New dictyodendrins as BACE inhibitors from a southern Australian marine sponge, Ianthella sp.

Abstract

Chemical analysis of a southern Australian marine sponge, an Ianthella sp., yielded dictyodendrins F–J (1–5) as new examples of a rare class of marine alkaloid. Structures were assigned on the basis of detailed spectroscopic analysis, while biosynthetic considerations suggested a relationship between the dictyodendrins and co-metabolites belonging to the lamellarin and ianthellidone structure classes. The dictyodendrins 1 and 3–5 exhibited significant BACE inhibitory activity (IC50 1–2 μM), with the differential cytotoxicity displayed by 1–4 towards two human colon cancer cell lines (IC50 2–16 μM) marking them as both cytotoxins and probable substrates for the multi-drug resistance efflux pump P-glycoprotein. The dictyodendrins 1–5 did not inhibit growth of Gram −ve bacteria or fungi, but 1, 3, and 4 were selective Gram +ve antibacterials (IC50 1–3 μM). Dictyodendrin J (5), with its unique seco-carbon skeleton and unusual 1,2-diketone functionality, exhibited a promising non-cytotoxic biological activity profile, inclusive of significant BACE inhibitory activity (IC50 2 μM), supportive of further investigation.