SYNTHESIS AND EFFICACY OF SQUARE-PLANAR COPPER-COMPLEXES DESIGNED TO NUCLEATE BETA-SHEET STRUCTURE

The synthesis of four 6,6'-bis(acylamino)-2,2'-bipyridine-based amino acids 1a-c and 2 are described. These residues, when coordinated to Cu(II), are designed to replace the i + 1 and i + 2 residues of a beta-turn. Amino acids 1a-c and 2 were incorporated into several different peptides to evaluate their efficacy as beta-sheet nucleators. Matrix assisted laser desorption mass spectroscopy and UV spectroscopy reveal that peptides incorporating these residues bind Cu(II) ions under alkaline and acidic conditions with a 1:1 binding stoichiometry. In an effort to predict the geometry of the metal binding site of peptides containing beta-turn mimics 1a-c and 2, three model compounds, 18, 19, and 20, were prepared, and their crystal structures were determined. The crystal structure of 6,6'-bis(phenylacetamide)-2,2'-bipyridin (18) suggests that the bipyridine rings of peptides containing these residues should exist in a transoid conformation in the absence of Cu(II) ions and other stabilizing forces. The crystal structures of neutral (deprotonated) Cu(II) complex 19 and 2+ charged (protonated) Cu(II) complex 20 suggest that peptides containing residues 1a-c and 2 bind Cu(II) ions under alkaline and acid conditions resulting in a cisoid bipyridine ring conformation with a nearly perfect square planar geometry about the copper atom. Spectroscopic studies on: peptides incorporating residue 1b indicate that this residue is capable of nucleating an antiparallel beta-sheet conformation upon binding a single Cu(II) ion in basic aqueous buffer. Peptides incorporating residue 2 behave differently than those containing residue 1b in that they are capable of adopting an antiparallel beta-sheet conformation either in the absence or presence of Cu(II) ions. The chemical structure of residue 2 is such that the cisoid nucleating conformation may be stabilized by hydrophobic interactions in the absence of transition metal binding.