Abstract
In order to access β-secretase (BACE1), and enzyme strongly implicated in the cause of Alzheimer’s disease, inhibitors must possess sufficient lipophilicity to traverse two lipid bilayers. Current drug candidates, which are almost totally peptide-derived, are thus inefficient because cell permeability presents a serious limiting factor. In this study, lipophilic alkylated (C 10–C 5) flavanones from Sophora flavescens were examined for their inhibitory effects against β-secretase. Lavandulyl flavanones ( 1, 2, 5, 6, and 8) showed potent β-secretase inhibitory activities with IC 50s of 5.2, 3.3, 8.4, 2.6, and 6.7 μM, respectively, while no significant activity was observed in the corresponding hydrated lavandulyl flavanones ( 4 and 7) and prenylated flavanone ( 3). As we expected, lavandulyl flavanones reduced Aβ secretion dose-dependently in transfected human embryonic kidney (HEK-293) cells. In kinetic studies, all compounds screened were shown to be noncompetitive inhibitor.
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