Histidine Analog Amino Acids Providing Metal-Binding Sites Derived from Bioinorganic Model Systems

Metalloproteins are of utmost importance for nearly all biological processes. Valuable information about their functionalities came from mutagenesis studies and led to the de novo design of artificial proteins. Advances in peptide chemistry enable the total synthesis of complete proteins and allow the incorporation of non-proteinogenic amino acids. Chelating amino acids utilized to introduce artificial metal-binding sites into proteins should mimic the side chains of the natural residues in order to minimize structural consequences within the target proteins. In this paper a synthetic method is described for the preparation of amino acids bearing a metal ligand system connected to the P-carbon via triazole formation. Thereby, a histidine isoster is generated with an additional metal-binding site in proximity to the peptide backbone. Two representative building blocks bearing the ligands triazacyclononane (tacn) and bis(picoloyl)-amine (bpa) were synthesized and incorporated into model peptides. ((C) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)