PDF(Pubmed)
Abstract：
Alzheimer\'s disease (AD) is a progressive neurodegenerative disorder marked by the accumulation of amyloid-beta plaques and hyperphosphorylated tau proteins, leading to cognitive decline and neuronal death. However, despite extensive research, there are still no effective treatments for this condition. In this study, a series of chloride-substituted Ramalin derivatives is synthesized to optimize their antioxidant, anti-inflammatory, and their potential to target key pathological features of Alzheimer\'s disease. The effect of the chloride position on these properties is investigated, specifically examining the potential of these derivatives to inhibit tau aggregation and beta-site amyloid precursor protein cleaving enzyme 1 (BACE-1) activity. Our findings demonstrate that several derivatives, particularly RA-3Cl, RA-4Cl, RA-26Cl, RA-34Cl, and RA-35Cl, significantly inhibit tau aggregation with inhibition rates of approximately 50%. For BACE-1 inhibition, Ramalin and RA-4Cl also significantly decrease BACE-1 expression in N2a cells by 40% and 38%, respectively, while RA-23Cl and RA-24Cl showed inhibition rates of 30% and 35% in SH-SY5Y cells. These results suggest that chloride-substituted Ramalin derivatives possess promising multifunctional properties for AD treatment, warranting further investigation and optimization for clinical applications.
摘要：
阿尔茨海默病（AD）是一种进行性神经退行性疾病，其特征是淀粉样β斑块和过度磷酸化tau蛋白的积累，导致认知衰退和神经元死亡。然而,尽管进行了广泛的研究，这种情况仍然没有有效的治疗方法。在这项研究中,合成了一系列氯化物取代的Ramalin衍生物，以优化其抗氧化剂，抗炎,以及它们靶向阿尔茨海默病关键病理特征的潜力。研究了氯化物位置对这些特性的影响，特别检查这些衍生物抑制tau聚集和β位点淀粉样前体蛋白裂解酶1（BACE-1）活性的潜力。我们的研究结果表明，几种衍生物，特别是RA-3Cl，RA-4Cl,RA-26Cl,RA-34Cl,和RA-35Cl,显著抑制tau聚集，抑制率约为50%。对于BACE-1抑制，Ramalin和RA-4Cl也显著降低了40%和38%的N2a细胞中BACE-1的表达,分别,而RA-23Cl和RA-24Cl对SH-SY5Y细胞的抑制率分别为30%和35%。这些结果表明，氯化物取代的Ramalin衍生物具有用于AD治疗的有希望的多功能特性，保证临床应用的进一步研究和优化。
