1-Hydroxyethylhalenaquinone: A new proteasome inhibitor from the marine sponge Xestospongia SP

A new halenaquinone derivative, 1-hydroxyethylhalenaquinone (1), was isolated from the marine sponge Xestospongia sp. as a proteasome inhibitor together with three known compounds, halenaquinone (2) and 3-ketoadociaquinones A (3) and B (4). 1-Hydroxyethylhalenaquinone (1) was the first halenaquinone derivative containing an alkyl group at the keto-furan C-1 position. Compounds 1 and 2 inhibited the chymotrypsin-like activity of the proteasome with IC50 values of 0.19 and 0.63 μM, respectively, whereas 3 or 4, each containing a thiomorpholine 1,1-dioxide moiety, scarcely inhibited its activity, even at a concentration of 5 μM. Halenaquinone (2, Figure 1) is a pentacyclic compound that has been isolated from marine sponges. This compound and its derivatives are known to exhibit antimicrobial, antifungal, cytotoxic, and antimalarial activities and also inhibit various enzymes, such as v-Src tyrosine kinase, phosphoinositide 3-kinase (PI3K), Cdc25B phosphatase, RAD51 (homologous-paring activity), phospholipase A2, and farnesyltransferase. In our search for biologically active natural products, we found that the extract of the marine sponge Xestospongia sp. inhibited proteasome activity. We here described the bioassay-guided isolation of a new halenaquinone derivative, 1-hydroxyethylhalenaquinone (1, Figure 1), and 2 as proteasome inhibitors. HETEROCYCLES, Vol. 89, No. 11, 2014 2605