Xanthenylacetic Acid Derivatives Effectively Target Lysophosphatidic Acid Receptor 6 to Inhibit Hepatocellular Carcinoma Cell Growth.

Despite the increasing incidence of hepatocellular carcinoma (HCC) worldwide, current pharmacological treatments are still unsatisfactory. We have previously shown that lysophosphatidic acid receptor 6 (LPAR6) supports HCC growth and that 9-xanthenylacetic acid (XAA) acts as an LPAR6 antagonist inhibiting HCC growth without toxicity. Here, we synthesized four novel XAA derivatives, (±)-2-(9H-xanthen-9-yl)propanoic acid (compound 4 - MC9), (±)-2-(9H-xanthen-9-yl)butanoic acid (compound 5 - MC6), (±)-2-(9H-xanthen-9-yl)hexanoic acid (compound 7 - MC11), and (±)-2-(9H-xanthen-9-yl)octanoic acid (compound 8 - MC12, sodium salt) by introducing alkyl groups of increasing length at the acetic α-carbon atom. Two of these compounds were characterized by X-ray powder diffraction and quantum mechanical calculations, while molecular docking simulations suggested their enantioselectivity for LPAR6. Biological data showed anti-HCC activity for all XAA derivatives, with the maximum effect observed for MC11. Our findings support the view that increasing the length of the alkyl group improves the inhibitory action of XAA and that enantioselectivity can be exploited for designing novel and more effective XAA-based LPAR6 antagonists.