School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China.
School of Environmental and Chemical Engineering, Jiangsu Ocean University, Lianyungang, 222005, China.
Anal Chim Acta. 2023 Oct 23;1279:341818. doi: 10.1016/j.aca.2023.341818. Epub 2023 Sep 12.
The pathogenesis of Alzheimer's disease (AD) is complex. So far there is no effective drug to treat the disease. The pathological changes of AD began 30 years before symptoms, so early diagnosis is considered to be important for AD treatment. Integrating diagnosis and therapy into a single regent has provided a new opportunity for AD treatment. Given that metal dyshomeostasis is thought to be one of the key factors to cause AD, a Schiff base substituted coumarin (probe 1) has been designed and synthesized as a selective metal chelator for multi-factor anti-AD in this work. The results of metal ions recognition showed that probe 1 had high selective fluorescent turn-on response to Al and fluorescent turn-off response to Cu, due to intramolecular charge transfer (ICT) mechanism. Meanwhile, the results of both in vitro and in vivo bioactivities evaluation including metal chelation, reactive oxide species (ROS) elimination, self-/Cu-induced Aβ aggregation showed that 1 and 1-Cu(II) complex had excellent synergistic anti-AD activities. In addition, 1 had low cytotoxicity and was predicted to cross the blood-brain barrier (BBB). Noticeably, X-ray single crystal diffraction of 1-Cu(II) provided molecular level information to explain the structure and theranostic activity relationship. To sum up, 1 may be a promising candidate for the development of AD theranostic agent.
阿尔茨海默病（AD）的发病机制复杂。目前尚无有效的药物可以治疗这种疾病。AD 的病理变化在症状出现前 30 年就已经开始，因此早期诊断被认为对 AD 的治疗很重要。将诊断和治疗整合为单一药物为 AD 的治疗提供了新的机会。鉴于金属动态平衡失调被认为是导致 AD 的关键因素之一，本工作设计并合成了一种席夫碱取代香豆素（探针 1），作为一种多因素抗 AD 的选择性金属螯合剂。金属离子识别结果表明，探针 1 对 Al 具有高选择性的荧光开启响应，对 Cu 具有荧光关闭响应，这归因于分子内电荷转移（ICT）机制。同时，体外和体内生物活性评价结果，包括金属螯合、活性氧（ROS）清除、自/Cu 诱导 Aβ聚集表明，1 和 1-Cu（II）复合物具有优异的协同抗 AD 活性。此外，1 具有低细胞毒性，并被预测可以穿透血脑屏障（BBB）。值得注意的是，1-Cu（II）的 X 射线单晶衍射提供了分子水平的信息，以解释结构和治疗活性关系。综上所述，1 可能是开发 AD 治疗药物的有前途的候选药物。
