Chemical and Pharmacological Prospection of the Ascidian Cystodytes dellechiajei

Marine invertebrates are a traditional source of natural products with relevant biological properties. Tunicates are soft-bodied, solitary or colonial, sessile organisms that provide compounds unique in their structure and activity. The aim of this work was to investigate the chemical composition of the ascidian , selected on the basis of a positive result in biological screening for ligands of relevant receptors of the innate immune system, including TLR2, TLR4, dectin-1b, and TREM2. Bioassay-guided screening of this tunicate extract yielded two known pyridoacridine alkaloids, shermilamine B ( ) and N-deacetylshermilamine B ( ), and a family of methyl-branched cerebrosides ( ). Compounds and showed selective binding to TREM2 in a dose-dependent manner. N-deacetylshermilamine B ( ), together with its acetylated analogue, shermilamine B ( ), was also strongly cytotoxic against multiple myeloma cell lines. TREM2 is involved in immunomodulatory processes and neurodegenerative diseases. N-deacetylshermilamine B ( ) is the first example of a polycyclic alkaloid to show an affinity for this receptor.