Development of copper peptide complexes as anti-Inflammatory drugs

Hammouda, Ahmed N H

Development of copper peptide complexes as anti-Inflammatory drugs

Doctoral Thesis

2015

Publisher

University of Cape Town

Department

Department of Chemistry

Faculty

Faculty of Science

Abstract

Copper complexes have been reported to have anti-inflammatory activities for the alleviation of inflammation associated with rheumatoid arthritis (RA). The present study focuses on the design of new drugs that could be used to change the bioavailability of copper and hence alleviate inflammation. The ligands chosen were sarcosyl-L-histidyl-L-lysine, sarcosyl-Llysyl- L-histidine, sarcosyl-L-histidyl-L-histidine, sarcosyl-L-lysyl-L-lysine and sarcosyl-Lglycyl- L-histidine. Equilibrium constants of H+, Cu(II), Ni(II) and Zn(II) with the peptides were measured in aqueous solution at 25±0.01oC and an ionic strength of 0.15M (NaCl) using glass electrode potentiometry. The tripeptides species showed significantly different coordination behaviour. The results that Cu(II) coordinates to one amino group, two deprotonated peptides and one imidazole nitrogen atoms to give a neutral complex. The structures of the complex species were investigated using ultraviolet-visible (Uv-Vis), nuclear magnetic resonance (NMR), electrospray ionisation mass spectrometry (ESI-MS) spectroscopy as well as molecular mechanics (MM) calculations. The visible spectra obtained for the different species in solution were typical of Cu(II) and Ni(II) complexes. 1H NMR identified the active binding sites to be the imidazole nitrogen, the amide nitrogen and the terminal amino group. The imidazole nitrogen was involved in coordination first, followed by the amide and then the terminal amine groups. The ԑ-amino group of lysine did not coordinate to the Cu(II). Molecular mechanics was used to support the Cu(II) structures postulated from potentiometric and spectroscopic data. The prefered method of increasing the available pool of low molecular weight Cu(II) species in vivo is via dermal absorption. For this reason the drugs were designed so that they could be administered dermally and be selective for Cu(II) so that they do not affect the speciation of other metal ions in blood plasma. Speciation calculations of Cu(II) using a computer model of blood plasma indicated that Sar-Lys-His was the best at mobilising copper in vivo. This study also considered percutaneous skin absorption. Octanol/water partition coefficients and Franz cell permeation studies showed that the Cu(II) complexes are hydrophilic but that Sar-Gly-His caused a 2 fold increase in membrane permeability of Cu(II).

Keywords

Chemistry

Reference:

Collections

PhD / Doctoral

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