Kirin Srećko I, Dübon Pierre, Weyhermüller Thomas, Bill Eckhard, Metzler-Nolte Nils
Institute of Pharmacy and Molecular Biotechnology, University of Heidelberg, Im Neuenheimer Feld 364, D-69120 Heidelberg, Germany.
Inorg Chem. 2005 Jul 25;44(15):5405-15. doi: 10.1021/ic048343b.
Four chelating nitrogen ligands 2-5 derived from N,N-bis(2-picolyl)amine (bpa, 1) were synthesized, namely, (PyCH(2))(2)N-CH(2)-p-C(6)H(4)-CO(2)R (R = Me, 2, and R = H, 3) and (PyCH(2))(2)N-(CH(2))(n)-CO(2)H (n = 2, 4, and n = 5, 5). Amino acid conjugates 6 and 7 were formed by condensation of 3 with H-Phe-OMe and H-betaAla-OMe, respectively. Cu(II) and Zn(II) complexes of 1-7 were prepared and fully characterized. The X-ray structures of 1(Zn), 2(Zn), 4(Cu), and 7(Cu) were determined. The Zn complexes 1(Zn) and 2(Zn) as well as 7(Cu) show a distorted trigonal bipyramidal coordination environment in the solid state. An octahedral complex is observed for 4(Cu) which forms chains along the crystallographic b axis by intermolecular coordination of the carboxylic acid to the metal ion of a neighboring complex. Ligand 3 was used to prepare the peptide bioconjugate 8 (3-Ahx-Pro-Lys-Lys-Lys-Arg-Lys-Phe-NH(2)) with a nuclear localization signal (nls) heptapeptide by solid phase synthesis. Cu(II) and Zn(II) complexes of 8 were synthesized in situ and studied by FAB-MS, ESI-MS, UV/vis, and EPR (for 8(Cu)), and FAB-MS, ESI-MS, and NMR (for 8(Zn)). All spectroscopic results clearly support metal coordination to the bpa ligand in the bioconjugates 8(M), even in the presence of other potential ligands from amino acid side chains of the peptide. We suggest metal-peptide conjugates like 8(M) as artificial metallochaperones because they have the potential to deliver metal ions to specific compartments in the cell as determined by the peptide moieties.
合成了四种由N,N-双(2-吡啶甲基)胺(bpa, 1)衍生而来的螯合氮配体2-5，即(PyCH₂)₂N-CH₂-p-C₆H₄-CO₂R (R = Me, 2；R = H, 3) 以及 (PyCH₂)₂N-(CH₂)ₙ-CO₂H (n = 2, 4；n = 5, 5)。氨基酸缀合物6和7分别通过3与H-Phe-OMe和H-βAla-OMe缩合而成。制备并全面表征了1-7的铜(II)和锌(II)配合物。测定了1(Zn)、2(Zn)、4(Cu)和7(Cu)的X射线结构。锌配合物1(Zn)和2(Zn)以及7(Cu)在固态时呈现扭曲的三角双锥配位环境。观察到4(Cu)为八面体配合物，其通过羧酸与相邻配合物的金属离子的分子间配位沿结晶学b轴形成链状结构。配体3用于通过固相合成制备带有核定位信号(nls)七肽的肽生物缀合物8 (3-Ahx-Pro-Lys-Lys-Lys-Arg-Lys-Phe-NH₂)。8的铜(II)和锌(II)配合物原位合成，并通过FAB-MS、ESI-MS、UV/vis和EPR（对于8(Cu)）以及FAB-MS、ESI-MS和NMR（对于8(Zn)）进行研究。所有光谱结果都清楚地支持在生物缀合物8(M)中金属与bpa配体配位，即使存在来自肽的氨基酸侧链的其他潜在配体。我们建议像8(M)这样的金属-肽缀合物作为人工金属伴侣，因为它们有潜力将金属离子递送至细胞中的特定区室，这由肽部分决定。
