Anthonoic Acids A–C, Sulfated and N-(2-Hydroxyethyl)-Substituted Lipidic Amino Acids from the Marine Sponge Antho ridgwayi with In Vitro Cytoprotective Activities

Anthonoic acids A-C (<b>1</b>-<b>3</b>), the first representatives of sulfated and <i>N</i>-(2-hydroxyethyl)-substituted lipidic <i>α</i>-amino acids, were isolated along with their plausible precursor, anthamino acid A (<b>4</b>), from the marine sponge <i>Antho ridgwayi</i>. The structures of these compounds were determined using the analysis of 1D and 2D NMR and HR ESI mass spectra. A structural feature of <b>1</b>-<b>4</b>, compared to all previously known lipidic amino acids, is the presence of a sulfate group near the end opposite the amino acid terminus. At a concentration of 1 µM, anthonoic acids A-C (<b>1</b>-<b>3</b>) effectively protected H9c2 and SH-SY5Y cells in biotests, which modeled hypoxia induced by the addition of CoCl₂ to the medium and damage caused by ischemia/reperfusion. These natural products act via the Nrf2-mediated pathway by reducing intracellular ROS levels, accompanied by the upregulation of SOD activity, which is controlled by the Nrf2 transcriptional factor. Anthonoic acids A-C (<b>1</b>-<b>3</b>) do not activate the transcriptional activity of NF-<i>κ</i>B but inhibit ATP-induced cell damage and calcium influx, indicating the involvement of P2X7 receptors in the cytoprotective effect of anthonoic acids A-C.