Bioactive Dihydro-β-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-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.
Eskitis Institute for Drug Discovery, Griffith University , Brisbane, QLD 4111, Australia.
Mario
M
Wibowo
Eskitis Institute for Drug Discovery, Griffith University , Brisbane, QLD 4111, Australia.|Australian Prostate Cancer Research Centre-Queensland, Institute of Health and Biomedical Innovation, Queensland University of Technology, Princess Alexandra Hospital, Translational Research Institute , Brisbane, QLD 4102, Australia.
Claire
C
Levrier
Australian Prostate Cancer Research Centre-Queensland, Institute of Health and Biomedical Innovation, Queensland University of Technology, Princess Alexandra Hospital, Translational Research Institute , Brisbane, QLD 4102, Australia.
Martin C
MC
Sadowski
Australian Prostate Cancer Research Centre-Queensland, Institute of Health and Biomedical Innovation, Queensland University of Technology, Princess Alexandra Hospital, Translational Research Institute , Brisbane, QLD 4102, Australia.
Colleen C
CC
Nelson
Origins of Cancer Program, Centenary Institute, University of Sydney , Camperdown, NSW 2050, Australia.|Sydney Medical School, University of Sydney , Sydney, NSW 2006, Australia.
Qian
Q
Wang
Origins of Cancer Program, Centenary Institute, University of Sydney , Camperdown, NSW 2050, Australia.|Sydney Medical School, University of Sydney , Sydney, NSW 2006, Australia.
Jeff
J
Holst
School of Natural Sciences, Griffith University , Brisbane, QLD 4111, Australia.
Peter C
PC
Healy
Eskitis Institute for Drug Discovery, Griffith University , Brisbane, QLD 4111, Australia.|Faculty of Veterinary and Agricultural Sciences, The University of Melbourne , Parkville, Victoria 3010, Australia.
Andreas
A
Hofmann
Eskitis Institute for Drug Discovery, Griffith University , Brisbane, QLD 4111, Australia.
Rohan A
RA
Davis
D001315:Australia; D018360:Crystallography, X-Ray; D006801:Humans; D029755:Maytenus / Q000737:chemistry*; D008968:Molecular Conformation; D015394:Molecular Structure; D065947:Rainforest; D012717:Sesquiterpenes / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*
D012717:Sesquiterpenes; C079978:dihydroagarofuran