Development of a Potent Inhibitor of Metastasis Based on a Cyclic Lysophosphatidic Acid

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Cyclic phosphatidic acid (1-acyl-sn-glycero-2,3-cyclic phosphate; cPA) is a naturally occurring analog of lysophosphatidic acid (LPA) with a variety of distinctly different biological activities from those of LPA. In sharp contrast to LPA, a potent inducer of tumor cell invasion, we previously discovered that palmitoyl-cPA inhibits FBS- and LPA-induced transcellular migration and metastasis. Cyclic phosphate is not a stable molecule. It might be hydrolyzed either by chemically or enzymatically. In this regard, we have observed that LPA and cPA are enzymatically produced from phosphatidyl choline by phospholipase D (PLD). It is quite important to design a novel molecule of cPA origin which resists to hydrolysis because resulting hydrolyzed product, LPA is known to induce metastasis. In order to prevent the conversion of cPL to LPA, we carried out a modification on cyclic phosphate moiety. One of the molecules which we designed is a carba analog. Carba derivatives, in which the phosphate oxygen was replaced with a methylene group either at the sn-2 or the sn-3 position, showed much more potent inhibitory effects on MM! tumor cell transcellular migration and the pulmonary metastasis of B16-F0 melanoma than the natural Pal-cPA. The antimetastatic effect of carba-cPA was accompanied by the inhibition of Pho activation and was not due to the inhibition or the activation of LPA receptors.