Department of Chemistry and Physics, Southwestern Oklahoma State University, Weatherford, OK, USA 73096.
Dalton Trans. 2019 Feb 19;48(8):2785-2801. doi: 10.1039/c8dt04728f.
A number of disease states including WHIM syndrome, HIV infection and cancer have been linked to the chemokine receptor CXCR4. High-affinity CXCR4 antagonist transition metal complexes of configurationally restricted bis-tetraazamacrocyclic ligands have been identified in previous studies. Recently synthesised and structurally characterised Co2+/Co3+ and Ni2+ acetate complexes of mono-macrocycle cross-bridged ligands have been used to mimic their known coordination interaction with the aspartate side chains on binding to CXCR4. Here, X-ray crystal structures for three Co2+/Co3+ acetate complexes and five Ni2+ acetate complexes are presented and demonstrate flexibility in the mode of binding to the acetate ligand concomitantly with the requisite cis-V-configured cross-bridged tetraazamacrocyle. Complexes of the smaller Co3+ metal ion exclusively bind acetate by chelating both oxygens of acetate. Larger Co2+ and Ni2+ metal ions in cross-bridged tetraazamacrocycles show a clear tendency to coordinate acetate in a monodentate fashion with a coordinated water molecule completing the octahedral coordination sphere. However, in unbridged tetraazamacrocycle acetate structures reported in the literature, the coordination preference is to chelate both acetate oxygens. We conclude that the short ethylene cross-bridge restricts the equatorial bulk of the macrocycle, prompting the metal ion to fill the equator with the larger monodentate acetate plus water ligand set. In unbridged ligand examples, the flexible macrocycle expands equatorially and generally only allows chelation of the sterically smaller acetate alone. These results provide insight for generation of optimised bis-macrocyclic CXCR4 antagonists utilising cobalt and nickel ions.
包括 WHIM 综合征、HIV 感染和癌症在内的许多疾病状态都与趋化因子受体 CXCR4 有关。在之前的研究中，已经确定了具有受限构象的双四氮大环配体的高亲和力 CXCR4 拮抗剂过渡金属配合物。最近合成并结构表征的 Co2+/Co3+和 Ni2+乙酸盐配合物的单大环交叉桥联配体已被用于模拟它们与 CXCR4 结合时已知的与天冬氨酸侧链的配位相互作用。这里，呈现了三个 Co2+/Co3+乙酸盐配合物和五个 Ni2+乙酸盐配合物的 X 射线晶体结构，并证明了在与必需的顺式-V 构型交叉桥联四氮大环配位的同时，与乙酸盐配体结合的方式具有灵活性。较小的 Co3+金属离子的配合物通过螯合乙酸盐的两个氧原子来专一地结合乙酸盐。较大的 Co2+和 Ni2+金属离子在交叉桥联四氮大环中显示出明显的趋势，以单齿方式与配位水分子一起配位乙酸盐，从而完成八面体配位球体。然而，在文献中报道的无桥四氮大环乙酸盐结构中，配位偏好是螯合两个乙酸盐氧原子。我们得出结论，短的乙烯交叉桥限制了大环的赤道体积，促使金属离子用较大的单齿乙酸盐加水分子配体填充赤道。在无桥配体实例中，柔性大环在赤道方向扩展，通常仅允许螯合较小的空间乙酸盐。这些结果为利用钴和镍离子生成优化的双大环 CXCR4 拮抗剂提供了深入了解。
