Background: Xanthohumol has been reported to have cytoprotection through activation of
Nrf2−ARE signaling pathway and; it has capability of scavenging free radicals, suggesting its potential
for the prevention of neurodegeneration. However, the bio-incompatibility and blood-brain barrier impermeability
of xanthohumol hindered its in vivo efficacy potential for treating Alzheimer’s disease
Objective: We designed and prepared a series of xanthohumol derivatives to enhance the desirable
physical, biological and pharmacological properties in particular the blood-brain barrier permeability for
intervention of AD.
Methods: We designed and synthesized a novel series of 9 xanthohumol derivatives. Their inhibitory
effect on amyloid-β (1-42), Aβ1-42, oligomerization and fibrillation as well as neuroprotection against
amyloid-β induced toxicities, were explored.
Results: Among the 9 xanthohumol derivatives, some of them exhibited a moderate to high inhibitory
effect on Aβ1-42 oligomerization and fibrillation. They were biocompatible and neuroprotective to the
SH-SY5Y cells by reducing the ROS generation and calcium uploading that were induced by the amyloid-
β. Importantly, two of the derivatives were found to be blood-brain barrier permeable showing
promising potential for AD treatment.
Conclusion: Two derivatives have been identified to be biocompatible, non-toxic, neuroprotective
against Aβ-induced toxicities and blood-brain barrier permeable highlighting their promising potential
as AD drug candidates for future clinical use.