Aqueous Solution Equilibria and Spectral Features of Copper Complexes with Tripeptides Containing Glycine or Sarcosine and Leucine or Phenylalanine

Abstract

Copper(II) complexes of glycyl-L-leucyl-L-histidine (GLH), sarcosyl-L-leucyl-L-histidine (Sar-LH), glycyl-L-phenylalanyl-L-histidine (GFH) and sarcosyl-L-phenylalanyl-L-histidine (Sar-FH) have potential anti-inflammatory activity, which can help to alleviate the symptoms associated with rheumatoid arthritis (RA). From pH 2–11, the MLH, ML, MLH-1 and MLH-2 species formed. The combination of species for each ligand was different, except at the physiological pH, where CuLH-2 predominated for all ligands. The prevalence of this species was supported by EPR, ultraviolet-visible spectrophotometry, and mass spectrometry, which suggested a square planar CuN4 coordination. All ligands have the same basicity for the amine and imidazole-N, but the methyl group of sarcosine decreased the stability of MLH and MLH-2 by 0.1–0.34 and 0.46–0.48 log units, respectively. Phenylalanine increased the stability of MLH and MLH-2 by 0.05–0.29 and 1.19–1.21 log units, respectively. For all ligands, 1H NMR identified two coordination modes for MLH, where copper(II) coordinates via the amine-N and neighboring carbonyl-O, as well as via the imidazole-N and carboxyl-O. EPR spectroscopy identified the MLH, ML and MLH-2 species for Cu-Sar-LH and suggested a CuN2O2 chromophore for ML. DFT calculations with water as a solvent confirmed the proposed coordination modes of each species at the B3LYP level combined with 6-31++G**.

Cornerstones in Contemporary Inorganic Chemistry

“…Copper(II) complexes have also demonstrated anti-inflammatory properties that can be exploited in the treatment of rheumatoid arthritis. Jackson et al explored a series of Cu(II) tripeptide complexes, in which Cu(II) was square planar and first demonstrated that the complexes have sufficiently low stability constants to allow for their release in vivo [11]. Then, using techniques including EPR, NMR, absorption spectroscopy and DFT calculations, the authors were able to develop reasonable models to describe the coordination modes for each complex.…”