Department of Pharmacology and Toxicology, Charles University, Faculty of Pharmacy in Hradec Králové, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic.
Department of Pharmaceutical Botany and Ecology, Charles University, Faculty of Pharmacy in Hradec Králové, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic.
J Trace Elem Med Biol. 2018 Mar;46:88-95. doi: 10.1016/j.jtemb.2017.11.014. Epub 2017 Nov 27.
Due to the limited array of the currently available copper chelators, research of such compounds continues to be of clinical interest. Notably, o-dihydroxycoumarins have been previously shown to be potent iron chelators under neutral conditions. Within this study, the interaction of a series of natural coumarins and their synthetic analogs with copper has been evaluated in order to obtain structure-activity relationships under different pathophysiological pH conditions. Both competitive and non-competitive methods have been employed. Analysis of cupric ion reduction has also been performed. Under mildly competitive conditions, cupric chelation was observed for o-dihydroxycoumarins, and partially for o-diacetoxycoumarin. Non-competitive studies showed that cuprous ions are not chelated at all and that the stoichiometries of the most active 6,7- and 7,8-dihydroxycoumarins to cupric ions ranged from 1:1 to 2:1 depending on pH and concentration. Interestingly, under highly competitive conditions, coumarins were not capable of chelating cupric ions, either. Reduction experiments have shown that 13 out of the 15 coumarins included in this study reduced cupric ions. However, significant differences depending on their structures were apparent in their potencies. O-dihydroxycoumarins were the most potent ones again.
O-dihydroxycoumarins are moderately active cupric ion chelators with potent copper reducing properties.
由于目前可用的铜螯合剂种类有限，因此此类化合物的研究仍然具有临床意义。值得注意的是，先前已经证明邻二羟基香豆素在中性条件下是有效的铁螯合剂。在本研究中，评估了一系列天然香豆素及其合成类似物与铜的相互作用，以在不同的病理生理 pH 条件下获得结构-活性关系。采用了竞争性和非竞争性方法。还进行了铜离子还原分析。在轻度竞争性条件下，观察到邻二羟基香豆素对铜离子的螯合作用，部分邻二乙酰氧基香豆素也具有螯合作用。非竞争性研究表明，铜离子根本没有被螯合，最活跃的 6,7-和 7,8-二羟基香豆素与铜离子的化学计量比范围为 1:1 至 2:1，具体取决于 pH 值和浓度。有趣的是，在高度竞争性条件下，香豆素也不能螯合铜离子。还原实验表明，在本研究中包含的 15 种香豆素中有 13 种能够还原铜离子。然而，根据它们的结构，它们的效力存在明显差异。邻二羟基香豆素再次是最有效的。
邻二羟基香豆素是中度活性的铜离子螯合剂，具有很强的铜还原特性。
