Synthesis, characterization and Cu2+ binding studies of l-histidine ester of 8-hydroxyquinoline

• l-histidine ester of 8-Hydroxyquinoline (His-HQ) was synthesized and characterized.
• His-HQ formed a [1 Cu2+:2 His-HQ] complex in methanol:Tris (60:40), pH 7.5.
• His-HQ bound Cu2+ 60–70-fold less strongly than its precursors, His and HQ.
• Methanol stabilized the copper complex in solution and prevented its hydrolysis.

8-Hydroxyquinoline (HQ) and its derivatives are metal chelators used in the treatment of diseases involving metal ion overload. New derivatives of HQ are being sought as potential therapeutic agents with improved properties in restoring metal ion balance. In this work, a new l-histidine (His) ester of HQ was synthesized and its chemical structure confirmed using elemental analysis and spectroscopic methods including IR, UV–Vis, 1H NMR and mass spectrometry. The stoichiometry and thermodynamic parameters of Cu2+ binding to the ester and its synthetic precursors, HQ and His, were determined using isothermal titration calorimetry (ITC) in a methanol:buffer mixture (10 mM Tris–HCl, 15 mM NaCl, 60% (v) CH3OH, pH 7.5). The inclusion of methanol in the buffer not only increased HQ solubility, necessary for the calorimetric studies, but also stabilized the ester–Cu2+ complex in solution, preventing it from undergoing hydrolysis. The ester was found to bind Cu2+ in a 1:2 (Cu2+:ligand) stoichiometry and the same was true for HQ and His. However, the ester bound Cu2+ with 60- and 70-fold weaker affinity than for HQ and His, respectively. Within error, HQ and His exhibited similar affinity for Cu2+ in the methanol:buffer mixture. The presence of methanol increased Cu2+ affinity of His by 150-fold and changed its complex composition from 1:1 (Cu2+:ligand) in buffer to 1:2 in the methanol:buffer mixture.

The l-histidine (His) ester of 8-hydroxyquinoline (HQ), or His-HQ, was synthesized and its chemical structure confirmed. The Cu2+ binding thermodynamics of the ester and its precursors were studied in a buffer:methanol mixture using isothermal titration calorimetry (ITC). Methanol added to the buffer successfully prevented the complex from precipitation and hydrolysis. The graphic shows the raw data and the binding isotherm for Cu2+ titration into His-HQ in 10 mM Tris–HCl, 15 mM NaCl and 60% (v) CH3OH at pH 7.5. His-HQ and its precursors all bond Cu2+ in a 1:2 (Cu2+:ligand) stoichiometry with His-HQ exhibiting significantly weaker (60–70-fold) affinity than its synthetic precursors.Figure optionsDownload as PowerPoint slide