Isolation of Picrotoxanes from Austrobuxus carunculatus Using Taxonomy-Based Molecular Networking

A unique collection of 292 extracts from 107 New Caledonian Euphorbiaceae species sensu lato was profiled by LC-MS 2 and the metabolite content organized by molecular networking. Based on the assumption that taxon-specific molecules are more likely to be structurally novel, taxonomic data were mapped on spectral networks to detect genus-specific clusters. Using this approach, a group of compounds unique to the genus Austrobuxus was highlighted. The subsequent MS-guided purification of the fruit EtOAc extract of Austrobuxus carunculatus led to the isolation of 13 new monolactone and "norditerpene" picrotoxanes ( 2 - 14 ), along with the known tutin ( 1 ). The structures of the new compounds were elucidated by HRESIMS and NMR spectroscopic data analysis, and the absolute configurations of compounds 1 , 3 , 7 , 11 , 12 , and 14 were determined by single-crystal X-ray diffraction analysis. The relative and absolute configurations of compounds 4 and 5 were ascertained by chemical transformation of compound 3 . The absolute configurations of other members of the series have been proposed on the basis of biogenetic considerations and specific rotation values of similar sign and magnitude. Compounds 1 - 14 were evaluated for their antiproliferative activities against HCT116 colon, U87-MG glioblastoma, and A549 lung human cancer cell lines. Compounds bearing an acyl chain at C-2 (i.e., 2 , 4 , and 13 ) showed IC 50 values in the micromolar range for the three cell lines used.