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 (AD).
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.
Method: We designed and synthesized a novel series of 9 xanthohumol derivatives. Their
inhibitory effect on amyloid-β (1-42), A β 1-42 , 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 Aβ 1-42 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 A β -induced toxicities and blood-brain barrier permeable highlighting
their promising potential as AD drug candidates for future clinical use.