A new bis(3-hydroxy-4-pyridinone)-IDA derivative as a potential therapeutic chelating agent. Synthesis, metal-complexation and biological assays
作者:M. Amélia Santos、Sofia Gama、Lurdes Gano、Guilhermina Cantinho、Etelka Farkas
DOI:10.1039/b409357g
日期:——
A new bis(3-hydroxy-4-pyridinone) derivative of iminodiacetic acid, imino-bis(acetyl(1-(3′-aminopropyl)-3-hydroxy-2-methyl-4-pyridinone)), IDAPr(3,4-HP)2, has been prepared and studied in its interaction with a set of hard metal ions. This tetradentate ligand presents a much higher chelating efficiency for trivalent hard metal ions (Fe, Ga, Al) than the monodentate derivative Deferriprone, namely at the diluted conditions prevailing in physiological conditions and at low clinical doses. A similar behaviour was also observed for the complexation with Zn(II) but at a significantly lower extent. This compound presents a moderate hydrophilic character at physiological pH (logD
=
−1.72). In vivo assays showed much more rapid clearance of 67Ga from most tissues of metal-loaded mice than the drug Deferriprone and the radioactivity excretion occurs mostly through the kidneys. Therefore, results from in vitro and in vivo studies indicated good perspectives for this compound to be a potential decorporating agent for hard metal ions in overload situations without depletion of essential metal ions such as zinc.
一种新型的双(3-羟基-4-吡啶酮)衍生物亚氨基双(乙酰(1-(3'-氨基丙基)-3-羟基-2-甲基-4-吡啶酮)),IDAPr(3,4-HP)2,已被合成并研究其与一系列硬金属离子的相互作用。该四齿配体对三价硬金属离子(如铁、镓、铝)的螯合效率显著高于单齿衍生物Deferriprone,尤其是在生理条件下的稀释状态和低临床剂量下。此外,在与Zn(II)的配位作用中也观察到类似的行为,但程度明显较低。该化合物在生理pH值下表现出适度的亲水性(logD = -1.72)。体内实验显示,与药物Deferriprone相比,67Ga在金属负载小鼠的多数组织中清除得更快,且放射性排泄主要通过肾脏进行。因此,体外和体内研究的结果表明,该化合物在硬金属离子过量情况下有望成为一种潜在的去除剂,而不会耗竭锌等必需金属离子。