Interactions of zinc(II) complexes with N-donor ligands with 5’-GMP and their cytotoxic activity

Design of novel non-platinum DNA and protein targeting metal-based anticancer agents with potential in vitro toxicity have gained importance in recent years (Bertini, I. et al, Biological Inorganic Chemistry. Structure and Reactivity. University Science Books. Sausalito, CA. 2007. The non-platinum antitumor complexes could be alternatives to platinum-based drugs due to their better characteristics and less negative side effects. (Pessoa, J.C., et al. J. Inorg. Biochem. 2011, 105, 637-644). The mechanism of substitution from tetrahedral [ZnCl2(en)] and square-pyramidal [ZnCl2(terpy)] complexes (where en = 1,2-diaminoethane or ethylenediamine; terpy= 2,2′:6′,2′′-terpyridine) by guanosine-5’-monophospahate (5’-GMP) have been investigated by 1H NMR spectroscopy. Information about the structures of the final products in solution were obtained from the DFT calculations (B3LYP/6-31G(d)) and experimental 1H NMR data acquired during the course of the reaction. The cytotoxic activity of zinc(II) complexes was tasted on human breast cancer cell line MDA-MB-231, human colon cancer cell line HCT-116 and normal human lung fibroblast cell line MRC-5. Both complexes reduced cell viabilities, while [ZnCl2(terpy)] complex was significantly cytotoxic on MDA-MB-231 after 72 h, and HCT-116 after 24 h without dose dependence. The differences in reactivity toward 5’-GMP and cytotoxic activity of Zn(II) complexes may be attributed to the very stable square-pyramidal geometry of [ZnCl2(terpy)] complex in solution, while weak ligand effect of the en compared to the terpy affected slow interaction of tetrahedral [ZnCl2(en)] complex with the target bio-molecule (Soldatovic, E., et al. J. Coord. Chem. 2019, 72(4), 690-706). Acknowledgements: T. Soldatovic and E. Selimovic gratefully acknowledge financial support from State University of Novi Pazar, Novi Pazar, Republic of Serbia. R. Puchta would like to thank the Regionales Rechenzentrum Erlangen (RRZE) for a generous allotment of computer time, Prof. Tim Clark for hosting this work at the CCC. B.M. Alzoubi thanks Al-Balqa Applied University for its support. The authors are grateful for the support to the Ministry of Education, Science and Techhnological Development of the Republic of Serbia (Projects No. III41010, OI172016 and OI172036)