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

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 mu M), with the differential cytotoxicity displayed by 1-4 towards two human colon cancer cell lines (IC50 2-16 mu M) 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 mu M). 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 mu M), supportive of further investigation.