Comparison of Inhibitory Activities of Stereo-Isomers of Cyclic Phosphatidic Acid (cPA) on Autotaxin

Abstract

Cyclic phosphatidic acid (cPA) has a similar structure to that of lysophosphatidic acid (LPA), but possesses distinct biological functions. For example, cPA suppresses cancer cell invasion and metastasis through the inhibition of autotaxin (ATX) and transient activation of low molecular weight GTPase, RhoA. We designed and chemically synthesized several metabolically stabilized derivatives of cPA, and revealed that 2-carba-cPA was the most potent inhibitor of cancer cell invasion and metastasis. We have developed a novel method of 2ccPA enantiomeric synthesis, and here we examined the effects of natural (R)-cPA, both enantiopure 2ccPA, and (S)-3ccPA (corresponding to the configuration of (R)-2ccPA) on ATX. We also predicted the effects of (R)-cPA, (R)-2ccPA and (S)-3ccPA on ATX activity by combined quantum mechanics and molecular mechanics (QM/MM) computational methods. By these methods, we demonstrated that 2ccPA was the most potent inhibitor on ATX, and the chirality of 2ccPA was not involved in ATX inhibition. These results suggest that racemic-2ccPA may be utilized as an effective compound for cancer therapeutics.