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Hemivannusal (6), a bicyclic sesquiterpenoid with an unprecedented skeleton, has been isolated from the marine ciliate Euplotes vannus (strain TB6). The relative configuration of 6 has been established through an extended conformational search performed by molecular mechanics and refined through ab initio quantum chemical calculations. Another strain (CM1) of the same morphospecies has been found to produce the linear prevannusadial A (7) and the monocyclic prevannusadial B (8), which could represent key intermediates for the biosynthesis both of hemivannusal (6) and of the C30 terpenoids vannusals A and B (5a and 5b), the latter pair being metabolites isolated from conspecific strains (Sil21 and

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Cutaneous melanoma is the most serious type of skin cancer, so new cytotoxic weapons against novel targets in melanoma are of great interest. Euplotin C (EC), a cytotoxic secondary metabolite of the marine ciliate Euplotes crassus, was evaluated in the present study on human cutaneous melanoma cells to explore its anti-melanoma activity and to gain more insight into its mechanism of action. EC exerted a marked cytotoxic effect against three different human melanoma cell lines (A375, 501Mel and MeWo) with a potency about 30-fold higher than that observed in non-cancer cells (HDFa cells). A pro-apoptotic activity and a decrease in melanoma cell migration by EC were also observed. At the molecular level, the inhibition of the Erk and Akt pathways, which control many aspects of melanoma aggressiveness, was shown. EC cytotoxicity was antagonized by dantrolene, a ryanodine receptor (RyR) antagonist, in a concentration-dependent manner. A role of RyR as a direct target of EC was also suggested by molecular modelling studies. In conclusion, our data provide the first evidence of the anti-melanoma activity of EC, suggesting it may be a promising new scaffold for the development of selective activators of RyR to be used for the treatment of melanoma and other cancer types.