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Dihydro-β-agarofurans from the roots of the Australian endemic rainforest tree Maytenus bilocularis act as leucine transport inhibitors

Wibowo, Mario, Wang, Qian, Holst, Jeff, White, Jonathan M., Hofmann, Andreas, Davis, Rohan A.
Phytochemistry 2018 v.148 pp. 71-77
Maytenus, X-ray diffraction, amino acid transporters, chemical constituents of plants, human cell lines, humans, inhibitory concentration 50, leucine, nuclear magnetic resonance spectroscopy, prostatic neoplasms, rain forests, roots, sesquiterpenoids, trees
Phytochemical studies of the roots of the Australian plant, Maytenus bilocularis, resulted in the identification of six previously undescribed dihydro-β-agarofuran sesquiterpenoids, bilocularins D–I, along with three known natural products, namely 1α,2α,6β,15-tetraacetoxy-9β-benzoyloxydihydro-β-agarofuran, pristimerin, and celastrol. The structures of all compounds were characterized via analysis of 1D/2D NMR and MS data. The absolute configuration of bilocularin D was defined by X-ray crystallography analysis. Bilocularins D and G, 1α,2α,6β,15-tetraacetoxy-9β-benzoyloxydihydro-β-agarofuran, and celastrol inhibited leucine transport in the human prostate cancer cell line LNCaP with IC50 values ranging from 2.5–27.9 μM, which were more potent than the L-type amino acid transporter (LAT) family inhibitor 2-aminobicyclo[2,2,1]-heptane-2-carboxylic acid (BCH). Bilocularins D–F are the first examples of dihydro-β-agarofurans bearing a hydroxyacetate group.