Rhodanine-based tau aggregation inhibitors in cell models of tauopathy
Rhodanine-based tau aggregation inhibitors in cell models of tauopathy
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DOI：
10.1002/anie.200704051
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发表时间：
2007-01-01
影响因子：
16.6
通讯作者：
Waldmann, Herbert
中科院分区：
文献类型：
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作者：
Bulic, Bruno;Pickhardt, Marcus;Waldmann, Herbert
阿尔茨海默病（AD）的两个组织病理学特征是由淀粉样前体蛋白（APP）的β-淀粉样蛋白片段形成的细胞外淀粉样蛋白斑块和细胞内神经纤维缠结和神经纤维丝，其由微管相关蛋白tau形成具有高度有序结构的成对螺旋丝组成，如最近通过X射线显微晶体学证实的。[1]此外，类似于AD的tau沉积物发生在几种“tau蛋白病”中。[2，3] tau的正常功能是稳定微管网络，用于运输神经细胞中的囊泡和细胞器，这对于细胞之间的通信以及大脑活动是必要的。当tau聚集时，认为用于运输的轨道（微管）被破坏并且运输被中断。[4-6]此外，tau与β淀粉样蛋白诱导的神经变性的相关性已在小鼠模型中得到证实。[7，8]因此，非常希望找到保持tau处于功能状态并防止或逆转异常聚集的方法。对阿尔茨海默病的治疗方法的探索是非常激烈的。迄今为止，可用的疗法利用胆碱酯酶抑制剂和NMDA受体拮抗剂，[9，10]并且更新的方法集中于例如抑制tau磷酸化和氨肽酶活化。[11-14]因此，开发也能够解聚细丝的tau聚集抑制剂可以为现有策略提供替代方案。[15-18]在此，我们报告了在体外和在由神经母细胞瘤细胞系组成的细胞模型中对具有这些性质的取代的绕丹宁的研究，所述神经母细胞瘤细胞系以可诱导的方式表达tau，随后发生聚集。在最初的高通量筛选中，[19，20]鉴定了几种聚集抑制剂。从这些命中，罗丹宁（2-硫代噻唑烷-4-酮，图la）是
The two histopathological hallmarks that characterize Alzheimer s disease (AD) are the extracellular amyloid plaques that are formed by β-amyloid fragments of the amyloid precursor protein (APP), and intracellular neurofibrillary tangles and neuropil threads, which consist of the microtubule-associated protein tau forming paired helical filaments with highly ordered structures, as recently corroborated by X-ray microcrystallography.[1] In addition, tau deposits similar to those of AD occur in several “tauopathies”.[2, 3] The normal function of tau is to stabilize the microtubule network for the transport of vesicles and organelles in nerve cells, which is necessary for the communication between cells and thus for brain activity. When tau aggregates, it is thought that the tracks for transport (microtubules) break down and the transport is interrupted.[4–6] Moreover, the relevance of tau for neurodegeneration induced by β amyloid has been demonstrated in a mouse model.[7, 8] It would therefore be highly desirable to find methods to keep tau in a functional state and prevent or reverse abnormal aggregation. The quest for cures for Alzheimer s disease is very intense. Available therapies to date make use of cholinesterase inhibitors and NMDA receptor antagonists,[9, 10] and newer approaches focus, for example, on inhibition of tau phosphorylation and aminopeptidase activation.[11–14]Thus, the development of tau aggregation inhibitors that are also able to disaggregate filaments could provide an alternative to existing strategies.[15–18] Herein we report the investigation of substituted rhodanines with these properties in vitro and in a cell model consisting of a neuroblastoma cell line that expresses tau in an inducible fashion with subsequent aggregation. In an initial high-throughput screen,[19, 20] several aggregation inhibitors were identified. From these hits, rhodanines (2-thioxothiazolidin-4-ones, Figure 1 a) were