Site‐Specific Recognition of Dipeptides Through Non‐Covalent Inter‐Ligand Interactions for the Hydrolysis of Dipeptide to Amino Acid Ligands Mediated by Ternary Cobalt(III) Complexes

Abstract

AbstractMolecular recognition of dipeptide (DP) compounds is performed with a ternary cobalt(III) complex containing thetripodal tetradentate ligand bis‐N,N‐carboxymethyl‐L‐phenylalanine (H3bcmpa). The coordination structure of the complex [Co(bcmpa)(dp)]– (1–14) was spectroscopically assigned by UV/Vis, CD, and 1H NMR spectroscopic methods. Site‐specific recognition of the dipeptide on the ternary complex is achieved by various weak, non‐covalent, inter‐ligand interactions, such as hydrogen bonding, steric repulsion, and electrostatic interaction, etc. Some dipeptides having C‐terminal aromatic side‐chains also demonstrate inter‐ligand CH–π interactions between the aromatic ring and the α‐hydrogen of bcmpa. Coordination of the N‐terminal nitrogen atom of the dipeptide to cobalt at the trans(N)‐position to the tertiary nitrogen of bcmpa in the octahedral geometry provides an aminopeptidase model. Under slightly alkaline conditions, the dipeptide ligand of some of these complexes is cleaved to give the ternary complex, [Co(bcmpa)(aa)]– (aa = amino acidato). The rate for the hydrolysis of dipeptide decreases upon increasing the steric bulkiness of the C‐terminal side‐chain. In the cases of the ternary complexes [Co(bcmpa)(gly‐phe)]– (6 and 11), which have C‐terminal L‐ or D‐phenylalanine, the hydrolysis of gly‐phe to gly was completely prevented. On the other hand, the ternary cobalt(III) complexes [Co(bcmga)(gly‐phe)]– (18 and 19), where H3bcmga (bis‐N,N‐carboxymethyl‐L‐glutamic acid) is the more hydrophilic tripodal ligand, give a small amount of the corresponding cleavage product [Co(bcmga)(gly)]–. The hydrophobic sphere generated around the metal complex in 6 and 11 regulates approach of OH– ion to the amide carbonyl group. Multi‐site interactions mediated on the ternary complexes are available for the design of an artificial hydrolysis enzyme. This is the first report describing the substrate‐specific cleavage of peptides using a simple enzyme model complex. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)