Synthesis and pharmacological evaluation of the stereoisomers of 3-carba cyclic-phosphatidic acid |
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Authors: | Gupte Renuka Siddam Anjaih Lu Yan Li Wei Fujiwara Yuko Panupinthu Nattapon Pham Truc-Chi Baker Daniel L Parrill Abby L Gotoh Mari Murakami-Murofushi Kimiko Kobayashi Susumu Mills Gordon B Tigyi Gabor Miller Duane D |
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Affiliation: | Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN 38163, USA. |
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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. |
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