Enantiomeric lignans with anti-β-amyloid aggregation activity from the twigs and leaves of Pithecellobium clypearia Benth

Abstract

To develop potential agents for slowing the progression of Alzheimer's disease, two pairs of new enantiomeric lignans, including a couple of rarely 8',9'-dinor-3',7-epoxy-8,4'-oxyneolignanes named (7S, 8S)- and (7R, 8R)-pithecellobiumin A (1a/1b) and a pair of 2',9'-epoxy-arylnaphthalenes named (7R, 8R, 8'R)- and (7S, 8S, 8'S)-pithecellobiumin B (2a/2b) were separated by chiral high performance liquid chromatography (HPLC). Their planar structures were elucidated by spectroscopic data analyses. The absolute configurations were determined by comparing of experimental and calculated electronic circular dichroism (ECD). The inhibitory activity on Aβ aggregation of all optical pure compounds was tested by ThT assay. Interestingly, enantiomeric inhibitors 1a (62.1%) and 1b (81.6%) exhibited different degrees of anti-Aβ aggregation activity. However, 2a (65.4%) and 2b (68.4%) showed similar inhibition rate. The different inhibition profiles were explained by molecular dynamics and docking simulation studies.

Keywords: Alzheimer’s disease; Aβ aggregation; Enantiomers; Lignans; Molecular docking; Molecular dynamics.