphodiesterase I / antagonists & inhibitors
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Phosphodiesterase I / metabolism
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Phosphoric Diester Hydrolases
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Pyrophosphatases / antagonists & inhibitors
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Pyrophosphatases / metabolism
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Receptors, Lysophosphatidic Acid / agonists
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Receptors, Lysophosphatidic Acid / metabolism
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Stereoisomerism
Substances
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3-carba cyclic-phosphatidic acid
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Multienzyme Complexes
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Phosphatidic Acids
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Receptors, Lysophosphatidic Acid
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Lysophospholipase
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Phosphoric Diester Hydrolases
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Phosphodiesterase I
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alkylglycerophosphoethanolamine phosphodiesterase
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Pyrophosphatases