Centro de Química Estrutural, Instituto Superior Técnico, Universidade Técnica de Lisboa, Av. Rovisco Pais 1, 1049-001 Lisboa, Portugal.
Dalton Trans. 2013 May 7;42(17):6033-45. doi: 10.1039/c2dt32361c. Epub 2012 Dec 6.
A new tripodal hexadentate ligand, NTP(PrHPM)(3), having three hydroxypyrimidinone (HPM) chelating units attached to a nitrilotripropionic acid (NTP) has been prepared and studied in terms of thermodynamic stability of the complexes with iron, aluminium and gallium and it has been subsequently in vivo assayed for its capacity to remove hard metal ions from an animal model overloaded with (67)Ga. The anchoring of the HPM units to the NTP scaffold revealed to be an interesting alternative to the reported hexadentate tris(3-hydroxy-4-pyridinone) analogue, NTP(PrHP)(3), because the new tris-HPM ligand still keeps high chelating capacity for hard metal ions and presents better water-solubility (log P = -1.51). The in vivo studies show that NTP(PrHPM)(3) induces a faster clearance from main organs and an enhancement of overall excretion, as compared with the commercial drug, DFP, or the bidentate HPM compound (HOPY-PrN), albeit slightly lower than the tris-hydroxypyridinone analogue, NTP(PrHP)(3). The solution and in vivo results herein presented encourage further studies envisaging the potential clinical applications of hexadentate HPM derivatives as metal sequestering agents.
一种新的三脚架六齿配体，NTP(PrHPM)(3)，具有三个羟嘧啶酮（HPM）螯合单元连接到氮三乙酸（NTP）上，已经被制备并研究了其与铁、铝和镓形成的配合物的热力学稳定性，随后在体内测定了其从动物模型中去除过负荷的（67）Ga 的硬金属离子的能力。将 HPM 单元锚定到 NTP 支架上，与报道的六齿三（3-羟基-4-吡啶酮）类似物 NTP(PrHP)(3)相比，这是一种有趣的替代方法，因为新的三-HPM 配体仍然保持对硬金属离子的高螯合能力，并且具有更好的水溶性（log P = -1.51）。体内研究表明，与商业药物 DFP 或双齿 HPM 化合物（HOPY-PrN）相比，NTP(PrHPM)(3)可诱导更快地从主要器官清除，并增强整体排泄，尽管略低于三羟基吡啶酮类似物 NTP(PrHP)(3)。本文提供的溶液和体内结果鼓励进一步研究，设想将六齿 HPM 衍生物作为金属螯合剂的潜在临床应用。
