Total Synthesis of Stylissatin A, A Cyclic Peptide That Inhibits Nitric Oxide Production

Abstract

Abstract Stylissatin A is a proline-rich cyclic heptapeptide isolated from the Papua New Guinean marine sponge Stylissa massa. The first synthesis of stylissatin A was achieved by a combination of solid-phase and solution-phase peptide synthesis. The natural and synthetic samples of stylissatin A showed comparable inhibitory effects on nitric oxide production with negligible cytotoxicity in lipopolysaccharide (LPS)-stimulated murine macrophage RAW264.7 cells (EC50 = 73 µM for synthetic sample). Furthermore, while the d-allo-Ile5 epimer was less potent, a tert-butyl ether analog of stylissatin A was approximately six times more potent than the natural product (EC50 = 12 µM).