Bioactive Dihydro-Beta-Agarofuran Sesquiterpenoids From The Australian Rainforest Plant Maytenus Bilocularis

Chemical investigations of the CH2Cl2 extract obtained from the leaves of the Australian rainforest tree Maytenus bilocularis afforded three new dihydro-beta-agarofurans, bilocularins A-C (1-3), and six known congeners, namely, celastrine A (4), 1 alpha,6 alpha,8 alpha-triacetoxy-9 alpha-benzoyloxydihydro-beta-agarofuran (5), 1 alpha,6 beta-diacetoxy-9 alpha-benzoyloxy-8 alpha-hydroxydihydro-beta-agarofuran (6), Ejap-10 (11), 1 alpha,6 beta-diacetoxy-9 beta-benzoyloxydihydro-beta-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 mu M), 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