Department of Physical and Environmental Sciences, University of Toronto Scarborough , 1265 Military Trail, Toronto, Ontario M1C 1A4, Canada.
ACS Chem Neurosci. 2013 Feb 20;4(2):339-49. doi: 10.1021/cn300171c. Epub 2012 Nov 20.
Alzheimer's disease (AD) is a complex neurodegenerative disorder marked by numerous causative factors of disease progression, termed pathologies. We report here the synthesis of a small library of novel sym-triazine compounds designed for targeted modulation of multiple pathologies related to AD, specifically human acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and Aβ aggregation. Rational targeting of AChE was achieved by the incorporation of acetylcholine substrate analogues into a sym-triazine core in either a mono-, di-, or trisubstituted regime. A subset of these derivatives demonstrated improved activity compared to several commercially available cholinesterase inhibitors. High AChE/BuChE selectivity was characteristic of all derivatives, and AChE steady-state kinetics indicated a mixed-type inhibition mechanism. Further integration of multiple hydrophobic phenyl units allowed for improved β-sheet intercalation into amyloid aggregates. Several highly effective structures exhibited fibril inhibition greater than the previously reported β-sheet-disrupting penta-peptide, iAβ5p, evaluated by thioflavin T fluorescence spectroscopy and transmission electron microscopy. Highly effective sym-triazines were shown to be well tolerated by differentiated human neuronal cells, as demonstrated by the absence of adverse effects on cellular viability at a wide range of concentrations. Parallel targeting of multiple pathologies using sym-triazines is presented here as an effective strategy to address the complex, multifactorial nature of AD progression.
阿尔茨海默病（AD）是一种复杂的神经退行性疾病，其发病过程涉及众多病因，这些病因被称为病理学。我们在此报告了一系列新型对称三嗪化合物的合成，这些化合物旨在针对与 AD 相关的多种病理学进行靶向调节，特别是人类乙酰胆碱酯酶（AChE）、丁酰胆碱酯酶（BuChE）和 Aβ 聚集。通过将乙酰胆碱底物类似物整合到对称三嗪核中，可以实现对 AChE 的合理靶向，整合方式为单取代、二取代或三取代。这些衍生物中的一部分与几种市售的胆碱酯酶抑制剂相比，表现出了更好的活性。所有衍生物均表现出高 AChE/BuChE 选择性，AChE 稳态动力学表明其抑制机制为混合型。进一步整合多个疏水性苯基单元，允许化合物更好地插入到淀粉样纤维中。几个高效结构表现出的纤维抑制作用强于之前报道的β-折叠破坏五肽 iAβ5p，这是通过硫代黄素 T 荧光光谱法和透射电子显微镜评估的。分化的人神经元细胞对高效的对称三嗪化合物具有良好的耐受性，这表现为在广泛浓度范围内对细胞活力没有不良影响。使用对称三嗪化合物对多种病理学进行平行靶向被认为是解决 AD 进展的复杂多因素性质的有效策略。
