(2016 - 2019)
In recent years, the field of medicinal inorganic chemistry has received considerable attention for the design of anticancer agents. Zinc(II) ion plays an important role in bioinorganic processes because of the potential formation of coordination compounds in which zinc(II) ion can readily accommodate four-, five-, or six molecules. The advantage of zinc-based anticancer drugs could be their selectivity toward specific cellular targets thanks to specific coordination ability and kinetic properties (Bertini I., et al., Biological Inorganic Chemistry. Structure and Reactivity, University Science Books: Sausalito, CA, 2007; Roat-Malone R.M. (Ed.), Bioinorganic Chemistry: A Short Course, John Wiley & Sons, Inc., Hoboken, NJ, 2002).
The mole-ratio method was used for determining metal-ligand stoichiometry between [ZnCl2(en)] (where en= 1,2-diaminoethane or ethylenediamine) and imidazole at pH 7.2 in the presence of different chloride concentrations. The results indicated step-wise formation of 1:1 and 1:2 complexes in the presence of 0.010 M NaCl and 1:1 complexes in the presence of 0.001 M NaCl. Those results are correlated with additional coordination of chlorides in the first coordination sphere and with changes in coordination geometry. In the presence of 0.001 M NaCl, five-coordinate complex anion [ZnCl3(en)]- is formed initially, and then substitution reaction with imidazole occurred. In the presence of 0.010 M NaCl the octahedral complex anion [ZnCl4(en)]2- formed.
The kinetics of ligand substitution reactions between complex and relevant nitrogen nucleophiles such as imidazole, 1,2,3-triazole and L-histidine were investigated at pH 7.2 as a function of nucleophile concentration in the presence of 0.001 M and 0.010 M NaCl. The reactions were followed under pseudo-ﬁrst-order conditions by UV-vis spectrophotometry. The substitution reactions included two steps of consecutive displacement of chlorido ligands and changes in coordination geometry of [ZnCl2(en)] complex. Results are discussed in terms of mechanisms of interactions between potential antitumor zinc-based drugs and biomolecules.
Transition metal ions exhibit a unique role in diverse biological activities of proteins by acting as cofactors. In particular, zinc and copper ions modulate enzymes activities as well as many catalytic and oxidative/reductive processes. The kinetics and mechanism of the substitution reactions of dichloro [ZnCl2(terpy)] and [CuCl2(terpy)] (terpy = 2,2′:6′,2′′-terpyridine) with biologically relevant ligands have been studied as a function of nucleophile concentrations at pH 7.38, under pseudo-first-order condition by UV-Vis spectrophotometric techniques. The interactions of Cu(II) and Zn(II) complexes with tripeptide glutathione (GSH) were investigated under pseudo-first-order conditions with respect to the complex concentration. For the substitution process of Zn(II) complex with glutathione (GSH), pre-equilibrium and chelate formation have been noted. The [CuCl2(terpy)] is more reactive than [ZnCl2(terpy)] complex and the second-order rate constants for the first step follow the order of reactivity: GSH > DL-Asp > L -Met > 5’-GMP ~ 5’-IMP for Cu(II) complex, while for Zn(II) the order of reactivity is: DL-Asp > L -Met > GSH ~ 5’-GMP > 5’-IMP. The results are discussed in terms of mechanisms of interactions between metalloproteins and biomolecules.
Zinc(ll) and copper(II) complexes with organic molecules are used in clinical medicine, e.g. (i) complex of zinc(ll) acetate with erythromycin is used for ache therapy, (ii) copper chelating agents were developed to treat Wilson disease, an autosomal recessive genetic disorder that causes copper accumulation primarily in the liver. In general, organic ligands can contribute to better transport of metal ions through the lipophillic regions of cell membranes. However, it is also possible that some metal complexes are not able to reach their site of action in sufficient concentration due to their decreased solubility. Antibacterial activity of model [ZnCl2(terpy)] and [CuCl2(terpy)] complexes was tested against seven strains of bacteria. The complexes were more effective against Gram-positive than Gram-negative bacteria. Between complexes, stronger effect was observed for [CuCl2(terpy)] complex. The best effect was exhibited against Sarcina lutea (5 mg/ml). Escherichia coli showed low sensitivity to both complexes. Results of the study of the antibacterial activity suggest an absence of permeability of the complexes through the membrane proteins.