Unprecedented oxidation of a biologically active aroylhydrazone chelator catalysed by iron(III): serendipitous identification of diacylhydrazine ligands with high iron chelation efficacy
Unprecedented oxidation of a biologically active aroylhydrazone chelator catalysed by iron(III): serendipitous identification of diacylhydrazine ligands with high iron chelation efficacy
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DOI：
10.1007/s007750100258
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发表时间：
2001-10-01
影响因子：
3
通讯作者：
Richardson, DR
中科院分区：
文献类型：
--
作者：
Bernhardt, PV;Chin, P;Richardson, DR
2-吡啶基甲醛异烟酰腙类的配体显示出高的铁（Fe）螯合功效，并且具有作为治疗Fe超负荷疾病的药剂的潜力。我们已经调查了负责其高活性的机制。X-射线晶体学研究表明，三齿螯合物2-吡啶甲醛异烟酰腙发生了意想不到的氧化异烟酰（吡啶甲酰基）肼时，与铁-III络合。相反，在不存在Fel的情况下，母体腙在需氧水溶液中不被氧化。为了检验二酰肼是否可以负责2-吡啶基甲醛异烟酰腙的生物效应，比较它们的铁螯合效力。与其母体腙相比，二酰肼表现出很小的铁螯合活性。电位滴定表明，这可能是因为二酰肼在生理pH值下带电，阻碍其穿过膜进入细胞内Fe池。与此相反，该二酰肼的Fe络合物是电中性的，这可能允许通过膜的容易移动。这些数据允许该化合物的Fe螯合模型被提出：母体aroylhydrazone扩散通过细胞膜结合Fe，随后被氧化为二酰基肼络合物，然后从细胞中扩散。在生理pH下为电中性的其他二酰肼类似物表现出高的Fe螯合功效。因此，对于这类配体，螯合剂的电荷似乎是决定其进入细胞内Fe的能力的重要因素。本研究结果对了解2-吡啶甲醛异烟酰腙的生物活性和设计新型双酰肼螯合剂具有重要意义。
Ligands of the 2-pyridylcarbaldehyde isonicotinoylhydrazone class show high iron (Fe) sequestering efficacy and have potential as agents for the treatment of Fe overload disease. We have investigated the mechanisms responsible for their high activity. X-ray crystallography studies show that the tridentate chelate 2-pyridylcarbaldehyde isonicotinoylhydrazone undergoes an unexpected oxidation to isonicotinoyl(picolinoyl)hydrazine when complexed with Fe-III. In contrast, in the absence of Fel the parent hydrazone is not oxidized in aerobic aqueous solution. To examine whether the diacylhydrazine could be responsible for the biological effects of 2-pyridylcarbaldehyde isonicotinoylhydrazone, their Fe chelation efficacy was compared. In contrast to its parent hydrazone, the diacylhydrazine showed little Fe chelation activity. Potentiometric titrations suggested that this might be because the diacylhydrazine was charged at physiological pH, hindering its access across membranes to intracellular Fe pools. In contrast, the Fe complex of this diacylhydrazine was charge neutral, which may allow facile movement through membranes. These data allow a model of Fe chelation for this compound to be proposed: the parent aroylhydrazone diffuses through cell membranes to bind Fe and is subsequently oxidized to the diacylhydrazine complex which then diffuses from the cell. Other diacylhydrazine analogues that were charge neutral at physiological pH demonstrated high Fe chelation efficacy. Thus, for this class of ligands, the charge of the chelator appears to be an important factor for determining their ability to access intracellular Fe. The results of this study are significant for understanding the biological activity of 2-pyridylcarbaldehyde isonicotinoylhydrazone and for the design of novel diacylhydrazine chelators for clinical use.