1-Hydroxyethylhalenaquinone: A New Proteasome Inhibitor from the Marine Sponge Xestospongia sp.

Abstract

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 IC 50 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) 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, 2 phosphoinositide 3-kinase (PI3K), 3 Cdc25B phosphatase, 4 RAD51 (homologous-paring activity), 5 phospholipase A 2 , 6 and farnesyltransferase. 6 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.