Over the past decades, transition metal complexes have attracted considerable attention in medicinal inorganic chemistry, especially as synthetic metallonucleases and metal-based anticancer drugs that are able to bind to DNA under physiological conditions (Pessoa, J.C., et al. J. Inorg. Biochem. 2011, 105, 637-644). Copper(II) complexes offer various potential advantages as antimicrobial, antiviral, anti-inflammatory, antitumor agents, enzyme inhibitors, chemical nucleases, and they are also beneficial against several diseases like copper rheumatoid and gastric ulcers (Fricker, S.P., Dalton Trans. 2007, 43, 4903-4917).

Substitution reactions of square-planar [CuCl₂(en)] and square-pyramidal [CuCl₂(terpy)] complexes (where en= 1,2-diaminoethane and terpy= 2,2’:6’,2’’- terpyridine) with bio-relevant nucleophiles have been investigated at pH 7.4 in the presence of 0.010 M NaCl. Mechanism of substitution was probed via mole-ratio, kinetic, mass spectroscopy and EPR studies. In the presence of an excess of chloride, the octahedral complex anion [CuCl₄(en)]^2- forms rapidly while equilibrium reaction was observed for [CuCl₂(terpy)]. Different order of reactivity of selected bio-molecules toward Cu(II) complexes was observed. The nature of the buffer just affects the Cu(II) complexes conformational dynamics. According to EPR data L-Methionine forms a most stable complex with [CuCl₂(en)] among the bio-ligands considered while [CuCl₂(terpy)] complex is very stable and there are no significant changes in its square-pyramidal geometry in the presence of buffers or bio-ligands. The obtained results represent progress in investigation of the mechanism of substitution reactions between Cu(II) complexes and biological relevant nuclepohiles. Also, they provide very useful information for the future design of potential copper-based anticancer drugs (Selimović, E., et al. J. Coord. Chem. 2018, 71(7), 1003-1019).