Structure-activity relationship of cyanine tau aggregation inhibitors.
Structure-activity relationship of cyanine tau aggregation inhibitors.
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DOI：
10.1021/jm900116d
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发表时间：
2009-06-11
影响因子：
7.3
通讯作者：
Kuret J
中科院分区：
文献类型：
--
作者：
Chang E;Congdon EE;Honson NS;Duff KE;Kuret J
用过滤捕捉法研究了对称的人tau聚集花菁抑制剂的构效关系。拮抗活性依赖于花菁杂环、多亚甲基桥长度以及中取代基和N-取代基的性质。该系列中的一个强有力的成员，3，3‘-二乙基-9-甲基硫代碳菁碘(化合物11)，保持了亚微摩尔效力，并计算了与血脑屏障和细胞膜穿透性一致的物理性质。从JNPL3转基因小鼠(表达具有聚集倾向的P301L突变的人tau)制备的器官型切片与化合物11接触一周，显示出双相剂量-反应关系。低纳米分子浓度使不溶性tau聚集体减少到仅用赋形剂处理的切片中观察到的一半。相反，高浓度(≥300nM)可增强tau聚集，并导致组织微管蛋白水平异常。这些数据表明，某些对称的碳菁染料可以调节切片生物模型中tau的聚集，其浓度远低于与毒性相关的浓度。
A structure-activity relationship for symmetrical cyanine inhibitors of human tau aggregation was elaborated using a filter trap assay. Antagonist activity depended on cyanine heterocycle, polymethine bridge length, and the nature of meso- and N-substituents. One potent member of the series, 3,3’-diethyl-9-methylthiacarbocyanine iodide (compound 11), retained submicromolar potency and had calculated physical properties consistent with blood-brain barrier and cell membrane penetration. Exposure of organotypic slices prepared from JNPL3 transgenic mice (which express human tau harboring the aggregation prone P301L tauopathy mutation) to compound 11 for one week revealed a biphasic dose response relationship. Low nanomolar concentrations decreased insoluble tau aggregates to half those observed in slices treated with vehicle alone. In contrast, high concentrations (≥300 nM) augmented tau aggregation and produced abnormalities in tissue tubulin levels. These data suggest that certain symmetrical carbocyanine dyes can modulate tau aggregation in the slice biological model at concentrations well below those associated with toxicity.
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