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.