Lanthanide(III) complexes with two hexapeptides incorporating unnatural chelating amino acids: Secondary structure and stability

Article abstract of DOI:10.1002/chem.200900747

Unnatural metal-chelating amino acids bearing aminodiacetate side-chains have been introduced into two hexapeptides to obtain efficient lanthanide-binding peptides. The synthesis of the enantiopure Fmoc-Ada.,(tBu)₂-OH synthons is described with overall yields of 32 and 50% for n = 2 and n = 3 side-chain carbon atoms, respectively. The two peptides AcWAda_nPGAda_nGNH₂ (Pⁿ) were synthesized from the protected synthons by standard solid-phase peptide synthesis. Studies of the lanthanide complexes of the two peptides P" by luminescence titrations, mass spectrometry, circular dichroism, and solution NMR spectroscopy demonstrate that the Ada., chain length has a dramatic effect on the complexation properties. Indeed, the flexible compound P³ forms a mononuclear complex of moderate stability (β₁₁ = 10 ^9.9), which tends to transform into a binuclear species in the presence of excess of the metal ion. Interestingly, the more compact peptide P² provides stable Ln³⁺ complexes with the exclusive formation of the mononuclear LnP² adduct. The stability constant of TbP² is two orders of magnitude higher (β₁₁ = 10 ^12.1) than that measured for P³. The 800 MHz NMR spectrum of the La³⁺ complex of P² evidences a well-defined type II ss-turn as well as a hydrophobic Trp(indole)-Pro interaction. These interactions exemplify the non-innocent character of the peptide spacer in the complex LaP² as well as the role of a peptide secondary structure in the stabilization of metal complexes.