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 (CuSO ₄ ) demonstrated that stylimassalins A and B ( 1 and 2 ) could serve as a promising lead scaffold for treating inflammation.