Synthesis and pharmacological evaluation of the stereoisomers of 3-carba cyclic-phosphatidic acid.
Gupte R, Siddam A, Lu Y, Li W, Fujiwara Y, Panupinthu N, Pham TC, Baker DL, Parrill AL, Gotoh M, Murakami-Murofushi K, Kobayashi S, Mills GB, Tigyi G, Miller DD.
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.