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 (1-2), 3, and 5, together with two known compounds (4 and 6), were isolated from Stylissa massa. Compounds 2, 4, and 6 are the C-2 brominated analogues of 1, 3, and 5, respectively. Their structures display three different scaffolds, of which scaffold 1 (compounds 1,2) 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 (3 and 4), are recognized as a key bridged scaffold, to afford PIA analogues (1,2 and 5,6). An anti-inflammatory evaluation in a zebrafish inflammation model induced by copper sulphate (CuSO4) demonstrated that stylimassalins A and B (1 and 2) could serve as a promising lead scaffold for treating inflammation.