Dihydro-β-agarofurans from the Australian Endemic Rainforest Plant Denhamia pittosporoides Inhibit Leucine Transport in Prostate Cancer Cells

Abstract

Two previously unknown dihydro-β-agarofuran sesquiterpenoids, denhaminol I (1) and denhaminol J (2), together with four related and known metabolites, 1α,2α,6β,15-tetraacetoxy-9α-benzoyloxy-8-oxodihydro-β-agarofuran (3), wilforsinine F (4), 1α,2α,6β,8α,15-pentaacetoxy-9α-benzoyloxydihydro-β-agarofuran (5), and 1α,2α,6β,15-tetraacetoxy-9β-benzoyloxydihydro-β-agarofuran (6), were isolated from the leaves of an Australian rainforest plant, Denhamia pittosporoides. The structures of compounds 1 and 2 were determined by analysis of their 1D/2D NMR and MS data. The absolute configuration of compound 1 was established by single-crystal X-ray diffraction analysis. Compounds 1 and 4 were shown to inhibit leucine transport in the human prostate cancer cell line LNCaP, with IC50 values of 51.5 and 95.5 μm, respectively. Both compounds 1 and 4 were more potent than the l-type amino acid transporter (LAT) family inhibitor 2-aminobicyclo[2.2.1]-heptane-2-carboxylic acid (BCH). This is the first report of dihydro-β-agarofurans from D. pittosporoides.