Synthesis of bilocularin A carbamate derivatives and their evaluation as leucine transport inhibitors in prostate cancer cells

Abstract

Large-scale extraction of the leaves of the Australian rainforest tree Maytenus bilocularis followed by extensive purification studies afforded the targeted and abundant dihydro-β-agarofuran, bilocularin A, in sufficient quantities (>500 mg) for detailed semi-synthetic chemistry. Eight bilocularin A carbamate analogues were synthesised using a series of commercially available isocyanate reagents in high purity (>95%) and variable yields (9–91%). All previously undescribed analogues were spectroscopically characterised using NMR, UV, IR and MS data. One compound afforded crystalline material and subsequent single crystal X-ray analysis (Cu-Kα) confirmed the chemical structure along with the absolute configuration. All compounds were evaluated for anti-proliferative activity against the human prostate cancer cell line LNCaP; none of the compounds showed significant (>50%) growth inhibition at 20 μM. Compounds were also tested for their ability to inhibit leucine transport in LNCaP cells, and two analogues showed moderate activity with IC50 values of 8.9 and 8.5 μM. This is the first reported synthesis of dihydro-β-agarofuran carbamate derivatives.