Peptide-bond modification for metal coordination: Peptides containing two hydroxamate groups

Peptide-bond modification via N-hydroxylation has been explored as a strategy for metal coordination to induce conformational rigidity and orient side chains for specific molecular recognition. N-Hydroxyamides were prepared by reacting N-benzyloxyamino acid esters or amides with Fmoc-AA-Cl/AgCN (Fmoc: 9-fluorenylmethoxycarbonyl; AA: amino acid) in toluene or Fmoc-AA/HATU/DIEA in DMF (HATU: O-(7-azabenzotriazol-lyl)-1,1,3,3-tetramethyluronium hexafluorophosphate; DIEA: N,N-diisopropylethylamine; DMF: N,N-dimethylformamide), followed by deblocking of benzyl protecting groups. Novel linear and cyclic N,N′-dihydroxypeptides were efficiently assembled using Fmoc chemistry in solution and/or on a solid support. As screened by electrospray ionization-mass spectroscopy (ESI-MS), high iron-binding selectivity and affinity were attainable. Compounds having a spacer of two α-amino acids between the amino acids bearing the two hydroxamates, i.e., a spacer of 8 atoms, generated 1:1 iron complex species in the gas phase. Moreover, high performance liquid chromatography (HPLC), uv/vis, and ¹H-NMR analyses provided direct evidence for complex formations in solution. Significantly, the representative compound cyclo(Leu-Ψ [CON(OH)]-Phe-Ala-Pro)₂ (P8) may serve as a robust metal-binding scaffold in construction of a metal-binding library for versatile metal-mediated molecular recognition.