Development of comprehensive approaches to characterizing CuII complexes: structures in solution and solid-state, dynamic behavior, and bioactivity

Cu-II ternary systems with aromatic N-donors (1,10-phenanthroline, dipyrido-[3,2-f:2',3'-h]-quinoxaline, and 2-methyldipyrido-[3,2-f:2',3'-h]-quinoxaline) and amino acids have been extensively studied in water solution under closely physiological conditions using several techniques, including potentiometric pH titration, mathematical modeling, nuclear magnetic relaxation, EPR, and DFT calculations. Based on the distribution diagrams of the complex species, single crystal syntheses of the ternary systems Cu-II-aromatic N-donor-L-amino acid were carried out. As a result, several crystal structures of the complexes with the desired copper-to-ligand ratio were established by X-ray diffraction analysis. The most successful synthetic attempts were with L-proline and L-serine, resulting in the crystals with the desired copper(II) to ligand ratio. The developed approach made it possible to thoroughly describe systems with major proteinogenic amino acids in the L-configuration. Numerous non-covalent interactions such as H-bonds, pi-pi stacking, d-pi interactions, lone electron pair-pi interactions between Cu-II atom, conjugated aromatic ligand system, counterions, and water molecules were found to affect the stability and structure of the resulting complex particles. It has been found that in the Cu-II-N-donor-amino acid systems there is an acceleration of ligand exchange by a factor of 2-25 compared to Cu-II-amino acid systems, which is explained by taking into account steric effects, d-pi interactions, and the pseudo Jahn-Teller effect. The investigated systems were tested for antitumor activity against MCF-7, PC-3, OVCAR-4, SNB-19, and M-14 cell lines, and most samples, in particular, Cu-II-Phen-L-His, Cu-II-MeDPQ-L-Val and Cu-II-MeDPQ-L-Ser, showed a therapeutic activity index greater than 2 for all selected cell types, which opens up prospects for their medical application.