Biological studies of copper complexes based on polyimidazole ligands

Chelating agents represent a good strategy against a lot of diseases including antibiotic resistance, neurodegenerative diseases or genetic disorders linked to dyshomeostasis of metal. Examples of these chelators are the polypyridine ligands (1) which are good ligands of zinc, copper and iron showing the selectivity of antiproliferative activity in colon cancer cells (2). Recently, polyimidazole ligands N,N′-bis((imidazol-4-yl)methyl)-ethylenediamine BISIM, N,N,N′-tris((imidazol-4-yl)methyl)-ethylenediamine TRISIM, and N,N,N,N′-tetra((imidazol-4- yl-methyl)-ethylenediamine TETRAIM were investigated as inhibitors of Metallo Beta Lactamases(3). We studied the complexing properties polyimidazole ligands and the biological activity of copper(II) complexes. In particular, we investigated the antiproliferative activity of the three ligands alone and in the presence of copper (II) towards three human cancer cell lines, K562 (chronic myeloid leukemia), CaCo-2 (colorectal adenocarcinoma), SH-SY5Y (neuroblastoma) and a normal keratinocyte line, HaCat cells. Cells were exposed to increasing concentrations (from 6.25 to 100 µM) of compounds for 48 h, in the presence or absence of 20 μM CuCl2. A significant cytotoxic effect was observed only on K562 cells treated with 50 and 100 µM TETRAIM in the absence of CuCl2. To better clarify the mechanism of antiproliferative activity induced by TETRAIM in K562 cells, we investigated apoptotic markers. It was observed about 33% and 60% of apoptotic cells after 48 h of treatment with 50 and 100 µM TETRAIM, respectively. These results indicate that the inhibition of K562 cell proliferation, induced by TETRAIM, is associated with the activation of the apoptotic pathway. Moreover, the apoptotic activity of TETRAIM on K562 cells seems to be related to its chelating properties, since the addition of Cu2+ ions reverses the effect. REFERENCES: 1 L. La Piana, V. Viaggi, L. Principe, S. Di Bella, F. Luzzaro, M. Viale, N. Bertola, G. Vecchio, J. Inorg. Biochem. 2021, 215, 111315. 2 S. Schaefer-Ramadan, M. Barlog, J. Roach, M. Al-Hashimi, H. S. Bazzi, K. Machaca, Bioorganic Chem. 2019, 87, 366–372. 3 N. Bognanni, F. Brisdelli, A. Piccirilli, L. Basile, L. La Piana, S. Di Bella, L. Principe, G. Vecchio, M. Perilli, J. Inorg. Biochem. 2023, 242, 112163.