Evaluation of the Chemical Stability, Membrane Permeability and Antiproliferative Activity of Cyclic Diarylheptanoids from European Hornbeam ( Carpinus betulus L.).

Four cyclic diarylheptanoids-carpinontriols A ( 1 ) and B ( 2 ), giffonin X ( 3 ) and 3,12,17-trihydroxytricyclo [12.3.1.1 2,6 ]nonadeca-1(18),2(19),3,5,14,16-hexaene-8,11-dione ( 4 )-were isolated from Carpinus betulus (Betulaceae). Chemical stability of the isolated diarylheptanoids was evaluated as a function of storage temperature (-15, 5, 22 °C) and time (12 and 23 weeks). The effect of the solvent and the pH (1.2, 6.8, 7.4) on the stability of these diarylheptanoids was also investigated. Compounds 2 and 4 showed good stability both in aqueous and methanolic solutions at all investigated temperatures. Only 2 was stable at all three studied biorelevant pH values. Degradation products of 1 and 3 were formed by the elimination of a water molecule from the parent compounds, as confirmed by ultrahigh-performance liquid chromatography-high-resolution tandem mass spectrometry (UHPLC-HR-MS). The permeability of the compounds across biological membranes was evaluated by the parallel artificial membrane permeability assay (PAMPA). Compound 3 possesses a log Pe value of -5.92 ± 0.04 in the blood-brain barrier-specific PAMPA-BBB study, indicating that it may be able to cross the blood-brain barrier via passive diffusion. The in vitro antiproliferative activity of the compounds was investigated against five human cancer cell lines, confirming that 1 inhibits cell proliferation in A2058 human metastatic melanoma cells.