Discovery of Anti-Inflammatory Alkaloids from Sponge Stylissa massa Suggests New Biosynthetic Pathways for Pyrrole–Imidazole Alkaloids

Pyrrole-imidazole alkaloids (PIAs) are a class of marine sponge derived natural products which have complex carbon frameworks and broad bioactivities. In this study, four new alkaloids, stylimassalins A-B (<b>1</b>-<b>2</b>), <b>3</b>, and <b>5</b>, together with two known compounds (<b>4</b> and <b>6</b>), were isolated from <i>Stylissa massa</i>. Compounds <b>2</b>, <b>4</b>, and <b>6</b> are the C-2 brominated analogues of <b>1</b>, <b>3</b>, and <b>5</b>, respectively. Their structures display three different scaffolds, of which scaffold 1 (compounds <b>1</b>,<b>2</b>) is new. A new biosynthetic pathway from oroidin, through spongiacidin, to latonduine and scaffold 1 was proposed by our group, in which the C12-N13-cleavaged compounds of spongiacidin (scaffold 2), dubbed seco-spongiacidins (<b>3</b> and <b>4</b>), are recognized as a key bridged scaffold, to afford PIA analogues (<b>1</b>,<b>2</b> and <b>5</b>,<b>6</b>). An anti-inflammatory evaluation in a zebrafish inflammation model induced by copper sulphate (CuSO₄) demonstrated that stylimassalins A and B (<b>1</b> and <b>2</b>) could serve as a promising lead scaffold for treating inflammation.