Rampa Angela, Tarozzi Andrea, Mancini Francesca, Pruccoli Letizia, Di Martino Rita Maria Concetta, Gobbi Silvia, Bisi Alessandra, De Simone Angela, Palomba Francesco, Zaccheroni Nelsi, Belluti Federica
Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy.
Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, Corso D'Augusto 237, 47921 Rimini, Italy.
Molecules. 2016 May 16;21(5):643. doi: 10.3390/molecules21050643.
Alzheimer's disease (AD) has been defined as a multi-factorial disorder resulting from a complex array of networked cellular and molecular mechanisms. In particular, elevated levels of Aβ protein and its aggregation products in the presence of metal ions proved to be highly neurotoxic and therapeutic strategies aimed at preventing Aβ generation and oxidative stress may represent an effective approach for AD treatment. A recent paradigm for the treatment of complex diseases such as AD suggests the employment of multifunctional compounds, single chemical entities capable of simultaneously modulating different targets involved in the pathology. In this paper, the "pharmacophores combination" strategy was applied, connecting the main scaffold of the BACE-1 ligand 1 to that of the chalcone 2, as metal chelating pharmacophore, to obtain a small library of compounds. Conjugate 5 emerged as the most interesting derivative, proving to inhibit BACE-1 with low-micromolar potency, and showing neuroprotective effects. In particular, 5 proved to be able to protect from metal-associated oxidative stress by hampering intracellular Cu(2+)-induced ROS formation without any direct neurotoxic effect.
阿尔茨海默病（AD）被定义为一种由一系列复杂的细胞和分子网络机制导致的多因素疾病。特别是，在金属离子存在的情况下，β-淀粉样蛋白（Aβ）及其聚集产物水平升高被证明具有高度神经毒性，而旨在预防Aβ生成和氧化应激的治疗策略可能是治疗AD的有效方法。最近一种治疗AD等复杂疾病的模式建议使用多功能化合物，即能够同时调节参与病理过程的不同靶点的单一化学实体。在本文中，应用了“药效团组合”策略，将BACE-1配体1的主要骨架与查尔酮2的骨架连接起来，作为金属螯合药效团，以获得一个化合物小文库。共轭物5成为最有趣的衍生物，证明其以低微摩尔效力抑制BACE-1，并显示出神经保护作用。特别是，5被证明能够通过阻碍细胞内铜离子（Cu(2+)）诱导的活性氧（ROS）形成来保护细胞免受金属相关的氧化应激，且没有任何直接神经毒性作用。
