Department of Chemistry, Hong Kong Baptist University, Hong Kong, SAR, China.
Curr Alzheimer Res. 2019;16(9):836-842. doi: 10.2174/1567205016666190827123222.
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).
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.
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.
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.
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.
已报道黄腐酚通过激活 Nrf2-ARE 信号通路具有细胞保护作用；它具有清除自由基的能力，表明其具有预防神经退行性变的潜力。然而，黄腐酚的生物不相容性和血脑屏障通透性阻碍了其用于治疗阿尔茨海默病（AD）的体内疗效。
我们设计并制备了一系列黄腐酚衍生物，以增强其理想的物理、生物和药理学特性，特别是血脑屏障通透性，用于干预 AD。
我们设计并合成了一系列 9 种黄腐酚衍生物。研究了它们对淀粉样蛋白-β（1-42）、Aβ1-42、寡聚化和纤维化的抑制作用以及对淀粉样蛋白-β诱导的毒性的神经保护作用。
在 9 种黄腐酚衍生物中，其中一些对 Aβ1-42 寡聚化和纤维化具有中度至高抑制作用。它们具有生物相容性，通过减少由淀粉样蛋白-β引起的 ROS 生成和钙加载对 SH-SY5Y 细胞具有神经保护作用。重要的是，发现两种衍生物可穿透血脑屏障，具有治疗 AD 的巨大潜力。
两种衍生物被鉴定为具有生物相容性、无毒、对 Aβ诱导的毒性具有神经保护作用且可穿透血脑屏障，这突出了它们作为未来临床使用的 AD 药物候选物的巨大潜力。
