Abstract:
Elevated levels of the amylo β-proteins (Aβ), particularly Aβ42, are associated with a high
risk of Alzheimer’s disease (AD). The Aβ proteins are produced from cellular processing of the amyloid precursor proteins (APPs). To identify natural products that block the formation of Aβ-proteins
from APPs, we previously screened a library of plant extracts and identified Xysmalobium undulaum
(Apocynaceae) as a potential plant for further research. Here, we provide a report on the isolation and
identification of the active principles from the plant species using a bioassay-guided fractionation.
Fractions and resulting pure compounds from the purification process of the extract of X. undulatum
were screened in vitro against APPs transfected HeLa cell lines. Three compounds, acetylated
glycosydated crotoxogenin (1), xysmalogenin-3, β-D-glucopyranoside (2), and crotoxigenin 3-Oglucopyranoside (3), were subsequently isolated and their structures elucidated using NMR and
mass spectrometry. Compound 1, a novel cardenolide, and 2 significantly decreased the Aβ42 levels
in a dose-dependent manner while compound 3 was inactive. In silico investigations identified
the AD’s β-secretase enzyme, BACE1, as a potential target for these compounds with the glycoside
moiety being of significance in binding to the enzyme active site. Our study provides the first report
of a novel cardenolide and the potential of cardenolides as chemical scaffolds for developing AD
treatment drugs.
