Amino Acid and Peptide Bioconjugates of Copper(II) and Zinc(II) Complexes with a Modified N,N-Bis(2-picolyl)amine Ligand

Four chelating nitrogen ligands 2-5 derived from N,N-bis(2-picolyl)amine (bpa, 1) were synthesized, namely, (PyCH2)2N-CH2-p-C6H4-CO2R (R = Me, 2, and R = H, 3) and (PyCH2)2N-(CH2)n-CO2H (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-(beta)Ala-OMe, respectively. Cu(II) and Zn(II) complexes of 1-7 were prepared and fully characterized. The X-ray structures of 1Zn, 2Zn, 4Cu, and 7Cu were determined. The Zn complexes 1Zn and 2Zn as well as 7Cu show a distorted trigonal bipyramidal coordination environment in the solid state. An octahedral complex is observed for 4Cu 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-NH2) 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 8Cu), and FAB-MS, ESI-MS, and NMR (for 8Zn). All spectroscopic results clearly support metal coordination to the bpa ligand in the bioconjugates 8M, even in the presence of other potential ligands from amino acid side chains of the peptide. We suggest metal-peptide conjugates like 8M as artificial metallochaperones because they have the potential to deliver metal ions to specific compartments in the cell as determined by the peptide moieties.