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Bioactive Dihydro-β-agarofuran Sesquiterpenoids from the Australian Rainforest Plant Maytenus bilocularis

Wibowo, Mario, Levrier, Claire, Sadowski, Martin C., Nelson, Colleen C., Wang, Qian, Holst, Jeff, Healy, Peter C., Hofmann, Andreas, Davis, Rohan A.
Journal of natural products 2016 v.79 no.5 pp. 1445-1453
Maytenus, X-ray diffraction, anticarcinogenic activity, chemical structure, cytotoxicity, drug resistance, humans, inhibitory concentration 50, leaves, leucine, leukemia, methylene chloride, nuclear magnetic resonance spectroscopy, prostatic neoplasms, rain forests, secondary metabolites, sesquiterpenoids, transporters, trees, verapamil
Chemical investigations of the CH₂Cl₂ extract obtained from the leaves of the Australian rainforest tree Maytenus bilocularis afforded three new dihydro-β-agarofurans, bilocularins A–C (1–3), and six known congeners, namely, celastrine A (4), 1α,6β,8α-triacetoxy-9α-benzoyloxydihydro-β-agarofuran (5), 1α,6β-diacetoxy-9α-benzoyloxy-8α-hydroxydihydro-β-agarofuran (6), Ejap-10 (11), 1α,6β-diacetoxy-9β-benzoyloxydihydro-β-agarofuran (12), and Ejap-2 (13). The major compound 1 was used in semisynthetic studies to afford four ester derivatives (7–10). The chemical structures of 1–3 were elucidated following analysis of 1D/2D NMR and MS data. The absolute configurations of bilocularins A (1) and B (2) were determined by single-crystal X-ray diffraction analysis. All compounds were evaluated for cytotoxic activity against the human prostate cancer cell line LNCaP; none of the compounds were active. However, several compounds showed similar potency to the drug efflux pump inhibitor verapamil in reversing the drug resistance of the human leukemia CEM/VCR R cell line. In addition, similar to verapamil, compound 5 was found to inhibit leucine uptake in LNCaP cells (IC₅₀ = 15.5 μM), which was more potent than the leucine analogue 2-aminobicyclo[2.2.1]heptane-2-carbocyclic acid. This is the first report of secondary metabolites from Maytenus bilocularis.