Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, United States.
Department of Biomedical Engineering, Cornell University, Ithaca, New York 14853, United States.
Inorg Chem. 2020 Apr 6;59(7):5116-5132. doi: 10.1021/acs.inorgchem.0c00372. Epub 2020 Mar 27.
Coordination compounds of the lanthanide ions (Ln) have important applications in medicine due to their photophysical, magnetic, and nuclear properties. To effectively use the Ln ions for these applications, chelators that stably bind them in vivo are required to prevent toxic side effects that arise from localization of these ions in off-target tissue. In this study, two new picolinate-containing chelators, a heptadentate ligand OxyMepa and a nonadentate ligand Oxyaapa, were prepared, and their coordination chemistries with Ln ions were thoroughly investigated to evaluate their suitability for use in medicine. Protonation constants of these chelators and stability constants for their Ln complexes were evaluated. Both ligands exhibit a thermodynamic preference for small Ln ions. The log = 12.21 and 21.49 for OxyMepa and Oxyaapa, respectively, indicating that the nonadentate Oxyaapa forms complexes of significantly higher stability than the heptadentate OxyMepa. X-ray crystal structures of the Lu complexes were obtained, revealing that Oxyaapa saturates the coordination sphere of Lu, whereas OxyMepa leaves an additional open coordination site for a bound water ligand. Solution structural studies carried out with NMR spectroscopy revealed the presence of two possible conformations for these ligands upon Ln binding. Density functional theory (DFT) calculations were applied to probe the geometries and energies of these conformations. Energy differences obtained by DFT are small but consistent with experimental data. The photophysical properties of the Eu and Tb complexes were characterized, revealing modest photoluminescent quantum yields of <2%. Luminescence lifetime measurements were carried out in HO and DO, showing that the Eu and Tb complexes of OxyMepa have two inner-sphere water ligands, whereas the Eu and Tb complexes of Oxyaapa have zero. Lastly, variable-temperature O NMR spectroscopy was performed for the Gd-OxyMepa complex to determine its water exchange rate constant of = (2.8 ± 0.1) × 10 s. Collectively, this comprehensive characterization of these Ln chelators provides valuable insight for their potential use in medicine and garners additional understanding of ligand design strategies.
镧系离子（Ln）的配位化合物由于其光物理、磁和核性质，在医学中有重要的应用。为了有效地将 Ln 离子用于这些应用，需要使用螯合剂将其在体内稳定结合，以防止这些离子在靶外组织中定位所产生的毒性副作用。在这项研究中，制备了两种新的含皮考啉酸的螯合剂，一种是七齿配体 OxyMepa，另一种是非齿配体 Oxyaapa，并对它们与 Ln 离子的配位化学进行了深入研究，以评估它们在医学中的适用性。评估了这些螯合剂的质子化常数和它们的 Ln 配合物的稳定常数。这两种配体都表现出对小 Ln 离子的热力学偏好。OxyMepa 和 Oxyaapa 的 log 分别为 12.21 和 21.49，表明非齿配体 Oxyaapa 形成的配合物稳定性明显高于七齿配体 OxyMepa。获得了 Lu 配合物的 X 射线晶体结构，表明 Oxyaapa 使 Lu 的配位球饱和，而 OxyMepa 则为一个结合的水分子配体留下一个额外的开放配位位。通过 NMR 光谱进行的溶液结构研究表明，这些配体在与 Ln 结合时存在两种可能的构象。应用密度泛函理论（DFT）计算来探测这些构象的几何形状和能量。DFT 计算得到的能量差异很小，但与实验数据一致。Eu 和 Tb 配合物的光物理性质进行了表征，发现其荧光量子产率<2%。在 HO 和 DO 中进行了荧光寿命测量，结果表明，OxyMepa 的 Eu 和 Tb 配合物具有两个内球水分子配体，而 Oxyaapa 的 Eu 和 Tb 配合物则没有。最后，对 Gd-OxyMepa 配合物进行了变温 O NMR 光谱研究，以确定其水交换速率常数为 = (2.8 ± 0.1) × 10 s。综上所述，对这些 Ln 螯合剂的全面表征为它们在医学中的潜在应用提供了有价值的见解，并进一步加深了对配体设计策略的理解。
